bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic analysis of Mycobacterium brumae sustains its nonpathogenic and immunogenic phenotype
Authors: Renau-Mínguez Chantal , Herrero-Abadía Paula , Ruiz-Rodriguez Paula , Sentandreu Vicente , Torrents Eduard , Chiner-Oms Álvaro , Torres-Puente Manuela , Comas Iñaki , Julián Esther , Coscolla Mireia
Published: January 2023

Mycobacterium brumae is a rapid-growing, non-pathogenic Mycobacterium species, originally isolated from environmental and human samples in Barcelona, Spain. Mycobacterium brumae is not pathogenic and it’s in vitro phenotype and immunogenic properties have been well characterized. However, the knowledge of its underlying genetic composition is still incomplete. In this study, we first describe the 4 Mb genome of the M. brumae type strain ATCC 51384T assembling PacBio reads, and second, we assess the low intraspecies variability by comparing the type strain with Illumina reads from three additional strains. Mycobacterium brumae genome is composed of a circular chromosome with a high GC content of 69.2% and containing 3,791 CDSs, 97 pseudogenes, one prophage and no CRISPR loci. Mycobacterium brumae has shown no pathogenic potential in in vivo experiments, and our genomic analysis confirms its phylogenetic position with other non-pathogenic and rapid growing mycobacteria. Accordingly, we determined the absence of virulence-related genes, such as ESX-1 locus and most PE/PPE genes, among others. Although the immunogenic potential of M. brumae was proved to be as high as Mycobacterium bovis BCG, the only mycobacteria licensed to treat cancer, the genomic content of M. tuberculosis T cell and B cell antigens in M. brumae genome is considerably lower than those antigens present in M. bovis BCG genome. Overall, this work provides relevant genomic data on one of the species of the mycobacterial genus with high therapeutic potential.
Abnormal functional connectivity of the frontostriatal circuits in type 2 diabetes mellitus
Authors: Fu Yingxia , Gu Meiling , Wang Rui , Xu Juan , Sun Shenglu , Zhang Huifeng , Huang Dejian , Zhang Zongjun , Peng Fei , Lin Pan
Published: January 2023

Background

Type 2 diabetes mellitus (T2DM) is a metabolic disorder associated with an increased incidence of cognitive and emotional disorders. Previous studies have indicated that the frontostriatal circuits play a significant role in brain disorders. However, few studies have investigated functional connectivity (FC) abnormalities in the frontostriatal circuits in T2DM.

Objective

We aimed to investigate the abnormal functional connectivity (FC) of the frontostriatal circuits in patients with T2DM and to explore the relationship between abnormal FC and diabetes-related variables.

Methods

Twenty-seven patients with T2DM were selected as the patient group, and 27 healthy peoples were selected as the healthy controls (HCs). The two groups were matched for age and sex. In addition, all subjects underwent resting-state functional magnetic resonance imaging (rs-fMRI) and neuropsychological evaluation. Seed-based FC analyses were performed by placing six bilateral pairs of seeds within a priori defined subdivisions of the striatum. The functional connection strength of subdivisions of the striatum was compared between the two groups and correlated with each clinical variable.

Results

Patients with T2DM showed abnormalities in the FC of the frontostriatal circuits. Our findings show significantly reduced FC between the right caudate nucleus and left precentral gyrus (LPCG) in the patients with T2DM compared to the HCs. The FC between the prefrontal cortex (left inferior frontal gyrus, left frontal pole, right frontal pole, and right middle frontal gyrus) and the right caudate nucleus has a significant positive correlation with fasting blood glucose (FBG).

Conclusion

The results showed abnormal FC of the frontostriatal circuits in T2DM patients, which might provide a new direction to investigate the neuropathological mechanisms of T2DM.
Knowledge domains and emerging trends of microglia research from 2002 to 2021: A bibliometric analysis and visualization study
Authors: Liu Guangjie , Li Tianhua , Yang Anming , Zhang Xin , Qi Songtao , Feng Wenfeng
Published: January 2023

Background

Microglia have been identified for a century. In this period, their ontogeny and functions have come to light thanks to the tireless efforts of scientists. However, numerous documents are being produced, making it challenging for scholars, especially those new to the field, to understand them thoroughly. Therefore, having a reliable method for quickly grasping a field is crucial.

Methods

We searched and downloaded articles from the Web of Science Core Collection with “microglia” or “microglial” in the title from 2002 to 2021. Eventually, 12,813 articles were located and, using CiteSpace and VOSviewer, the fundamental data, knowledge domains, hot spots, and emerging trends, as well as the influential literature in the field of microglia research, were analyzed.

Results

Following 2011, microglia publications grew significantly. The two prominent journals are Glia and J Neuroinflamm. The United States and Germany dominated the microglia study. The primary research institutions are Harvard Univ and Univ Freiburg, and the leading authors are Prinz Marco and Kettenmann Helmut. The knowledge domains of microglia include eight directions, namely neuroinflammation, lipopolysaccharide, aging, neuropathic pain, macrophages, Alzheimer’s disease, retina, and apoptosis. Microglial phenotype is the focus of research; while RNA-seq, exosome, and glycolysis are emerging topics, a microglial-specific marker is still a hard stone. We also identified 19 influential articles that contributed to the study of microglial origin (Mildner A 2007; Ginhoux F 2010), identity (Butovsky O 2014), homeostasis (Cardona AE 2006; Elmore MRP 2014); microglial function such as surveillance (Nimmerjahn A 2005), movement (Davalos D 2005; Haynes SE 2006), phagocytosis (Simard AR 2006), and synapse pruning (Wake H 2009; Paolicelli RC 2011; Schafer DP 2012; Parkhurst CN 2013); and microglial state/phenotype associated with disease (Keren-Shaul H 2017), as well as 5 review articles represented by Kettenmann H 2011.

Conclusion

Using bibliometrics, we have investigated the fundamental data, knowledge structure, and dynamic evolution of microglia research over the previous 20 years. We hope this study can provide some inspiration and a reference for researchers studying microglia in neuroscience.
Alterations of color vision and pupillary light responses in age-related macular degeneration
Authors: Decleva Diego , Vidal Kallene Summer , Kreuz Andre Carvalho , de Menezes Paulo Augusto Hidalgo Leite , Ventura Dora Fix
Published: January 2023

Introduction

Age-related macular degeneration (AMD) is the leading cause of irreversible central vision loss in developed countries and one of the leading causes of blindness. In this work, we evaluated color vision and the pupil light reflex (PLR) to assess visual function in patients with early and neovascular AMD (NVAMD) compared with the control group.

Methods

We recruited 34 early patients with dry AMD and classified them into two groups following AREDS: 13 patients with NVAMD and 24 healthy controls. Controls and patients with early dry AMD had visual acuity (VA) best or equal to 20/25 (0.098 logMAR). Color vision was assessed in controls and patients with early dry AMD using the Cambridge Color Test (CCT) 2.0 through the Trivector protocol. The PLR was evaluated using a Ganzfeld, controlled by the RETI–port system. The stimuli consisted of 1s blue (470 nm) and red (631 nm) light flashes presented alternately at 2-min intervals. To assess the cone contribution, we used a red flash at 2.4 log cd.m–2, with a blue background at 0.78 log cd.m–2. For rods, we used 470-nm flashes at –3 log cd.m–2, and for the melanopsin function of ipRGCs, we used 470 nm at 2.4 log cd.m–2.

Results

Patients with early dry AMD had reduced color discrimination in all three axes: protan (p = 0.0087), deutan (p = 0.0180), and tritan (p = 0.0095) when compared with the control group. The PLR has also been affected in patients with early dry AMD and patients with NVAMD. The amplitude for the melanopsin-driven response was smaller in patients with early dry AMD (p = 0.0485) and NVAMD (p = 0.0035) than in the control group. The melanopsin function was lower in patients with NVAMD (p = 0.0290) than the control group. For the rod-driven response, the latency was lower in the NVAMD group (p = 0.0041) than in the control group. No changes were found in cone-driven responses between the control and AMD groups.

Conclusion

Patients with early dry AMD present diffusely acquired color vision alteration detected by CCT. Rods and melanopsin contributions for PLR are affected in NVAMD. The CCT and the PLR may be considered sensitive tests to evaluate and monitor functional changes in patients with AMD.
Sex differences in the neuroadaptations associated with incubated cocaine-craving: A focus on the dorsomedial prefrontal cortex
Authors: Towers Eleanor Blair , Kilgore Madison , Bakhti-Suroosh Anousheh , Pidaparthi Lasyapriya , Williams Ivy L. , Abel Jean M. , Lynch Wendy J.
Published: January 2023

Introduction

Women have a shorter course from initial cocaine use to meeting the criteria for cocaine use disorder as compared to men. Preclinical findings similarly indicate that females develop key features of an addiction-like phenotype faster than males, including an enhanced motivation for cocaine and compulsive use, indicating that this phenomenon is biologically based. The goals of this study were to determine whether cocaine-craving, another key feature of addiction, also develops sooner during withdrawal in females than males and to determine whether there are sex differences in the molecular mechanisms associated with its development focusing on markers known to mediate cocaine-craving in males (i.e., dorsomedial prefrontal cortex, dmPFC, expression of brain-derived neurotrophic factor exon-IV, Bdnf-IV, and NMDA receptor subunits, Grin2a, Grin2b, and Grin1).

Methods

Cocaine-craving was assessed following extended-access cocaine self-administration and 2, 7, or 14 days of withdrawal using an extinction/cue-induced reinstatement procedure. Tissue was obtained from the dmPFC immediately after reinstatement testing and gene expression changes were analyzed using real-time qPCR.

Results

In males, cocaine-craving (total extinction and cue-induced reinstatement responding) progressively increased from early to later withdrawal time-points whereas in females, cocaine-craving was already elevated during early withdrawal (after 2 days) and did not further increase at later withdrawal time-points. Levels of cocaine-craving, however, were similar between the sexes. Gene expression changes differed markedly between the sexes such that males showed the expected relapse- and withdrawal-associated changes in Bdnf-IV, Grin2a, Grin2b, and Grin1 expression, but females only showed a modest increase Grin1 expression at the intermediate withdrawal timepoint.

Discussion

These findings indicate that cocaine-craving is similarly expressed in males and females although the time-course for its incubation appears to be accelerated in females; the molecular mechanisms also likely differ in females versus males.
A protocol for the integration of multi-omics bioinformatics: Mechanism of acupuncture as an adjunctive therapy for alcohol use disorder
Authors: Zhang Peiming , Lan Xiaochang , Fan Baochao , Chen Yiming , Wei Xiaojing , Li Xiangli , Fan Ni , Tang Chunzhi , Lu Liming
Published: January 2023

Background

Alcohol use disorder (AUD) has become a significant global factor in various diseases. As a non-pharmacological therapy, certain therapeutic potential has been found in acupuncture; however, in-depth mechanistic studies related to acupuncture for patients with AUD are still insufficient.

Methods

Based on a randomized control design and a multi-omics analysis plan, this protocol details the recruitment (42 AUD patients), group allocation (21 in acupuncture group vs. 21 in sham acupuncture group), intervention and follow-up (replacement drugs as a normal treatment, 2 weeks acupuncture duration, and 3 month follow-up), and data collection and analytical processes. For the clinical outcomes, in addition to the time required for alcohol withdrawal symptoms to subside as the primary outcome, changes in the alcohol withdrawal symptoms, alcohol craving, mood dysfunction, sleep disorder, fatigue, self-efficacy, gastrointestinal symptoms, the quality of life, and the relapse outcomes will be compared between the groups to confirm the acupuncture clinical effectiveness on alcohol withdraw. The gut microbiome and the fecal metabolomics will also be assessed to explore the association of the structure and the function of gut microflora and the mediation of acupuncture effect on AUD fully utilizing gut microflora multi-modal data and clinical information, via the combination of multi-omics methods, feature screening algorithms and appropriate models.

Discussion

The results of this study may help to strengthen clinical evidence of the mechanism of acupuncture intervention in patients with AUD, through understanding of the regulatory mechanism of acupuncture in the gut microbiome and its metabolism as well as AUD-related clinical manifestations.

Trial registration

Chinese Clinical Trial Registry ChiCTR2200058120. Registered on 24 Mar 2022.
Assessment of the capacity to modulate brain signals in a home-based SMR neurofeedback training setting
Authors: Autenrieth Miriam , Kober Silvia Erika , Wood Guilherme
Published: January 2023

Electroencephalogram (EEG)-based neurofeedback (NF) is mainly used in clinical settings as a therapeutic intervention or to optimize performance in healthy individuals. Home-based NF systems are available and might facilitate general access to NF training, especially when repeated training sessions are necessary. However, it remains an open question whether NF training at home is possible without remote monitoring. In the present study, we assessed the capacity of healthy individuals to modulate their own EEG activity when using a home-based NF training system in a comparable manner as if participants had purchased a commercially available NF system. Participants’ face-to-face contact with experimenters was reduced to a minimum, and instructions were provided only in the form of written information or videos. Initially, 38 participants performed 9 sessions of sensorimotor rhythm (SMR) (12–15 Hz) based NF training (three generalization sessions, six training sessions). An active control group (n = 19) received feedback on random EEG frequencies. Because of technical problems, bad EEG data quality, or non-compliance, 21 participants had to be excluded from the final data analysis, providing first evidence for the difficulties of non-supervised home-based NF training. In this study, participants were not able to modulate their own brain activity in a desired direction during NF training. Our results indicate that personal interaction with a NF expert might be of relevance and that remote supervision of the training data and more direct communication with the NF users are necessary to enable successful NF training performance. We provide suggestions for the development and implementation of home-based NF systems.
Differential neural response to psychoanalytic intervention techniques during structural interviewing: A single-case analysis using EEG
Authors: Buchheim Anna , Kernberg Otto F. , Netzer Nikolaus , Buchheim Peter , Perchtold-Stefan Corinna , Sperner-Unterweger Barbara , Beckenbauer Fabian , Labek Karin
Published: January 2023

Background

Previous studies detected changes in the electroencephalographic (EEG) signal as an effect of psychoanalytic interventions. However, no study has investigated neural correlates of specific psychoanalytic interventions in the EEG power spectrum yet. In the present case study, we contrasted three types of interventions (clarification, confrontation, and interpretation) and a neutral control condition during a structural psychoanalytic interview conducted while EEG was recorded.

Methods

A 27-year-old male patient diagnosed with major depressive disorder and borderline personality disorder with recurrent suicidal and self-injurious behavior underwent a structural interview while recording EEG. Two independent experts selected by consensus the characteristic episodes of the four conditions (clarification, confrontation, interpretation, and neutral control) within the interview, which were included in the EEG analyses. Fast Fourier transformation (FFT) was applied to subsegments of the intervention type to analyze the EEG power spectra. Alpha and beta power from central, frontal, and parietal sites were considered in linear mixed-effects models with segments as a random factor with maximum-likelihood estimates due to the lack of balance in the length of the interview segments.

Results

The interventions “interpretation” and “confrontation” showed a significantly lower alpha power compared with the control condition in the central electrodes. In the frontal and parietal sites of the alpha power and all beta power sites, the omnibus tests (full model/model without intervention) and comparisons relative to control conditions showed no significant overall result or failed significance after alpha error correction.

Conclusion

Incisive interventions, such as confrontation with discrepancies and interpretation of unconscious intrapsychic conflicts, may have provoked temporary emotional lability, leading to a change in psychic processing akin to interference from external stimuli. This conclusion is consistent with the finding that interpretations, which are potentially the most concise interventions, had the strongest effects on alpha power. Using EEG during therapeutic psychoanalytic intervention techniques might be a helpful tool to evaluate differential responses to the psychotherapeutic process on a neural level. However, this single-case result has to be replicated in a larger sample and does not allow generalizations.
Mechanism and effects of STING–IFN-I pathway on nociception: A narrative review
Authors: Yang Jinghan , Ding Hui , Shuai Bo , Zhang Yan , Zhang Yan
Published: January 2023

Since the discovery of STING in 2008, numerous studies have investigated its functions in immunity, inflammation, and cancer. STING activates downstream molecules including IFN-I, NLRP3, and NF-κB. The STING–IFN-I pathway plays a vital role in nociception. After receiving the upstream signal, STING is activated and induces the expression of IFN-I, and after paracrine and autocrine signaling, IFN-I binds to IFN receptors. Subsequently, the activity of ion channels is inhibited by TYK2, which induces an acute antinociceptive effect. JAK activates PIK3 and MAPK–MNK–eIF4E pathways, which sensitize nociceptors in the peripheral nervous system. In the mid-late stage, the STING–IFN-I pathway activates STAT, increases pro-inflammatory and anti-inflammatory cytokines, inhibits ER-phagy, and promotes microglial M1-polarization in the central nervous system, leading to central sensitization. Thus, the STING–IFN-I pathway may exert complex effects on nociception at various stages, and these effects require further comprehensive elucidation. Therefore, in this review, we systematically summarized the mechanisms of the STING–IFN-I pathway and discussed its function in nociception.
MOTS-c repairs myocardial damage by inhibiting the CCN1/ERK1/2/EGR1 pathway in diabetic rats
Authors: Wang Manda , Wang Gangqiang , Pang Xiaoli , Ma Jiacheng , Yuan Jinghan , Pan Yanrong , Fu Yu , Laher Ismail , Li Shunchang
Published: January 2023

Cardiac structure remodeling and dysfunction are common complications of diabetes, often leading to serious cardiovascular events. MOTS-c, a mitochondria-derived peptide, regulates metabolic homeostasis by accelerating glucose uptake and improving insulin sensitivity. Plasma levels of MOTS-c are decreased in patients with diabetes. MOTS-c can improve vascular endothelial function, making it a novel therapeutic target for the cardiovascular complications of diabetes. We investigated the effects of MOTS-c on cardiac structure and function and analyzed transcriptomic characteristics in diabetic rats. Our results indicate that treatment with MOTS-c for 8-week repaired myocardial mitochondrial damage and preserved cardiac systolic and diastolic function. Transcriptomic analysis revealed that MOTS-c altered 47 disease causing genes. Functional enrichment analysis indicated MOTS-c attenuated diabetic heart disease involved apoptosis, immunoregulation, angiogenesis and fatty acid metabolism. Moreover, MOTS-c reduced myocardial apoptosis by downregulating CCN1 genes and thereby inhibiting the activation of ERK1/2 and the expression of its downstream EGR1 gene. Our findings identify potential therapeutic targets for the treatment of T2D and diabetic cardiomyopathy.
Efficacy of intra-arterial chemotherapy with sequential anti-PD-1 antibody in unresectable gastric cancer: A retrospective real-world study
Authors: Xiang Xiaosong , Guo Feilong , Li Guoli , Ma Long , Zhu Xi , Abdulla Zulpikar , Li Jiafei , Zhang Junling , Huang Mengli
Published: January 2023

Background

The prognosis of unresectable gastric cancer is poor, while the efficacy of anti-PD antibodies has not been evaluated.

Methods

Patients with unresectable gastric cancer who received intra-arterial chemotherapy (IAC) with sequential anti-PD-1 antibody as induction therapy in Jinling Hospital were retrospectively analyzed. The primary outcome is R0 resection rate. The secondary outcomes include safety, conversion surgery rate, overall survival (OS) and progression free survival (PFS) after postoperative IAC and anti-PD-1 treatments. Meanwhile, Tumor immunity in the microenvironment (TIME) before and after IAC was comprehensively dissected with multiplex immunofluorescence in order to detect possible mechanisms favoring anti-PD-1 treatment response.

Results

Between May 2019 and October 2020, 36 patients received at least one cycle of IAC with sequential anti-PD-1 antibody in our institution. The objective response was achieved in 28 patients (77.8%). Thirty patients (83.3%) successfully underwent conversion surgery, among which R0 resection was managed in 25/30 patients, and 23.3% (7/30) was assessed as pathological complete remission. During the median follow-up period of 19.7 months, patients who underwent R0 resection displayed superior OS (HR 0.14 [95% CI 0.04-0.50], P < 0.0001) and PFS (HR 0.11 [0.03-0.44], P < 0.0001) than those who did not. Grade 3 adverse events (AEs) were only encountered in 19.4% patients, no grade 4 AEs observed. In TIME analysis, the number of tertiary lymphoid structures (TLSs) (P = 0.004) were greatly induced by IAC, as well as CD8+ T cells (P = 0.011) and PD-1+ cells (P = 0.025). Meanwhile, Tumor associated macrophages shifted towards anti-tumor M1-like subtypes, with CD68+CD163+ M2-like subpopulation significantly decreased (P = 0.04).

Conclusion

Preoperative IAC with sequential anti-PD-1 antibody exhibited promising clinical benefit for unresectable gastric cancer with remarkable conversion rate and R0 resection rate, and also prolonged survival as postoperative regimen. TIME transformation induced by ICA might mediate the additive effect with the immune checkpoint inhibitor.
New insight into strategies used to develop long-acting G-CSF biologics for neutropenia therapy
Authors: Theyab Abdulrahman , Alsharif Khalaf F. , Alzahrani Khalid J. , Oyouni Atif Abdulwahab A. , Hawsawi Yousef MohammedRabaa , Algahtani Mohammad , Alghamdi Saad , Alshammary Amal F.
Published: January 2023

Over the last 20 years, granulocyte colony-stimulating factors (G-CSFs) have become the major therapeutic option for the treatment of patients with neutropenia. Most of the current G-CSFs require daily injections, which are inconvenient and expensive for patients. Increased understanding of G-CSFs’ structure, expression, and mechanism of clearance has been very instrumental in the development of new generations of long-acting G-CSFs with improved efficacy. Several approaches to reducing G-CSF clearance via conjugation techniques have been investigated. PEGylation, glycosylation, polysialylation, or conjugation with immunoglobulins or albumins have successfully increased G-CSFs’ half-lives. Pegfilgrastim (Neulasta) has been successfully approved and marketed for the treatment of patients with neutropenia. The rapidly expanding market for G-CSFs has increased demand for G-CSF biosimilars. Therefore, the importance of this review is to highlight the principle, elimination’s route, half-life, clearance, safety, benefits, and limitations of different strategies and techniques used to increase the half-life of biotherapeutic G-CSFs. Understanding these strategies will allow for a new treatment with more competitive manufacturing and lower unit costs compared with that of Neulasta.
Raman spectroscopy: A prospective intraoperative visualization technique for gliomas
Authors: Zhang Yi , Yu Hongquan , Li Yunqian , Xu Haiyang , Yang Liu , Shan Peilin , Du Yuejiao , Yan Xiaokai , Chen Xuan
Published: January 2023

The infiltrative growth and malignant biological behavior of glioma make it one of the most challenging malignant tumors in the brain, and how to maximize the extent of resection (EOR) while minimizing the impact on normal brain tissue is the pursuit of neurosurgeons. The current intraoperative visualization assistance techniques applied in clinical practice suffer from low specificity, slow detection speed and low accuracy, while Raman spectroscopy (RS) is a novel spectroscopy technique gradually developed and applied to clinical practice in recent years, which has the advantages of being non-destructive, rapid and accurate at the same time, allowing excellent intraoperative identification of gliomas. In the present work, the latest research on Raman spectroscopy in glioma is summarized to explore the prospect of Raman spectroscopy in glioma surgery.
Association between early response of alpha-fetoprotein and treatment efficacy of systemic therapy for advanced hepatocellular carcinoma: A multicenter cohort study from China
Authors: Hou Gang , Liu Bo , Fan Zhong-Qi , Li Chao , Zhang Jian-Ping , Guo Yan-Hui , Zhang Ru-Yi , Zheng Yi , Zhu Hong , Wang Nan-Ya
Published: January 2023

Background

Alpha-fetoprotein (AFP) is a well-identified biomarker in hepatocellular carcinoma (HCC). However, only limited AFP-related studies have evaluated its early response to systemic therapy. This study was performed with the aim of assessing the value of early AFP response in predicting overall survival (OS) and progression-free survival (PFS) in advanced HCC patients receiving systemic therapy.

Methods

This cohort study included HCC patients with baseline AFP ≥ 200 ng/ml and no prior treatment history. A > 20% decline in the serum AFP level from baseline to the first follow-up (i.e., 4~6 weeks after treatment) was defined as an early AFP response. Patient demographic information, clinical characteristics, radiological response, and survival rates were compared between patients with early AFP response and patients without early AFP response. We further utilized multivariate Cox regression to seek characteristics related to OS and PFS.

Results

Among 154 patients, 69 patients (44.8%) showed an early AFP response. The disease control rate (76.8 vs. 54.1%; P = 0.003) and objective response rate (38.4 vs. 11.8%; P = 0.001) were significantly higher in patients with an early AFP response. By performing multivariate analysis, early AFP response remained a prognostic factor for longer PFS (HR 0.546; 95% CI 0.371-0.804; P = 0.002) and longer OS (HR 0.529; 95% CI 0.335-0.834; P = 0.006).

Conclusion

An early AFP response is correlated with longer overall survival and progression-free survival for advanced HCC patients receiving systemic therapy. Moreover, an early AFP response is an independent prognostic factor for longer OS and PFS.
Case report: Novel NIPBL-BEND2 fusion gene identified in osteoblastoma-like phosphaturic mesenchymal tumor of the fibula
Authors: Sakai Tomohisa , Okuno Yusuke , Murakami Norihiro , Shimoyama Yoshie , Imagama Shiro , Nishida Yoshihiro
Published: January 2023

Phosphaturic mesenchymal tumor (PMT) is a rare tumor that secretes fibroblast growth factor 23 (FGF23) and causes hypophosphatemia and tumor-induced osteomalacia (TIO). Fusion genes FN1-FGFR1 and FN1-FGF1 have been detected in some PMTs, but the pathogenesis of PMTs without these fusion genes remains unclear. Here, we report a 12-year-old boy with persistent muscle weakness and gait disturbance. Roentgenographic examination revealed a radiolucent lesion with endosteal scalloping in the left fibula, while his serum level of FGF23 was markedly increased. Combined with simple X-ray findings of other body parts, we suspected that TIO was caused by PMT, and resected the tumor. After resection, the serum level of FGF23 started to decrease immediately and normalized within 3 hours after resection, with this being earlier than normalization of the serum phosphorus level. In RNA sequencing, FN1-FGFR1 and FN1-FGF1 were not detected, but a novel NIPBL-BEND2 fusion gene was identified. When we forcedly expressed this fusion gene in HEK293T cells and MG63 cells, cell proliferation was enhanced in both cell lines. Furthermore, Gene set enrichment analysis of HEK293T cells showed significant upregulation of MYC-target genes. Our results suggest that this novel NIPBL-BEND2 fusion gene promotes cell proliferation possibly via the MYC pathway and might be one of the etiologies of PMTs other than FN1-FGFR1 or FN1-FGF1.
Zoledronic acid induces ferroptosis by reducing ubiquinone and promoting HMOX1 expression in osteosarcoma cells
Authors: Ren Tianhao , Huang Ju , Sun Wei , Wang Guangze , Wu Yuwen , Jiang Zewei , Lv Yingshuai , Wu Guang , Cao Jiawei , Liu Min , Gu Haihua
Published: January 2023

Aims: Ferroptosis plays important roles in tumorigenesis and cancer therapy. Zoledronic acid is known to inhibit the activity of farnesyl pyrophosphate synthase, a key enzyme in the mevalonate pathway. We examined whether zoledronic acid can inhibit the growth of osteosarcoma cells by inducing ferroptosis.

Methods: Cell viability was analyzed by using CCK8 reagent and counting cells with trypan blue exclusion. Ferroptosis markers including lipid peroxide and PTGS2 expression were examined by flow cytometry, western blot, and quantitative PCR analyses. Cellular ubiquinone content was determined using high performance liquid chromatography. Ferrostatin-1 and RSL3 were used as the ferroptosis inhibitor and inducer respectively.

Results: Zoledronic acid treatment decreased cell viability and promoted the increase in lipid peroxide content and PTGS2 expression. Addition of ferrostatin-1 reverted these effects of zoledronic acid on osteosarcoma cells, supporting a role of zoledronic acid in inducing ferroptosis. Mechanistically, zoledronic acid significantly decreased ubiquinone, a metabolite of the mevalonate pathway. Treating cells with exogenous ubiquinone prevented zoledronic acid-induced ferroptosis and decrease in the growth of osteosarcoma cells. In addition, zoledronic acid enhanced the expression of HMOX1, whereas knockdown of HMOX1 inhibited the zoledronic acid-induced increase in lipid peroxide level and decrease in cell growth. Finally, zoledronic acid together with RSL3 significantly enhanced the inhibitory effect on the growth of osteosarcoma cells.

Conclusion: Our results indicate that zoledronic acid induces ferroptosis by decreasing ubiquinone content and promoting HMOX1 expression in osteosarcoma cells. Zoledronic acid together with ferroptosis inducer may be a promising new strategy for the treatment of osteosarcoma.
Successful establishment and five-year sustainability of a neonatal-specific antimicrobial stewardship program in a low middle-income country
Authors: Maalouf Faouzi I. , Saad Therese , Zakhour Ramia , Yunis Khalid
Published: January 2023

Introduction: Antibiotic use varies substantially among neonatal intensive care units (NICUs) without any appreciable impact on outcomes. An increased use of antimicrobials has been reported in low-middle income countries. This raises the concern for potential overuse of antibiotics in a fragile patient population, thus increasing the rates of multidrug resistant organisms and affecting the developing microbiome. The presence of a neonatal-specific antimicrobial stewardship program can aid with the judicious use of antibiotics in the neonatal population and thus decrease the overuse of such medications.

Methods: In this quality improvement project, we established and implemented a neonatal-specific antimicrobial stewardship program with the aim of reducing antimicrobial use in the neonatal intensive care units within a year of starting. Several interventions using a multidisciplinary approach included implementing standard algorithms, direct audit and feedback, and automated hard stops.

Results: These series of interventions led to a 35% decrease in antimicrobial usage in the first 3 months and further decrease was seen with a median of 63% decline for a total of 5 years after project implementation. The use of the most commonly prescribed antibiotics, ampicillin and gentamicin, decreased by 63% and 79%, respectively. There was no evidence that this change in practice affected or jeopardized patient outcomes. Additionally, it showed sustainability and resilience despite the many challenges such as COVID-19 pandemic, political and financial unrest, and healthcare sector collapse.

Discussion: This model-based and multidisciplinary low-cost approach can lead to marked improvement affecting neonatal outcomes and can be replicated in other similar centers.
The role played by ailanthone in inhibiting bone metastasis of breast cancer by regulating tumor-bone microenvironment through the RANKL-dependent pathway
Authors: Wang Yajun , Zhong Zeyuan , Ma Miao , Zhao Yannan , Zhang Chongjing , Qian Zhi , Wang Biyun
Published: January 2023

Introduction: Bone metastasis of breast cancer (BC) is a process in which the disruption of the bone homeostatic microenvironment leads to an increase in osteoclast differentiation. Ailanthus altissima shows an inhibitory effect on osteoclast differentiation. Ailanthone (AIL) refers to a natural compound isolated from Ailanthus altissima, a Chinese herbal medicine, and has effective anti-tumor activity in numerous cell lines. Its impact on bone metastases for BC is yet unclear.

Methods: We measured the effect of AIL on MDA-MB-231 cells by wound healing experiments, Transwell and colony formation experiment. Using the Tartrate-resistant Acid Phosphatase (TRAP) staining tests, filamentous (F-actin) staining and bone resorption test to detect the effect of AIL on the osteoclast cell differentiation of the Bone Marrow-derived Macrophages (BMMs), activated by the MDA-MB-231 cell Conditioned Medium (MDA-MB-231 CM) and the Receptor Activator of Nuclear factor-κB Ligand (RANKL),and to explore its possibility Mechanisms. In vivo experiments verified the effect of AIL on bone destruction in breast cancer bone metastasis model mice.

Results:In vitro, AIL significantly decrease the proliferation, migration and infiltration abilities of MDA-MB-231 cells at a safe concentration, and also reduced the expression of genes and proteins involved in osteoclast formation in MDA-MB-231 cells. Osteoclast cell differentiation of the BMMs, activated by MDA-MB-231 CM and RANKL, were suppressed by AIL in the concentration-dependent manner. Additionally, it inhibits osteoclast-specific gene and protein expression. It was noted that AIL inhibited the expression of the osteoclast differentiation-related cytokines RANKL and interleukin-1β (IL-1β) that were secreted by the MDA-MB-231 cells after upregulating the Forkhead box protein 3 (FOXP3) expression. Furthermore, AIL also inhibits the expression of the Mitogen-Activated Protein Kinase (MAPK), Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), and Nuclear factor-κB Ligand (NF-κB) signaling pathways, which then suppresses the MDA-MB-231CM-induced development of Osteoclasts.

Conclusion: Our study shows that AIL blocks osteoclast differentiation in the bone metastasis microenvironment by inhibiting cytokines secreted by BC cells, which may be a potential agent for the treatment of BC and its secondary bone metastasis.
YIV-906 enhances nuclear factor of activated T-cells (NFAT) activity of T cells and promotes immune checkpoint blockade antibody action and CAR T-cell activity
Authors: Lam Wing , Hu Rong , Liu Shwu-Huey , Cheng Peikwen , Cheng Yung-Chi
Published: January 2023

YIV-906 is a systems biology botanical cancer drug, inspired by a traditional Chinese herbal formulation. Results from eight Phase I/II to II clinical studies demonstrated the potential of YIV-906 to prolong survival and improve the quality of life of cancer patients. As an immunomodulator in the tumor microenvironment, YIV-906 can turn cold tumors hot and potentiate anti-tumor activity for different classes of anticancer agents; and as a cytoprotector in the GI, YIV-906 can reduce non-hematological side effects and speed up damaged tissue recovery. YIV-906 enhanced anti-PD1 action against hepatoma in mice by stimulating both innate and adaptive immunity. In a Jurkat cell-staphylococcal superantigen E (SEE)-Raji cell culture model, YIV-906 promoted T cell activation with upregulation of CD69 by enhancing NFAT activity, with or without PD1-PD-L1 interaction. YIV-906 could trigger the phosphorylation of TCR downstream signaling cascades without the involvement of TCR. YIV-906 could inhibit SHP1 and SHP2 activities, which dephosphorylates TCR downstream proteins due to the PD1-PD-L1 interaction. Therefore, YIV-906 could enhance anti-PD1 action to rescue the depressed NFAT activity of Jurkat cells due to the PD1-PD-L1 interaction. In addition, YIV-906 enhanced the NFAT activity and killing capability of Jurkat cells expressing chimeric antigen receptor (CAR-CD19−CD3z) toward CD19 expressing cells, such as Raji cells, with or without PD1-PD-L1 overexpression. Ingredient herb S (Scutellaria baicalensis Georgi) of YIV-906 and some S compounds were found to play key roles in these activities. In conclusion, YIV-906 modulates adaptive immunity by activating T effector cells mainly through its action on SHP1/2. YIV-906 could also facilitate immune checkpoint blockade therapy or CAR-T cell therapy for cancer treatment.
An anoikis-based signature for predicting prognosis in hepatocellular carcinoma with machine learning
Authors: Guizhen Zhang , Weiwei Zhu , Yun Wang , Guangying Cui , Yize Zhang , Zujiang Yu
Published: January 2023

Background: Hepatocellular carcinoma (HCC) is a common malignancy with high mortality worldwide. Despite advancements in diagnosis and treatment in recent years, there is still an urgent unmet need to explore the underlying mechanisms and novel prognostic markers. Anoikis has received considerable attention because of its involvement in the progression of human malignancies. However, the potential mechanism of anoikis-related genes (ANRGs) involvement in HCC progression remains unclear.

Methods: We use comprehensive bioinformatics analyses to determine the expression profile of ANRGs and their prognostic implications in HCC. Next, a risk score model was established by least absolute shrinkage and selection operator (Lasso) Cox regression analysis. Then, the prognostic value of the risk score in HCC and its correlation with clinical characteristics of HCC patients were further explored. Additionally, machine learning was utilized to identify the outstanding ANRGs to the risk score. Finally, the protein expression of DAP3 was examined on a tissue microarray (TMA), and the potential mechanisms of DAP3 in HCC was explored.

Results: ANRGs were dysregulated in HCC, with a low frequency of somatic mutations and associated with prognosis of HCC patients. Then, nine ANRGs were selected to construct a risk score signature based on the LASSO model. The signature presented a strong ability of risk stratification and prediction for overall survival in HCC patients.Additionally, high risk scores were closely correlated with unfavorable clinical features such as advanced pathological stage, poor histological differentiation and vascular invasion. Moreover, The XGBoost algorithm verified that DAP3 was an important risk score contributor. Further immunohistochemistry determined the elevated expression of DAP3 in HCC tissues compared with nontumor tissues. Finally, functional analyses showed that DAP3 may promote HCC progression through multiple cancer-related pathways and suppress immune infiltration.

Conclusion: In conclusion, the anoikis-based signature can be utilized as a novel prognostic biomarker for HCC, and DAP3 may play an important role in the development and progression of HCC.
The importance of reminders and patient preferences to improve inhaler technique in older adults with COPD
Authors: Barnestein-Fonseca P. , Cotta-Luque VM. , Aguiar-Leiva VP. , Leiva-Fernández J. , Martos-Crespo Francisco , Leiva-Fernández F.
Published: January 2023

Objectives: Medication non-adherence in patients with chronic obstructive pulmonary disease is common. The aim is to evaluate the efficacy of two interventions to improve the inhalation technique (IT) in patients with pulmonary disease is common. Also determine optimal IT reminder time and to test the role of preferences in the intervention selection.

Method: 726 pulmonary disease in common patients (consecutive sampling) from two trials: 1) TECEPOC-study (patients’ preference trial/comprehensive cohort design) 2) TIEPOC-study (randomised controlled trial). Interventions: intervention-A (ad-hoc leaflet with instructions about correct IT according Spanish Respiratory Society), intervention B (intervention A+ individual training by instructors). Four visits were performed (baseline, 3, 6 and 12 months). Data on IT, sociodemographic and clinical characteristics, quality of life and respiratory drugs were recorded. Analysis under intention to treat principle. Multivariate analysis was conducted to measure the potential modifying factors of improvement in the IT along follow-up.

Results: 660 patients (90.9%) did not perform a correct IT at baseline 89.75% with Handihaler, 86.95% with Turbuhaler, 84.75% with Accuhaler and 87.35% with pMDI. At 12 months, 221 patients 29.9% performed correctly the IT; a decrease in the slope of the curve (correct IT) was detected at 3 months follow-up. Intervention B was the most effective in both trials compared to control group or intervention A, regardless of preferences: 1) TECEPOC Study (preference trial): Intervention B versus control group, NNT = 3.22 (IC95%, 2.27–5.52); and versus Intervention A, NNT = 3.57 (CI95%, 2.41–6.8). Preferences improved 6.7% in the correct IT without statistical significance. 2) TIEPOC Study (randomized controlled trial): Intervention B versus control group, NNT = 1.74 (IC95%, 1.47–2.17), and versus intervention A, NNT = 3.33 (CI 95%, 2.43–5.55). No differences were measured between Intervention A and control group.

Conclusion: Individual training significantly improves IT. Reminders every 3 months are recommended. Preferences do not influence the intervention effectiveness.
Dosimetric quantities and cell survival for spatially fractionated radiation therapy
Authors: Ahmed Mabroor , Bicher Sandra , Stewart Robert D. , Bartzsch Stefan , Schmid Thomas E. , Combs Stephanie E. , Meyer Juergen
Published: January 2023

Purpose: Spatially Fractionated Radiation Therapy (SFRT) is characterized by large differences in peak and valley doses. Preclinical and clinical studies suggest that differences in biological mechanisms lead to differential normal tissue and tumor response compared to uniform irradiation. We hypothesize that to evaluate clinical effectiveness and understand fundamental biological mechanisms, radiobiological rather than physical dose quantities should be utilized for comparisons. The aim of this work is to determine whether Equivalent Uniform Dose (EUD) is a superior predictor of cell survival than absorbed dose.

Methods: Absorbed dose parameters were compared to the Equivalent Uniform Dose to assess their predictive value for the relative effectiveness of uniform and SFRT with X-rays. A Bayesian bootstrap technique was utilized to model uncertainties in the biological fit parameters for a human fibroblast (MRC5) and two human tumor cell lines (LN18 and A549). Dose uncertainties were evaluated through measurements and error modeling of SFRT profiles. A dimensionless Relative Effectiveness Factor (REF) is proposed to quantify differences between uniform and SFRT irradiation.

Results: For all cell lines, cell survival after SFRT matched uniform irradiation within the estimated uncertainties at equal values of the EUD. Average and peak dose showed poor correlation with in vitro cell survival. The proposed REF factor is dose dependent and suggests enhanced cell killing for both tumor cell lines (1.14 ± .08 for LN18, 1.32 ± .13 for A549 at 8 Gy EUD) for SFRT. Normal human fibroblasts showed reduced cell killing relative to uniform irradiation (.58 ± .06 for MRC5). Synthetically generated SFRT dose profiles revealed that EUD uncertainties are dominated by valley dose uncertainties, especially at high doses.

Discussion: EUD is more predictive of cell survival than average or valley dose. Valley dose is close to equal to the EUD for values >10 Gy and has the advantage of being independent of uncertainties in biological parameters. The REF is a novel and useful metric to compare quantitative differences in SFRT and uniform irradiation.

Conclusion: EUD is recommended for comparisons of SFRT and uniform irradiation. The results suggest an increase in survival of normal-human fibroblast cells and reduced survival for both tumor cell lines after SFRT relative to uniform irradiation.
Data-driven modeling of beam loss in the LHC
Authors: Krymova Ekaterina , Obozinski Guillaume , Schenk Michael , Coyle Loic , Pieloni Tatiana
Published: January 2023

In the Large Hadron Collider, the beam losses are continuously measured for machine protection. By design, most of the particle losses occur in the collimation system, where the particles with high oscilla-tion amplitudes or large momentum error are scraped from the beams. The particle loss level is typically optimized manually by changing control parameters, among which are currents in the focusing and defocusing magnets. It is generally challenging to model and predict losses based only on the control parameters, due to the presence of various (non-linear) effects in the system, such as electron clouds, resonance effects, etc., and multiple sources of uncertainty. At the same time understanding the influence of control parameters on the losses is extremely important in order to improve the operation and performance, and future design of accelerators. Prior work [1] showed that modeling the losses as an instantaneous function of the control parameters does not generalize well to data from a different year, which is an indication that the leveraged statistical associations are not capturing the actual mechanisms which should be invariant from 1 year to the next. Given that this is most likely due to lagged effects, we propose to model the losses as a function of not only instantaneous but also previously observed control parameters as well as previous loss values. Using a standard reparameterization, we reformulate the model as a Kalman Filter (KF) which allows for a flexible and efficient estimation procedure. We consider two main variants: one with a scalar loss output, and a second one with a 4D output with loss, horizontal and vertical emittances, and aggregated heatload as components. The two models once learned can be run for a number of steps in the future, and the second model can forecast the evolution of quantities that are relevant to predicting the loss itself. Our results show that the proposed models trained on the beam loss data from 2017 are able to predict the losses on a time horizon of several minutes for the data of 2018 as well and successfully identify both local and global trends in the losses.