bluuebunny/crossref_metadata_2025_split huggingface dataset:
TMET-19. TARGETING AMINO ACID METABOLIC VULNERABILITIES IN IDH-MUTANT AND IDH-WILDTYPE GLIOMAS
Authors: Ohba Shigeo , Teranishi Takao , Hirayama Akiyoshi , Hitachi Keisuke , Yamaguchi Hisateru , Natsumeda Manabu , Tateishi Kensuke , Pieper Russell , Hirose Yuichi 
Published: November 2023

Abstract
IDH-wildtype and IDH-mutant glioma have different genetical and metabolic background although their histological appearances are similar. The aim of the study is to reveal the difference in metabolites between IDH-wildtype glioma and IDH-mutant glioma, and to find the effective treatment according to the status of IDH in gliomas. Two artificial cell lines made from human astrocyte were used: NHAE6E7hTERTRas (IDH-wildtype) and NHAE6E7hTERTIDHmut (IDH-mutant). Capillary electrophoresis- and ion chromatography–coupled mass spectrometry revealed that the amount of asparagine was lower in NHAE6E7hTERTRas cells compared with NHAE6E7hTERTIDHmut cells. L-asparaginase, which converts asparagine into aspartate, was more effective in former cells than latter cells. L-asparaginase induced autophagy and inhibition of autophagy by 3-MA suppressed L-asparaginase-induced antitumor effect, which meant that the antitumor effect was at least partially due to the L-asparaginase-induced autophagy. Metabolic assay also showed the lower amount of glutamine, glutamate and 2-oxoglutarate in NHAE6E7hTERTIDHmut cells than NHAE6E7hTERTRas cells. Pharmacological or genetical inhibition of GLUD1 which converts glutamate to 2-oxoglutarate, suppressed proliferation of the cells by inducing ROS and apoptosis in NHAE6E7hTERTIDHmut cells. ROS inhibitor, NAC suppressed GLUD1 inhibitor-induced ROS, apoptosis, and cytotoxicity in NHAE6E7hTERTIDHmut cells, revealing that cytotoxicity by GLUD1 inhibitor was at least partially due to the inhibitor-induced ROS. Mutant IDH1 overexpressed glioma cell line showed similar sensitivity to GLUD1 inhibitor to NHAE6E7hTERTIDHmut, which suggested that the difference of sensitivity to GLUD1 inhibitor was due to the status of mutant IDH. In addition, GLUD1 inhibitor suppressed the growth of xenografted glioma cells with overexpressed mutant IDH1. In conclusion, L-asparaginase and Glud1 inhibitor will be new therapeutic option for IDH-wildtype glioma and IDH-mutant glioma, respectively.
TMIC-29. BEVACIZUMAB IS ASSOCIATED WITH INCREASED RATE OF RECURRENCE IN GLIOBLASTOMA
Authors: Mekonnen Mahlet , Vohra Sanah , Chandla Anubhav , Malkhasyan Yelena , Yang Isaac 
Published: November 2023

Abstract

BACKGROUND
The primary cause of Glioblastoma’s (GBM) dismal outcomes is the high rate of tumor recurrence, which is closely related to its resistance to standard therapies. Bevacizumab has increasingly been used in the treatment of recurrent GBM. However, the data on Bevacizumab has been mixed regarding its efficacy in improving patient survival. Moreover, there is no conclusive evidence in the literature regarding Bevacizumab treatment and its association with increased incidence of distant or diffuse recurrence. Objective: To provide conclusive evidence on the recurrence rate associated with Bevacizumab treatment in GBM patients

METHODS
UCLA GBM patients were reviewed for recurrence pre-and post-Bevacizumab treatment. Patients whose Bevacizumab treatment was not flanked by surgeries and patients with only one surgery were excluded. After exclusion criteria were applied, 94 patients were included in the results. The number of recurrences preceding and following Bevacizumab was recorded.

RESULTS
In a cohort of 94 patients, the average recurrence rate pre-Bevacizumab treatment was 0.29 ± 0.88, whereas the average recurrence rate post-Bevacizumab treatment was 2.51 ± 1.64. Overall, the recurrence rate was significantly higher in GBM patients post-Bevacizumab treatment (95% CI [1.83, 2.59]; p&lt; 0.0001).

CONCLUSION
Our results suggest that Bevacizumab treatment is associated with an increased rate of recurrence. This finding is indicative of tumor transition to a more aggressive phenotype that is associated with Bevacizumab treatment.
TMIC-31. MULTI-PLATFORM GENOMIC LANDSCAPE OF INTRA-TUMORAL HYPOXIA IN GLIOBLASTOMA
Authors: Mansouri Sheila , Patil Vikas , Liu Jeff , Gandhi Shreya , Sosa Julio , Wu Ron , Devaraja Kaviya , Singh Olivia , Ali Hafsah , Karimi Shirin , Mamatjan Yasin , Chen Sujun , Dvorkin-gheva Anna , Khan Shahbaz , He Hansen , Kislinger Thomas , Gaiti Federico , Wouters Bradley , Zadeh Gelareh 
Published: November 2023

Abstract
Hypoxia is a prominent characteristic of aggressive tumors, including glioblastoma (GB), and is linked to therapy resistance. Understanding the molecular mechanisms underlying hypoxia-induced changes in neoplastic and non-neoplastic cells is crucial for developing targeted therapies. In this study, we took a comprehensive approach to investigate the genomic, epigenomic, and spatial transcriptomic profiles of intra-tumoral hypoxia in GB at bulk and single-cell levels. Our objectives were to identify a GB-specific hypoxia gene signature and uncover novel mechanisms of GB's response to hypoxia. Pimonidazole (PIMO), a hypoxia marker, was administered to 77 GB patients. We utilized immune-guided laser microdissection to extract DNA and perform methylome profiling of PIMO+ (hypoxic) and PIMO- regions. Visium 10X spatial transcriptomics was employed to identify differentially expressed genes in PIMO+ tumor regions. Through single-nuclear multi-omics profiling, we examined gene expression and chromatin accessibility of the hypoxic neoplastic and non-neoplastic cells at the single-cell level. The hypoxia transcriptome in GB exhibited general commonalities, in addition to unique features, compared to other reported hypoxia signatures. Some of these alterations were accompanied by changes at the DNA methylome level. Importantly, we found a heterogenous molecular landscape across PIMO+ regions within each sample. While a general transition to a MES-like state was observed, we found a mixture of cell states across the different PIMO+ regions. We also found distinct sub-hypoxic microenvironments harboring unique immune cell populations that overlapped with specific cell type states, cell cycle states, and deregulation of specific cellular pathways. These sub-regions were associated with specific anatomic features and displayed prognostic utility in GBM patient cohorts. Our single-cell multi-omics analysis further revealed intra-tumoral copy number aberrations and changes in chromatin accessibility associated with hypoxic cells. Our findings demonstrate that the hypoxic microenvironment in GB is heterogenous with unique targetable features that could lead to novel treatment modalities.
TMIC-42. ACROLEIN PRODUCED BY GLIOMA CELLS UNDER HYPOXIA INHIBITS NEUTROPHIL AKT ACTIVITY AND SUPPRESSES ANTI-TUMORAL ACTIVITIES
Authors: Tong Zhen-Jie , Tsai Hong-Chieh , Hwang Tsong-Long , Wang Hsiang-Tsui 
Published: November 2023

Abstract
Glioblastoma (GBM), WHO grade 4 glioma, is the most malignant primary brain tumor. The median overall survival of GBM ranges from 12 to 16 months. The tumor microenvironment of GBM is characterized by tissue hypoxia and infiltration of immunosuppressive cells. Neutrophils have been reported to shift from an anti-inflammatory phenotype to a pro-tumoral role (N2 phenotype) during glioma progression. However, the mechanism of this transformation remains unclear. Acrolein (Acr) is a highly-reactive α,β-unsaturated aldehyde produced under hypoxic conditions via lipid peroxidation, resulting in cellular impairment through DNA or protein conjugation. In this study, we found that acrolein produced by U87MG cells under hypoxic conditions suppresses neutrophil superoxide generation, inhibits neutrophil tumor-suppressive activities, and induces N2 marker arginase 1 (Arg-1) expression. Scavenging acrolein with dimercaprol reverses these effects. Further investigation revealed that acrolein inhibits AKT enzymatic activity by forming Acr-AKT conjugates at Cys 310. In a syngeneic subcutaneous mice glioma model, dimercaprol treatment is associated with decreased tumor size, reduced acrolein conjugate expression in the tumor tissue, and restored neutrophil superoxide generation. In addition, we also found that the higher acrolein-DNA adduct expression in tumor tissues is associated with a poor prognosis of glioma patients, and the evaluated acrolein-protein conjugates in the serum of glioma patients are correlated to the functional impairment of neutrophils. These results suggest acrolein polarizes the neutrophils toward the N2 phenotype and contributes to the immunosuppressive microenvironment and glioma progression. Acrolein scavenging may be a novel strategy for glioma treatment.
TMIC-45. SEX DIFFERENCES IN YAP1-CD276 EXPRESSION AND FUNCTION IN MEDULLOBLASTOMA IMMUNE EVASION
Authors: Abdelfattah Nourhan , Natarajan Sivaraman , Madonado Jose , Borland Hannah , McMinimy Rachael , Chen Shu-hsia , Camargo Fernando , Olson James , George Joshy , Yun Kyuson 
Published: November 2023

Abstract
Sex differences in human diseases are well established; however, little is known about the molecules that link oncogenic events and sex as a biological variable in tumorigenesis and treatment response. Here, we report that Yap1 has a sex-specific role in SHH medulloblastoma (MB) progression and immune suppression. Through integrated genomic, transcriptomic, proteomic, and in vivo transcriptional target analyses, we show that Yap1 concurrently promotes stemness and blocks differentiation of cancer stem cells through at least two distinct but complementary molecular mechanisms. In parallel, Yap1 also promotes immune suppressive tumor microenvironment by directly regulating CD276, Csf1, Igf1, and Igfbp3 transcription and modulating the IL6-JAK-STAT3, TNFR1, TGF-β, and CCL5 immune pathways. Notably, while Yap1 function is critical for promoting stemness in male and female MB cells, Yap1 plays a more dominant role in promoting immune suppression and Th2 polarization in male MBs. Furthermore, we discovered that a YAP1-target gene, CD276, expression level is higher in female MBs in both mice and humans, demonstrating for the first-time sex differences in expression levels of an immune checkpoint molecule in MB. Functionally, anti-CD276 treatment is more effective in reversing T cell suppression from male MB cells compared to female MB cells, and CD276 expression level stratifies male but not female MB patient survival. Supporting the clinical relevance of our findings, we show that the sex difference in Yap1 function is evolutionarily conserved across multiple tumor types: YAP1 target gene signature predicts poor survival in males but not females in MB, glioblastoma, low-grade glioma, mesothelioma, and hepatocellular carcinoma. In summary, we provide the first evidence of sex-biased expression and function of YAP1 and CD276 in mouse and human cancers and identified the YAP1-CD276 axis as a key contributor to sex differences in immune checkpoint response.
Readministration of high-dose adeno-associated virus gene therapy vectors enabled by ImmTOR nanoparticles combined with B cell-targeted agents
Authors: Ilyinskii Petr O , Roy Christopher , Michaud Alicia , Rizzo Gina , Capela Teresa , Leung Sheldon S , Kishimoto Takashi Kei 
Published: November 2023

Abstract
Tolerogenic ImmTOR nanoparticles encapsulating rapamycin have been demonstrated to mitigate immunogenicity of adeno-associated virus (AAV) gene therapy vectors, enhance levels of transgene expression, and enable redosing of AAV at moderate vector doses of 2 to 5E12 vg/kg. However, recent clinical trials have often pushed AAV vector doses 10-fold to 50-fold higher, with serious adverse events observed at the upper range. Here, we assessed combination therapy of ImmTOR with B cell-targeting drugs for the ability to increase the efficiency of redosing at high vector doses. The combination of ImmTOR with a monoclonal antibody against B cell activation factor (aBAFF) exhibited strong synergy leading to more than a 5-fold to 10-fold reduction of splenic mature B cells and plasmablasts while increasing the fraction of pre-/pro-B cells. In addition, this combination dramatically reduced anti-AAV IgM and IgG antibodies, thus enabling four successive AAV administrations at doses up to 5E12 vg/kg and at least two AAV doses at 5E13 vg/kg, with the transgene expression level in the latter case being equal to that observed in control animals receiving a single vector dose of 1E14 vg/kg. Similar synergistic effects were seen with a combination of ImmTOR and a Bruton's tyrosine kinase inhibitor, ibrutinib. These results suggest that ImmTOR could be combined with B cell-targeting agents to enable repeated vector administrations as a potential strategy to avoid toxicities associated with vector doses above 1E14 vg/kg.
Real eigenvector distributions of random tensors with backgrounds and random deviations
Authors: Sasakura Naoki 
Published: November 2023

Abstract
As in random matrix theories, eigenvector/value distributions are important quantities of random tensors in their applications. Recently, real eigenvector/value distributions of Gaussian random tensors have been explicitly computed by expressing them as partition functions of quantum field theories with quartic interactions. This procedure to compute distributions in random tensors is general, powerful, and intuitive, because one can take advantage of well-developed techniques and knowledge of quantum field theories. In this paper we extend the procedure to the cases that random tensors have mean backgrounds and eigenvector equations have random deviations. In particular, we study in detail the case that the background is a rank-one tensor, namely, the case of a spiked tensor. We discuss the condition under which the background rank-one tensor has a visible peak in the eigenvector distribution. We obtain a threshold value, which agrees with a previous result in the literature.
Effect of Rhythmically Cued Exercise Interventions on Functions in Patients With Parkinson Disease: A Meta-Analysis
Authors: Huang Xin , Dong Ke , Gan Chu , Xu Zhiqin , Lei Di , Dong Xinghua , Liu Hanjun , Chen Xi 
Published: November 2023

Abstract

Objective
The purpose of this review was to investigate the efficacy of rhythmically cued exercise interventions on motor function, cognition, and mental state in patients with Parkinson disease.

Methods
PubMed, Cochrane Database, Web of Science, Embase, and CINAHL were searched June 15, 2023. Original studies investigating the efficacy of rhythmically cued exercise interventions on the functions of patients with Parkinson disease were included. The Cochrane risk-of-bias assessment tool was used to evaluate the risk of bias. The protocol was registered in PROSPERO (CRD42022371203).

Results
A total of 38 original studies involving 1486 participants were included. Rhythmically cued exercise interventions demonstrated superior effects on motor function compared to exercise therapy without rhythm (standardized mean difference [SMD] = −0.31). However, no significant improvements were observed in cognition and mental state. Overall, significant improvements were observed in motor examination (SMD = −0.61), Timed “Up & Go” Test (mean difference [MD] = −0.91), activities of daily living (SMD = −0.49), balance (SMD = 0.59), walking velocity (MD = 0.06), step length (MD = 2.65), and stride length (MD = 0.04) following rhythmically cued exercise interventions. No significant improvements were observed in freezing of gait and cadence. Assessment of publication bias showed no significant evidence of publication bias. Meta-regression analyses revealed a significant association between treatment duration and improvement in motor function. Furthermore, adverse events and dropout rates did not significantly differ between the 2 groups.

Conclusion
Rhythmically cued exercise interventions are effective in improving motor function in the early to middle stages of Parkinson disease. More than 10 weeks of intervention yielded better results. However, these interventions do not have a significant impact on cognition and mental states. Importantly, rhythmically cued exercise interventions are safe and well tolerated. Large-scale trials are needed for further confirmation.

Impact
This study contributes to the development of safe and reliable home rehabilitation programs, aiming to enhance the quality of life for patients with Parkinson disease.
A microRNA sponge, LINC02193, promotes neutrophil activation by upregulating ICAM1 and is correlated with ANCA-associated vasculitis
Authors: Liu Yun , Feng Yifan , Kong Xiufang , Wei Yuanyuan , Zhan Minglang , Wang Jinghua , Dai Xiaojuan , Wang Li , Ma Lili , Chen Huiyong , Jiang Lindi 
Published: November 2023

Abstract

Objective
To investigate the pathogenic role and underlying mechanisms of long noncoding RNAs (lncRNAs) in ANCA-associated vasculitis (AAV).

Methods
RNA-sequencing (RNA-seq) was applied to screen the expression profile of lncRNAs in peripheral leukocytes from five AAV patients and five healthy controls (HC). Candidate lncRNAs were preliminarily verified in peripheral leukocytes from 46 AAV patients and 35 HC by qRT-PCR. Then, the identified LINC02193 was further validated in peripheral neutrophils from 67 AAV patients, 45 HC and 64 disease controls. Correlation between LINC02193 levels and disease activity was analysed. Then, a loss-of-function study was conducted to investigate the role of LINC02193 in neutrophils activation. Furthermore, bioinformatics analysis, dual luciferase reporter and RNA immunoprecipitation assays were performed to explore the mechanism of LINC02193 regulating neutrophils activation.

Results
A total of 467 upregulated and 412 downregulated lncRNAs were identified in AAV patients. From the top five upregulated lncRNAs, an elevation of LINC02193 was validated in a larger sample of AAV patients, and positively correlated with disease activity. Knockdown of LINC02193 inhibited reactive oxygen species and nitric oxide production, neutrophil extracellular traps release and adhesion to endothelial cells of differentiated human promyelocytic leukaemia HL-60 cells, whereas overexpression of ICAM1 counteracted these effects. Mechanistic analysis demonstrated that LINC02193 acted as an miR-485-5p sponge to relieve the repressive effect of miR-485-5p on ICAM1, thus promoting ICAM1 expression.

Conclusion
LINC02193, a novel lncRNA identified in AAV, could function as competing endogenous RNAs for miR-485-5p to promote ICAM1 expression and neutrophils activation, suggesting its potential as a therapeutic target of AAV.
Reported Outcome Measures in Mohs Micrographic Surgery in Studies With Defined Techniques for Embedding and Processing of Tissue: A Systematic Review
Authors: Govas Panayiota , Ha Megan V. , Wessel Charles B. , Hurst Anne , Gordon Beth R. , Carroll Bryan T. 
Published: November 2023

BACKGROUND
Mohs micrographic surgery (MMS) is a technique that combines surgical excision and histologic evaluation to achieve higher cure rates for skin cancer than traditional surgical excision. Competing performance measures have fostered numerous histologic techniques for MMS.

OBJECTIVE
To analyze differences in primary outcomes in the published literature regarding the technique of tissue processing and embedding during the MMS process.

METHODS
A systematic review was performed of the published literature in MEDLINE, PubMed, Embase, and Cochrane library that included a description of the manipulation of tissue during the grossing and embedding steps of MMS.

RESULTS
Inclusion criteria were met by 61 articles. Of these studies, the cure/recurrence rate was assessed in 1 article (1.6%), tissue conservation was assessed in 47 (77%), time-saving was assessed in 35 (57%), cost-saving was assessed in 6 (10%), and decreased artifact were assessed in 20 (33%).

CONCLUSION
There is a lack of standardization for assessing clinical outcomes in the published literature regarding MMS process techniques. Cure is a critical outcome in studies comparing MMS processing methodologies.
Clinical Outcomes in Sebaceous Carcinoma: A Retrospective Two-Center Cohort Study
Authors: Kibbi Nour , Petric Ursa B. , El-Banna Ghida , Beaulieu Derek M. , Rajan Neil , Srivastava Divya , Aasi Sumaira Z. 
Published: November 2023

BACKGROUND
Sebaceous carcinoma (SC) is a rare, potentially recurrent, and life-threatening cutaneous malignancy that can be associated with Muir–Torre syndrome (MTS), a DNA mismatch repair-driven genodermatosis. Earlier studies examining factors associated with recurrence have focused on periocular tumors only.

OBJECTIVE
Examine outcomes of SC and identify factors associated with recurrence.

MATERIALS AND METHODS
Retrospective study from 2 tertiary care centers.

RESULTS
Sixty-seven cases from 63 patients were identified, including 7 cases of MTS and 13 arising in the context of immunosuppression. Fifty-five cases (82.1%) were treated with complete circumferential peripheral and deep margin assessment (CCPDMA) methods. Five recurrences developed during the postoperative period. On univariate analysis, periocular location (odds ratio [OR] 7.6, p = .0410), and lesion size ≥2 cm (OR 9.6, p = .005) were associated with recurrence, whereas CCPDMA (OR 0.052, p = .0006) was inversely associated with recurrence. On multivariate analysis, only lesion size ≥2 cm (OR 9.6, p = .0233) and CCPDMA approaches (OR 0.052, p = .007) were significant.

CONCLUSION
Non–complete circumferential peripheral and deep margin assessment methods and large lesion size were independent risk factors predicting recurrence, whereas anatomic subtype and MTS status were not. These findings can assist in identifying SC cases that may benefit from more aggressive treatment and closer surveillance.
Refractive cataract surgery
Authors: Narang Rhea , Agarwal Ashvin 
Published: November 2023

Purpose of review
The aim of this study to provide an overview of recent publications and opinions in refractive cataract surgery.

Recent findings
With the advent of intraocular lenses (IOLs) on different platforms, the surgeon has a wide arena of types of IOL to choose, depending on the patient's visual requirement. Optimization of the tear film, integrating tomography and topography devices for appropriate keratometry values, biometry, use of advanced formulas for IOL power calculation and application of newer IOLs can help achieve target refraction in cases scheduled for cataract surgery. Intraoperative aberrometry can be a useful aid for cataract surgery in postrefractive cases and can help minimize residual postoperative astigmatism.

Summary
Evolvement and rapid advancement of technology allows to impart desired refractive outcomes in most of the cases postcataract surgery. Appropriate preoperative and intraoperative factors should be considered to achieve the desired postoperative outcome.