bluuebunny/crossref_metadata_2025_split huggingface dataset:
TMIC-50. IMPACT OF ZOTIRACICLIB ON GLIOMA TUMOR MICROENVIRONMENT
Authors: Lu Peng , Li Qi , Kim Olga , Sergi Zach , Gilbert Mark , Zhang Meili , Zhang Wei , Song Hua , Briceno Nicole , Davis Dionne , Wong Zalman , Castro Maria G , Wu Jing 
Published: November 2024

Abstract

BACKGROUND
Zotiraciclib, an orally administered multi-kinase inhibitor, has shown anti-glioma effect via suppression of transcriptional process and mitochondrial function. Here, we investigate the impact of zotiraciclib on the glioma immune microenvironment.

METHODS
Mouse glioma was generated by intracranial injection of mouse syngeneic cells (IDH1-wildtype NPA cells or IDH1R132H-mutant NPAI cells) in C57BL/6 mice. Zotiraciclib was administered (30 mg/kg, intraperitoneal injection, twice per week) starting seven days after tumor implantation. NPA and NPAI tumors were dissected after 10 and 22 days’ treatment, respectively. Immune cells in the tumor tissue were isolated and examined using flow cytometry. Primary human CD8+ cells and CD14+ monocytes isolated from the blood of a healthy donor were used to further investigate the effect of zotiraciclib (15 nM and 50 nM) on human cytotoxic T cell activation and immunosuppressive M2 macrophage polarization, respectively, using flow cytometry.

RESULTS
No significant difference in the abundance of T cells, myeloid cells, NK cells, NKT cells, DCs, and B cells between zotiraciclib-treated and vehicle-treated groups was detected in neither NPA nor NPAI tumors. The treatment-induced change in the abundance of cytotoxic T cells, helper T cells, macrophages, monocytes, neutrophils, M-MDSCs, PMN-MDSCs, Tregs, and M2 macrophages wasn’t observed. Zotiraciclib reduced the expansion of human CD8+ cytotoxic T cells, but did not affect the expression of CD25, HLA-DR, TNFα and IFNγ after activation in vitro. The viability of human M2 macrophages during differentiation and polarization was not affected, while the expression of CD163 and CD206 was reduced by zotiraciclib.

CONCLUSIONS
The immunophenotyping performed for this study demonstrates that zotiraciclib does not alter the mouse glioma immune microenvironment. Complementary studies using human immune cells shows that zotiraciclib does not suppress the activation of cytotoxic T cells but reduces the polarization of immunosuppressive M2 macrophages, supporting combining zotiraciclib and immune stimulatory approach in glioma treatment.
TMIC-55. CHARACTERIZATION OF THERAPEUTICS EFFECTS IN GLIOBLASTOMA THROUGH INTEGRATED SPATIAL SINGLE-CELL MULTIOME PROFILING OF LONGITUDINAL SAMPLES: UNVEILING CLINICALLY RELEVANT SUBTYPES OF PATHOLOGICAL CHANGES
Authors: Vanmechelen Maxime , Pouya Nazari , Beckervordersandforth Jan , Leunissen Daphne , Cole Basiel , Decraene Brecht , De Visser Yanti , Shankar Gautam , Verduin Maikel , Bravo Carmen , Moors Tom , Telang Jayesh , Messiaen Julie , Eekers Danielle , Claeys Annelies , Derweduwe Marleen , Zurhausen Axel , Bosisio Francesca , Weyns Frank , Daenekindt Thomas , Van Eyken Peter , Govers Mieke , Mennens Ferdinand , Hovinga Koos , De Vleeschouwer Steven , Paul Clement , Broen Martijn , Vooijs Marc , Sciot Raf , Antoranz Asier , Pey Jon , Speel Ernst Jan , Hoeben Ann , De Smet Frederik 
Published: November 2024

Abstract
Glioblastoma (GBM) remains a highly malignant, intrinsically resistant and inevitably recurring brain tumor with dismal prognosis. The aggressiveness and lack of effective GBM treatments can be attributed to the highly heterogeneous and plastic nature of GBM tumor cells, which easily confer resistance to standard-of-care (SOC) therapy. While tumor progression has also been attributed to interactions with the tumor microenvironment, quantitative data describing these interactions are still largely missing. Here, we used an multiome approach combining high-dimensional, multiplexed immunohistochemistry and spatial transcriptomics to map evolutions in the spatial, single-cell tissue architecture of 357 paired adult GBM tumor samples derived from 52 patients at diagnosis (ND) and upon recurrence (REC) following SOC treatment. We mapped the spatial distribution of a multitude of GBM tumoral subtypes across this multicentric cohort, through which we identified a high level of heterogeneity defined by specific tumoral niches within and across patients and which evolved when subjected to SOC therapy. In addition, we describe the relationship of the various tumoral niches with their local immune-infiltrates, highlighting an even more immunosuppressive environment following SOC resistance. Finally, by aligning these findings to the observed genomic aberrations and the clinical data of the patients, we are now able to more precisely describe the heterogeneous landscape of glioblastoma and how it evolves under SOC treatment at spatial, single-cell resolution.
TMIC-85. THE MECHANISM OF COMBINED HYDROGEN-CHEMICAL THERAPY BASED ON ACTIVE MAGNESIUM MICROMOTORS FOR INHIBITING GLIOBLASTOMA RECURRENCE BY MODULATING TUMOR MICROENVIRONMENT
Authors: Zhao Shiguang 
Published: November 2024

Abstract

OBJECTIVE
This study aims to develop an innovative therapeutic strategy to prevent postoperative recurrence of Glioblastoma (GBM), a condition with poor prognosis and high recurrence rates. The focus is on exploring the efficacy of synergistic hydrogen-chemical therapy in inhibiting GBM recurrence, especially by reducing surgery-induced inflammation and enhancing the sensitivity of GBM cells to chemotherapy.

METHODS
The study employed the fabrication of Mg-Motor-DOX using a biodegradable polylactic acid-glycolic acid copolymer (PLGA) and gelatin containing Doxorubicin (DOX). The reaction of Mg with water produces hydrogen (H2), which aids in scavenging reactive oxygen species (ROS) and inflammation, alongside the specific release of chemotherapy drugs at the tumor site. A thermosensitive hydrogel was developed for in situ delivery of Mg-Motor-DOX to the tumor residual cavity. Additionally, RNA sequencing was used to study the transcriptional changes in the GBM tumor microenvironment (TME) induced by this therapy.

RESULTS
The study presents initial evidence of the in vivo efficacy of synergistic hydrogen-chemical therapy against GBM. The Mg-Motor-DOX mediated therapy not only scavenged ROS and reduced inflammation but also specifically released chemotherapy drugs at the tumor site, enhancing their effectiveness. RNA-Seq technology elucidated the molecular mechanisms underlying the therapy’s efficacy, revealing significant transcriptional changes in the GBM TME.

CONCLUSION
Synergistic hydrogen-chemical therapy, facilitated by Mg-Motor-DOX, shows promising potential in preventing the postoperative recurrence of GBM. This innovative approach effectively combines anti-inflammatory benefits and enhanced chemosensitivity, offering new strategies for GBM treatment. The molecular insights provided by RNA-Seq technology contribute to a deeper understanding of tumor treatment mechanisms, paving the way for future clinical applications.
TMOD-03.BRAFV600E MUTATION INDUCES TWIST1 UPREGULATION ASSOCIATED WITH MIGRATION AND CEREBRAL FLUID DISSEMINATION IN GLIOBLASTOMA
Authors: Miyake Yohei , Furnari Frank 
Published: November 2024

Abstract

INTRODUCTION
BRAFV600E-mutant glioblastoma (GBM) with epithelioid features frequently show cerebrospinal fluid dissemination (CSFD), which results in poor prognoses. BRAF mutation is worth investigating since BRAF or downstream MEK inhibitors show dramatic response for BRAFV600E-mutant GBM including CSFD. This suggests BRAF mutation could play a role for inducing the clinical manifestation of CSFD found in newly diagnosed and recurrent BRAFV600E-mutant GBM. Because, BRAFV600E-mutant GBM often recur with CSFD, elucidating the mechanism by which BRAFV600E-mutant GBM exhibits CSFD is important to improve prognosis. (Objective) To elucidate the molecular mechanism of CSFD involved in BRAFV600E-mutant GBM.

METHODS
We introduced the heterozygous BRAFV600E mutation in human induced pluripotent stem cells (iPSC) in the context of GBM genetic alterations, CDKN2A/2B, and PTEN deletion, TERT promoter mutation and with EGFRvIII overexpression. We implanted these iPSC-derived neural progenitor cells into immunodeficient mouse brains to establish a BRAFV600E-mutant GBM model. At the same time, we created a model with the same genetic background without BRAFV600E. We compared their gene expression, pathology, and migration patterns to identify BRAFV600E specific characteristics.

RESULTS
RNA sequencing revealed BRAFV600E-mutant tumors upregulated migration, and downregulated cell-to-cell adhesion genes. TWIST1 was one of the most upregulated genes, and was validated by qPCR. Concomitant with TWIST1 expression we detected downregulation of E-cadherin. The BRAFV600E GBM model histologically showed a cluster-like invasion phenotype, while non-BRAF tumors showed homogenous invasion with typical GBM pathological findings. Immunohistochemical staining showed relatively high TWIST1 expression in cluster-like tumor cells of BRAFV600E tumors. Upon re-engraftment of primary tumor-derived cells, secondary BRAFV600E tumors presented leptomeningeal dissemination. TWIST1 knockdown resulted in a decrease in the migratory ability of our BRAFV600E model in vitro, and is under investigation in vivo.

CONCLUSION
BRAV600E mutation induces TWIST1 upregulation, and might facilitate migration and CSFD. This work nominates TWIST1 and its regulated genes as targets for BRAFV600E-mutant GBM with CSFD.
TMOD-08. DETAILED GENERATION OF AN ORTHOTOPIC INTRACRANIAL GLIOBLASTOMA (GBM) PATIENT-DERIVED XENOGRAFT (PDX) MODEL FOR PRECLINICAL IMMUNOTHERAPEUTIC STUDIES
Authors: Jung Tae-Young , Tran Thi-Anh-Thuy , Marcelina Correia Dircia Canisia , Kim Young-Hee , Park Sue-Jee , Kim Yeong Jin , Moon Kyung-Sub , Kim In-Young , Jung Shin , Lee Kyung-Hwa , Park Ae Kyung 
Published: November 2024

Abstract

PURPOSE
This study aimed to establish an orthotopic intracranial PDX mouse model using cryopreserved GBM tissues expanded in a heterotopic subcutaneous PDX model for immunotherapeutic studies. The model is designed to closely replicate human GBM, enabling the exploration of its pathophysiology and the development of effective immunotherapies for this type of cancer.

METHODS
Glioblastoma tissues from 16 fresh and cryopreserved samples were used to establish a heterotopic subcutaneous PDX mouse model for tumor expansion. Successful engraftments were then used to create an orthotopic intracranial PDX mouse model. The tumor formation rates and durations were estimated in both models. Tumor fidelity to the original GBM tumors was confirmed through immunohistology (GFAP, P53, and Ki67) and genetic analysis (whole exome sequencing, RNA sequencing, and methylome analysis). The therapeutic effects of immunotherapy (allogenic NK cells) in combination with Avastin and Irinotecan were tested in the orthotopic intracranial PDX model.

RESULTS
The orthotopic intracranial GBM mouse model achieved 100% engraftment from successful tumor growth in the subcutaneous PDX model. The overall success rate was 81.25% (85.71% for cryopreserved tissues), with a median process duration of 26.5 weeks (19 weeks for the subcutaneous and 7.5 weeks for intracranial establishment). No significant differences in tumor formation were observed within one year for cryopreserved tissue in the subcutaneous model. Molecular and genetic analysis confirmed similar tumor characteristics between the intracranial PDX tumors and the original patient tumors. Additionally, NK cells combined with Avastin and Irinotecan demonstrated efficacy in this model.

CONCLUSIONS
We successfully established an orthotopic intracranial PDX mouse model using cryopreserved GBM tissues, with no observed differences within one year. These models accurately mirror patients’ tumor characteristics, promising advancements in glioblastoma research and treatment, particularly for immunotherapy studies. Keywords: Glioblastoma (GBM), cryopreserved GBM tissues, patient-derived xenograft (PDX) model, NOD/SCID IL-12Rγnull (NSG) mice
TMOD-30. DISRUPTION OF NORMAL RADIAL GLIA DEVELOPMENT IN AN NF2-ALTERED NEUROEPITHELIAL STEM CELL MODEL
Authors: Burket Noah , Dershem Victoria , Dixon Shelley , Cooper Scott , Angus Steve , Clapp Wade , Tailor Jignesh 
Published: November 2024

Abstract
NF2-related schwannomatosis is a tumor predisposition syndrome caused by mutations in the NF2 gene and associated with spinal ependymomas (SP-EPN). SP-EPNs are suspected to originate from aberrations in the radial glia (RG) cell lineage. These tumors are only effectively treated through high-risk surgical resection, emphasizing the critical need for identification of targets for medical therapy. Yet, the role of NF2-dependent disruption in RG cell development is poorly understood. We hypothesize that this mutation may be halting normal RG cell differentiation, resulting in a RG-like stem cell that is driving SP-EPN formation. An NF2-knockout was generated in neuroepithelial stem (NES) cells using CRISPR/Cas9. Knockouts were validated using Western blot and Sanger sequencing. In vitro differentiation was induced with removal of growth factors. NF2-knockout phenotypes were assessed with real-time polymerase chain reaction and compared with wildtype NES cells. Preliminary data has shown that NF2-knockout cells express similar levels of early pan-neural and neural stem cell genes compared to wildtype after CRISPR editing. The NF2-knockout cells retain this stem cell-like gene expression following attempted differentiation, whereas wildtype cells take on a primarily neural phenotype. The knockout cells also form what appears to be pre-neoplastic spheres when allowed to differentiate. NF2-knockout NES cells fail to differentiate normally compared to wildtype NES cells. They retain early RG-like markers, including SOX2, BLBP, and GFAP. Furthermore, formation of spheres when growth factors were removed hints at NF2 loss being relevant to formation of pre-neoplastic growths. Future work will include investigating downstream effects of NF2 loss in this model.
Mimicking osteoid 3D porous dense microfiber silk fibroin embedded poly(vinyl alcohol) scaffold for alveolar ridge preservation
Authors: Sangkert Supaporn , Kannan Perumal Ramesh , Meesane Jirut , Santavalimp Kanokporn , Phongthanawarakun Jutharat , Promkaew Walaiporn , Anupan Wachiratan , Thuaksuban Nuttawut 
Published: November 2024

Abstract
Alveolar ridge loss presents difficulties for implant placement and stability. To address this, alveolar ridge preservation (ARP) is required to maintain bone and avoid the need for ridge augmentation using socket grafting. In this study, a scaffold for ARP was created by fabricating a 3D porous dense microfiber silk fibroin (mSF) embedded in poly(vinyl alcohol) (PVA), which mimics the osteoid template. The research utilized a freeze–thawing technique to create a mimicked osteoid 3D porous scaffold by incorporating different amounts of mSF into the PVA, namely, 1%, 3%, 5% and 7%. Subsequently, a 3D profilometer machine and a scanning electron microscope were employed to examine the morphology and size of the mSF and the mimicked osteoid 3D porous scaffold in all groups. Thermal characteristics and crystalline structure were analyzed before assessing the water contact angle, swelling behavior, degradation and mechanical properties. The experiment evaluated the biological performance of the mimicked osteoid 3D porous scaffold by examining the efficacy of osteoblast cell adhesion, proliferation, viability, protein synthesis, alkaline phosphatase (ALP) activity and calcium synthesis. Finally, the ability of osteoblast cells to regulate the osteoid matrix deposition on the osteoid 3D porous scaffold was assessed by mimicking the dynamic bone environment using rat mesenchymal stem cells. The findings suggest that incorporating mSF into PVA enhances the interconnective pore size, crystalline structure and thermal behavior of the mimicked osteoid 3D porous scaffold. The hydrophilicity of PVA decreased with an increase in the proportion of mSF, while a higher proportion of mSF resulted in increased swelling and mechanical characteristics. Incorporating a greater proportion of mSF, specifically 5% and 7%, led to a reduced rate of degradation. The addition of 5% mSF to the PVA 3D porous scaffold resulted in remarkable biological properties and excellent osteoconductive activity.
The Impact of Complication Timing on the Outcomes of Implant-based Breast Reconstruction
Authors: Alnaseri Tahera , Prabhu Shamit , Anderson Lexy , Kwan Lorna , Demirjian Maral , Kwok Alvin , Reid Christopher , Hollenbeck Scott , DeLong Michael R. 
Published: November 2024

Background:
The National Surgical Quality Improvement Program (NSQIP) database provides an important resource for determining complication rates and risk factors for surgical procedures. However, NSQIP is limited to 30-day follow-up, and it is unclear whether this is reliable for evaluating prosthetic breast reconstruction outcomes.

Methods:
A single-institution, cross-sectional, retrospective review was performed for patients undergoing mastectomy with immediate, prepectoral tissue expander reconstruction. Timing of complications was stratified as early (within 30 days of operation) versus late (after 30 days). Categorical variables were compared using χ2 (or Fisher exact) tests, and continuous variables were analyzed using Kruskal-Wallis or Wilcoxon rank-sum tests.

Results:
There were 301 patients (509 reconstructed breasts) included with a median follow-up time of 11 months. Of them, 176 patients (58%) experienced a postoperative complication—140 patients (47%) experienced an early complication and 36 patients (12%) experienced a late complication. Patients with late complications had a significantly higher rate of reconstructive failure compared with the early complication group (17% versus 10%; P = 0.001) and were more likely to require a flap (28% versus 7%; P = 0.001) for final reconstruction. Revision surgery rates after final implant placement were higher in the late complication group (36% versus 64%; P = 0.285).

Conclusions:
Late complications after prepectoral breast reconstruction have a more prominent impact on reconstructive failure and revisions than early complications. This finding may inform strategies to revise national databases such as NSQIP to include more detailed information and longer capture periods.
Case report: Peritonitis caused by Pantoea agglomerans from pet dog exposure in peritoneal dialysis
Authors: Kim Ji Yeon , Cho Nam-Jun , Park Samel , Gil Hyo-Wook , Lee Eun Young 
Published: November 2024

Rationale:
Peritonitis caused by Pantoea agglomerans is a rare occurrence in patients undergoing peritoneal dialysis. Cases potentially linked to pet dogs are even rarer, and there is limited literature available.

Patient concerns:
A patient undergoing peritoneal dialysis presented with symptoms of peritonitis, including abdominal pain and cloudy dialysis fluid.

Diagnoses:
Microbiological analysis identified P agglomerans as the causative organism.

Interventions:
The patient was treated with targeted antibiotic therapy and showed a positive response.

Outcomes:
During a subsequent medical interview, it was revealed that the patient had close contact with their pet dog, raising the possibility that the infection may have been associated with this exposure.

Lessons:
This case highlights the importance of considering zoonotic transmission as a potential source of infection in peritoneal dialysis patients, particularly when there is close contact with pets. Healthcare providers should educate patients about the potential risks posed by pets and implement preventive strategies to mitigate such risks.
Efficacy of four internal fixation devices on femoral neck fractures in young adults: A systematic review and network meta-analysis
Authors: Yuan Daotong , Zhang Zhimeng , Wang Xu , Chang Wenjie , Xie Wenpeng , Zhang Yongkui 
Published: November 2024

Background:
The primary treatment of femoral neck fracture in young adults is internal fixation. The high complication rate after femoral neck fracture greatly affects the life of patients. There are many internal fixation devices for femoral neck fracture, but each has its advantages and disadvantages. Our aim was to determine the best internal fixation for young people with femoral neck fractures.

Methods:
We searched 5 databases from January, 2016 to December, 2023. Randomized controlled trials and cohort studies that met the inclusion criteria were assessed for quality using the RoB.2 and ROBINS-I scales, respectively. The network meta-analysis was conducted within a Bayesian framework utilizing a random effect model. Data analysis was performed using the “multinma” package within the R 4.2.0 software.

Results:
A network meta-analysis of 34 studies involving 2291 patients was conducted. Results indicated that the inverted triangular cannulated screws demonstrated the lowest intraoperative bleeding volume (surface under the cumulative ranking curve [SUCRA] = 0.8732) based on the SUCRA. The medial buttress plate (MBP) exhibited superior efficacy in improving the Harris hip score (SUCRA = 0.8465), reducing complications (SUCRA = 0.9251), and accelerating fracture healing time (SUCRA = 0.8111). Additionally, the femoral neck system was ranked highest in terms of operation time (SUCRA = 0.7749) and femoral neck shortening (SUCRA = 0.7933).

Conclusion:
This network meta-analysis findings indicated that MBP resulted in superior postoperative hip function, reduced complication rate, faster fracture healing time. Considering the good physical condition of young adults, surgeon may consider utilizing MBP to achieve improved postoperative outcomes.
Fuzheng–Buyi formula for treating castration-resistant prostate cancer: A systematic review and meta-analysis
Authors: Liang Xiao , Peng Shirong , Huang Hai , Xu Jia , Liu Wenjuan , Wang Hailong , Li Qi 
Published: November 2024

Background:
The study was designed to systematically evaluate the efficacy and safety of Fuzheng–Buyi formula in treating castration-resistant prostate cancer (CRPC).

Methods:
A computer-based search were conducted in the databases, including CNKI, WanFang Data, VIP, CBM, PubMed, EMbase, and the Cochrane database to identify all randomized controlled trials. The studies investigating the efficacy and safety of Fuzheng–Buyi formula combined with Western medicine for the treatment of CRPC were included from January 1st, 2010 to December 31st, 2023. The quality of the included studies was evaluated according to the Cochrane Handbook manual, and meta-analysis was performed using Review Manager 5.3 and R Studio 4.2.3 software.

Results:
In this study, a total of 18 trials were included, encompassing a population of 1093 patients diagnosed with CRPC. The results of the meta-analysis showed that the combination of Fuzheng–Buyi formula and Western drugs was more effective in increasing the overall efficacy rate (risk ratio = 1.31, 95% confidence interval [CI] [1.17, 1.46], P < .00001), decreasing Traditional Chinese Medicine syndrome score (mean difference [MD] = −4.40, 95% CI [−6.10, −2.70], P < .00001), and quality of life scale (physiological condition MD = −2.31, 95% CI [−3.13, −1.48], P < .00001; social well-being MD = 1.26, 95% CI [0. 59, 1.94], P = .0002; emotional well-being MD = −2.04, 95% CI [−2.96, −1.12], P < .00001; functional well-being MD = −3.18, 95% CI [2.11, 4.26], P < .00001; others should be paid to MD = −3.15, 95% CI [−4.93, −1.37], P = .0005) compared with the Western medicine alone. And the incidence of adverse events was significantly lower in the combination treatment group compared with Western medicine group (risk ratio = 0.58, 95% CI [0.46, 0.73], P < .00001).

Conclusion:
The combination of Fuzheng–Buyi formula and Western medicine was more effective in improving the clinical efficacy and quality of life of CRPC patients, with lower incidence of adverse events compared with Western medicine alone.