bluuebunny/crossref_metadata_2025_split huggingface dataset:
TMOD-15. TOWARD BRAIN CANCER ORGANOID-INFORMED PRECISION MEDICINE FOR GLIOBLASTOMA
Authors: Storey Claire , Gately Lucy , Drummond Kate , Gogos Andrew , Mouradov Dmitri , Christie Michael , Brasier Helen , Priest Emma , Fakhri Alana , Gibbs Peter , Sieber Oliver 
Published: November 2024

Abstract

BACKGROUND
Improved preclinical models for glioblastoma are urgently needed to enhance the translation of research to clinical applications. Patient-Derived Tumor Organoids (PDTOs) offer a promising model that can be generated quickly. Here we explored their feasibility.

METHODS
Primary (n=16) and recurrent (n=2) PDTOs were established using the method described in Jacob et al. Cell. 2020 by dissecting tumours into small fragments, preserving their cytoarchitecture. Histological features of the parent tumour were compared to the matched PDTOs by a neuropathologist. To assess the molecular fidelity, comprehensive whole genome sequencing compared matched tumor tissue, PDTOs, and corresponding normal blood samples (n=11), along with RNA sequencing of matched tumor tissue and PDTOs (n=10). We assessed PDTO responses to regorafenib (n=18) and conventional TMZ (n=9), lomustine (n=9) and 10 Gy of ionizing radiation (IR) (n=6) using the automated imaging system IncuCyte S3® to evaluate whole spheroid brightfield and invasion areas following drug/IR treatment and assess viability.

RESULTS
We achieved a 100% establishment rate of primary GBMs using same-day procedures and an 80% rate if held under 3 days. Histological features were retained in the PDTO. Molecular overlap was greater than 90%, along with a high concordance in gene expression. PDTOs exhibited notable resistance to temozolomide and lomustine, however, showed a very modest response to IR and a moderate response to regorafenib. IncuCyte S3® analysis revealed discernible changes in whole spheroid brightfield and invasion area for regorafenib-treated PDTOs. Clinically relevant concentrations of regorafenib reduced GBM cell proliferation (Ki67 staining). Beyond this concentration, regorafenib exhibited efficacy in eliminating GBM cells.

CONCLUSION
PDTOs recapitulate the molecular and histological features of the original tumor and may enable the prediction of individual patient responses to therapies and guide more effective treatment selection. We are now applying our established methodology to assess a new set of promising drug candidates.
TMOD-24. DEVELOPMENT OF A 3D ORGANOTYPIC EXPLANT PLATFORM TO STUDY ONCOLYTIC VIRUS TREATMENT RESPONSE IN GLIOBLASTOMA
Authors: Abou-Mrad Zaki , Yu Kenny , Tabar Viviane 
Published: November 2024

Abstract

BACKGROUND
Oncolytic viruses (OVs) are a promising strategy to induce an anti-tumor immune response in the lymphocyte-depleted environment of glioblastoma (GBM), however the mechanism of their oncolytic function is not well understood. Immune-intact experimental systems would be highly valuable in dissecting immune versus direct viral contribution to oncolysis. Here, we report on the development of an immune-intact organotypic explant (OE) model, amenable to perturbations and T-cell activity monitoring.

METHODS
OEs were made from fresh tumor samples and cultured in groups of 4-5. CAN-3310 OVs and T-cells were injected into each OE under a dissecting microscope. Cultured OEs were either fixed for immunofluorescence (IF) or dissociated into single-cell suspensions for flow cytometry and 5’ single-cell RNA (scRNA) and TCR sequencing.

RESULTS
Cultured OEs maintain the cellular density of the original tumor in both short- and long-term cultures. Ki67 IF shows that tumor cells retain their proliferative potential, allowing for renewal and repopulation. The TME, mainly microglia and macrophages, is maintained throughout culture. IF imaging of OV-treated OEs, 7 days post-treatment, shows significant GFP positivity in tumor cells demonstrating the feasibility of using OEs as an ex vivo model with OV. Additionally, autologous T-cells from the patient’s blood can survive in OEs, completing the TME with the equivalent of circulating T-cells. Finally, scRNA-seq of the original tumor and cultured OEs showed that the different cell types were represented at all time points. Tumor cell meta-module analysis showed an increase in hypoxic signatures recapitulating features of in vivo tumor cell growth.

CONCLUSIONS
OEs maintain tumor architecture and TME. OE co-culture with autologous T-cells allows us to better understand the oncolytic mechanisms of OVs. Future endeavors will include identifying expanded T-cell clones to create an OV-specific TCR repertoire. This OE system provides a new tool as an ex vivo platform to dissect glioma responses to therapy in a purely human system.
TMOD-26. GENERATION OF A CHROMOSOME 8 GAIN;NF1-/- HIPSC-DERIVED SCHWANN CELL PRECURSOR MODEL
Authors: Oztosun Gorkem , Acar Simge , Bhatia Himanshi , Neilson Amber , Cui Xiaoxia , Hirbe Angela 
Published: November 2024

Abstract
Neurofibromatosis type 1 (NF1) is an autosomal dominant cancer predisposition syndrome caused by a germline mutation in the NF1 gene. The loss of the second copy of NF1 within Schwann cell precursors (SCPs) contributes to the formation of plexiform neurofibromas (PNs) found in 30-50% of NF1 patients. PNs can progress into malignant peripheral sheath tumors (MPNSTs), an aggressive form of cancer and a leading cause of mortality in NF1 patients. Our lab previously demonstrated frequent chromosome 8 (Chr8) gain in NF1-MPNST patient-derived xenografts (PDX) and patient tumors. To investigate Chr8 gain’s role, we created isogenic NF1-/- iPSC cell lines with and without Chr8 gain. Trisomy 8 fibroblasts were obtained and single-cell cloned to establish wildtype (WT) and Chr8 gain populations. Washington University’s Genome Engineering & Stem Cell Center (GESC@MGI) reprogrammed these cells into human induced pluripotent stem cells (hiPSCs). Using synthetic gRNA and CRISPR/Cas9, NF1 knockout lines were generated. Four iPSC cell lines were differentiated into SCPs, and cell survival and proliferation were assessed using Incucyte cell survival and CellTiter-Glo® Assay. Fluorescence in situ hybridization (FISH) and karyotyping validated the human iPSCs. qPCR revealed high expression of iPSC markers OCT3/4 and SOX2 in all iPSC lines. After differentiation, SCP markers (GAP43 and ITGA4) were upregulated in WT, NF1-/-, and Chr8 gain;NF1-/- SCP lines, demonstrating successful differentiation. Furthermore, Chr8 gain; NF1-/- SCPs displayed enhanced proliferation and increased cell survival compared to WT and NF1-/- SCPs, suggesting improved characteristics in the presence of Chr8 gain. In summary, our research provides insights into Chr8 gain and NF1 loss effects on SCP differentiation, proliferation, and survival. Understanding these molecular mechanisms may contribute to developing targeted therapies for NF1.
TMOD-29. BETA INTEGRINS REGULATE MITOCHONDRIALLY-MEDIATED CELL MIGRATION IN H3K27M-DIFFUSE MIDLINE GLIOMA
Authors: Cartaxo Rodrigo , Nieblas-Bedolla Edwin , Niculcea Michael , Natarajan Siva , Adam Tiffany , Clausen Madison , Miclea Madeline , Siada Ruby , Schwark Kallen , Ji Sunjong , Gera Ananya , Doherty Robert , Galban Stefanie , Nuechterlein Nicholas , Filbin Mariella , Venneti Sriram , Hara Toshiro , Koschmann Carl 
Published: November 2024

Abstract
Infiltration into the brain tissue is one of the main features of diffuse midline gliomas (DMG), also characterized by the histone mutation H3K27M and overall survival of 12-15 months from diagnosis. To study which genes are critical for H3K27M-DMG tumor cell migration in the brain, we established a novel two-step pooled whole genome CRISPR-Migration screen of metastatic H3K27M-DMG (n=3) and glioblastoma (GBM, n=2) stem cells by using serum-free conditions and laminin-dependent cell attachment, mimicking cell migration on brain vasculature scaffolds. Genes involved in focal adhesion (ITGB1, CRKL, PARVA, PTK2, FERMT2) were identified as significantly restricting migration in all H3K27M-DMG lines. From those, only knockout of ITGB1 (ITGB1-KO) fully ablated in vitro migration in all models. In human tumor RNAseq, expression of ITGB1 correlated with higher glioma grade and worse survival specifically in H3K27M-DMG across pediatric brain tumors. In H3K27M-DMG scRNAseq, increased ITGB1 expression was found in cells with OPC-like/Mesenchymal cell signature associated with leading edge and microvasculature. Unexpectedly, ITGB1-KO led to the decreased expression of multiple mitochondrial NADH dehydrogenase genes, and reduced levels of glycolysis and oxidative phosphorylation (OXPHOS) activity. Preliminary mechanistic data linked this phenotype to increased mitochondrial fusion. Genetic (ITGB1-KO) and pharmacologic (anti-ITGB1 antibody AIIB2, CNS delivered) targeting of ITGB1 in a novel orthotopic model of metastatic H3K27M-DMG (UMPED83) led to reduced proliferation and significant extension of survival (p=0.0003 ITGB1-KO, and p=0.0006 AIIB2). Interestingly, ITGB1-KO in another orthotopic H3K27M-DMG model (SVZ) led to upregulation of other integrins (ITGB3 and ITGB5) without change in survival, resulting in susceptibility to treatment with the ITGB3/5 inhibitor Cilengitide (p=0.006). Treatment with AIIB2 and Cilengitide alone or in combination was ineffective in an H3WT adult GBM orthotopic model suggesting unique H3K27M-DMG targetability. In summary, targeting of integrin pathways offers untapped therapeutic opportunities in H3K27M-DMG by impairing tumor cell survival through altered mitochondrial dynamics.
TMOD-32. MURINE MODELLING OF THE STING PATHWAY IN GLIOMAS
Authors: Low Justin , Lang Patrick , Bowie Michelle , Baker Eric , Wertman Virginia , Fuller Rebecca , Gibson Emiley , Ashley David 
Published: November 2024

Abstract
The stimulator of interferon genes (STING) pathway is a critical component of innate antitumor immunity through the recognition of pathogenic cytosolic DNA and stimulating the production of type 1 interferons and pro-inflammatory cytokines. We have previously shown that STING signaling is silenced in the neoplastic compartment of the GBM tumor microenvironment, but remains intact in vascular and immune cells. In human patient derived cell lines, such silencing appears to be mediated by hypermethylation of a region of the STING promoter and can be reversed by treatment with both the DNA methyltransferase (DNMT) inhibitor Decitabine and DNMT1-selective inhibitor GSK-3685032. These results suggest that neoplastic cell STING promoter methylation represents a therapeutic vulnerability that can be exploited by epigenetic therapies to inflame the glioma tumor microenvironment. Murine models are critical tools for exploring the translational implications of STING silencing in vivo. Distinct mouse models have been developed to optimally represent specific aspects of human glioma biology. Here we characterize the STING pathway in commonly used syngeneic murine glioma models, including CT2A, GL261, SB28, and SMA560. We show that the expression of STING pathway components varies significantly across these lines. Importantly, unlike in humans, murine STING (mSTING) expression is not suppressed by promoter methylation and does not respond to decitabine treatment. Additionally, the mSTING protein is expressed in neoplastic cells in vivo. These results demonstrate a fundamental difference in epigenetic regulation of STING between human and murine glioma cells, and suggest that murine modeling of STING epigenetics requires the use of patient derived cell lines implanted in immunodeficient mice. Meanwhile, immune competent syngeneic models are appropriate for exploring the tumor immune microenvironment but would require non-epigenetic approaches (e.g. genetic knock-outs/knock-ins) for modulating STING expression. Humanized mice represent a promising emerging approach for faithfully recapitulating both epigenetic control and immune environment of human gliomas.
Evolution of NAC transcription factors from early land plants to domesticated crops
Authors: Kim Taehoon , Alvarez Javier C , Rana Divya , Preciado Jesus , Liu Tie , Begcy Kevin 
Published: November 2024

Abstract
NAC [NO APICAL MERISTEM (NAM), ARABIDOPSIS TRANSCRIPTION ACTIVATOR FACTOR 1/2 (ATAF1/2), and CUP-SHAPED COTYLEDON (CUC2)] transcription factors are key regulators of plant growth, development, and stress responses but were also crucial players during land plant adaptation and crop domestication. Using representative members of green algae, bryophytes, lycophytes, gymnosperms, and angiosperms, we expanded the evolutionary history of NAC transcription factors to unveil the relationships among members of this gene family. We found a massive increase in the number of NAC transcription factors from green algae to lycophytes and an even larger increase in flowering plants. Many of the NAC clades arose later during evolution since we found eudicot- and monocot-specific clades. Cis-elements analysis in NAC promoters showed the presence of abiotic and biotic stress as well as hormonal response elements, which indicate the ancestral function of NAC transcription factor genes in response to environmental stimuli and in plant development. At the transcriptional level, the expression of NAC transcription factors was low or absent in male reproduction, particularly mature pollen, across the plant kingdom. We also identified NAC genes with conserved expression patterns in response to heat stress in Marchantia polymorpha and Oryza sativa. Our study provides further evidence that transcriptional mechanisms associated with stress responses and development emerged early during plant land adaptation and are still conserved in flowering plants and domesticated crops.
Getting lucid about lucid dreaming
Authors: Cowan Robert 
Published: November 2024

Abstract
Lucid dreams are a distinctive and intriguing phenomenon where subjects apparently possess, inter alia, conscious knowledge that they are dreaming while they are dreaming. I here develop and defend a new model of lucid dreaming, what I call the ‘Dyadic Model’, according to which lucid dreams involve the tokening of both dreaming and non-dreaming states. The model is developed to successfully defend the Imagination Theory of dreams, according to which to dream is to imagine, against the underexplored objection that it cannot account for lucid dreams. Moreover, as I explain, a range of theories of dreaming have reason to adopt the Dyadic Model, and it has further potential applications, including to false awakening and emotional responses to dreams. Hence, getting lucid about lucid dreaming reveals general insights for dream theorizing.
Clinical Comparison of Endoscopic Posterior Lumbar Interbody Fusion and Open Posterior Lumbar Interbody Fusion for Treating Lumbar Spondylolisthesis
Authors: Yang Lihui , Du Peng , Zang Lei , An Likun , Liu Wei , Li Jian , Diao Wenbo , Gao Jian , Yan Ming , Zhu Wenyi , Yuan Shuo , Fan Ning 
Published: November 2024

Study Design:
A retrospective case-control study.

Objective:
To compare the clinical efficacy of endoscopic (Endo) and open posterior lumbar interbody fusion (PLIF) in treating lumbar spondylolisthesis.

Background:
Endo-PLIF has emerged as a new technique for treating lumbar spondylolisthesis. We propose Endo-PLIF as an alternative method.

Materials and Methods:
Sixty-four patients with single-segment lumbar spondylolisthesis underwent Endo-PLIF (n = 39) or open PLIF (n = 25) treatment. Demographic data, perioperative parameters, and radiographic parameters were recorded. Clinical results were evaluated by Visual Analog Scale (VAS) and Oswestry Disability Index (ODI) scores. The fusion rate was evaluated by computed tomography at 12 months postoperatively. In addition, a case-control process was included to ensure unbiased comparisons.

Results:
The average operation time was longer in the Endo-PLIF group. Endo-PLIF showed advantages in reducing blood loss, shortening hospital stay, and early ambulation, but with a longer x-ray exposure time. Both VAS and ODI scores significantly improved in both groups, but the VAS for back pain was lower in the Endo-PLIF group. The radiographic results were similar in both groups. Three patients in the Endo-PLIF group had minor complications. Two patients in the open PLIF group experienced cerebrospinal fluid leakage. Both VAS and ODI scores significantly improved in both groups compared with preoperative scores, but the Endo-PLIF group showed more significant improvement at early follow-up (P < 0.05). There was no significant difference in interbody fusion rate between the two groups.

Conclusion:
Both Endo-PLIF and open PLIF are effective for treating single-segment lumbar spondylolisthesis. Endo-PLIF shows advantages in reducing blood loss, shortening hospital stays, and promoting early ambulation, with comparable fusion rates and patient satisfaction to open PLIF. Despite minor complications in the Endo-PLIF group and cerebrospinal fluid leakage in the open PLIF group, both procedures lead to significant improvements in pain and disability scores, with Endo-PLIF demonstrating more significant early improvements.
Recent advances in immunotherapy for small cell lung cancer
Authors: Ren Ziyuan , Shang Shijie , Chen Dawei 
Published: November 2024

Purpose of review
This review aims to provide an overview of recent advances in immunotherapy for small cell lung cancer (SCLC), with a focus on the current status of immune checkpoint inhibitors (ICIs), novel combination strategies, and key biomarkers.

Recent findings
The integration of ICIs into standard chemotherapy has established them as the first-line treatment for extensive-stage SCLC (ES-SCLC). The ADRIATIC trial further demonstrated the efficacy of ICI maintenance therapy in limited-stage SCLC. Additionally, combining radiotherapy with ICIs has shown promising synergistic effects, including the abscopal and radscopal effects. Ongoing investigations into the combination of ICIs with targeted therapies, such as antiangiogenic agents and DNA damage response inhibitors, have yielded encouraging preliminary results. Notably, the novel therapeutic agent tarlatamab, the first bispecific DLL3-directed CD3 T-cell engager, has recently received FDA approval for second-line treatment of ES-SCLC. Advances in omics technologies have shed light on the intra-tumor and inter-tumor heterogeneity of SCLC, leading to the identification of new molecular subtypes and biomarkers, thereby paving the way for precision medicine.

Summary
Despite the improved outcomes associated with immunotherapy in SCLC, the overall clinical benefit remains modest. Further preclinical and clinical studies are essential to identify optimal treatment regimens and enhance therapeutic efficacy.
Meteorological factors, population immunity, and COVID-19 incidence: A global multi-city analysis
Authors: Feurer Denise , Riffe Tim , Kniffka Maxi Stella , Acosta Enrique , Armstrong Ben , Mistry Malcolm , Lowe Rachel , Royé Dominic , Hashizume Masahiro , Madaniyazi Lina , Ng Chris Fook Sheng , Tobias Aurelio , Íñiguez Carmen , Vicedo-Cabrera Ana Maria , Ragettli Martina S. , Lavigne Eric , Correa Patricia Matus , Ortega Nicolás Valdés , Kyselý Jan , Urban Aleš , Orru Hans , Indermitte Ene , Maasikmets Marek , Dallavalle Marco , Schneider Alexandra , Honda Yasushi , Alahmad Barrak , Zanobetti Antonella , Schwartz Joel , Carrasco Gabriel , Holobâca Iulian Horia , Kim Ho , Lee Whanhee , Bell Michelle L. , Scovronick Noah , Acquaotta Fiorella , Coélho Micheline de Sousa Zanotti Stagliorio , Diaz Magali Hurtado , Arellano Eunice Elizabeth Félix , Michelozzi Paola , Stafoggia Massimo , de’Donato Francesca , Rao Shilpa , Di Ruscio Francesco , Seposo Xerxes , Guo Yuming , Tong Shilu , Masselot Pierre , Gasparrini Antonio , Sera Francesco 
Published: November 2024

Objectives:
While COVID-19 continues to challenge the world, meteorological variables are thought to impact COVID-19 transmission. Previous studies showed evidence of negative associations between high temperature and absolute humidity on COVID-19 transmission. Our research aims to fill the knowledge gap on the modifying effect of vaccination rates and strains on the weather-COVID-19 association.

Methods:
Our study included COVID-19 data from 439 cities in 22 countries spanning 3 February 2020 – 31 August 2022 and meteorological variables (temperature, relative humidity, absolute humidity, solar radiation, and precipitation). We used a two-stage time-series design to assess the association between meteorological factors and COVID-19 incidence. For the exposure modeling, we used distributed lag nonlinear models with a lag of up to 14 days. Finally, we pooled the estimates using a random effect meta-analytic model and tested vaccination rates and dominant strains as possible effect modifiers.

Results:
Our results showed an association between temperature and absolute humidity on COVID-19 transmission. At 5 °C, the relative risk of COVID-19 incidence is 1.22-fold higher compared to a reference level at 17 °C. Correlated with temperature, we observed an inverse association for absolute humidity. We observed a tendency of increased risk on days without precipitation, but no association for relative humidity and solar radiation. No interaction between vaccination rates or strains on the weather-COVID-19 association was observed.

Conclusions:
This study strengthens previous evidence of a relationship of temperature and absolute humidity with COVID-19 incidence. Furthermore, no evidence was found that vaccinations and strains significantly modify the relationship between environmental factors and COVID-19 transmission.
The concomitant of non-classical stereotactic body radiotherapy with tislelizumab based on multidisciplinary modalities for leiomyosarcoma: A case report
Authors: Han Xiaona , Zhang Xiaotao , Lin Yaru , Li Jinying , Yu Lan , Liu Li , Tong Wenzhi , Cheng Xi , Li Xiao , Liu Yanhao 
Published: November 2024

Background:
Stereotactic body radiotherapy (SBRT) and immune checkpoint inhibitors (ICIs) could obtain a certain synergistic effect on bone and soft tissue sarcoma (BSTS). Given its low radiosensitivity, BSTS usually require an irradiation dose >65 Gy to achieve local control. Herein, we developed a non-classical SBRT technique called “onion-shaped simultaneous boost (OSB),” and reported a patient with prostatic leiomyosarcoma which received non-classical SBRT and other systemic treatments.

Methods:
In the case, a 49-year-old male patient was diagnosed with prostatic leiomyosarcoma in November 2018. In the radiotherapy plans, the maximum doses of the targets were more than 65 Gy, while the doses of the organs at risk (OARs) were strictly limited.

Results:
After receiving radiotherapy, ICI, and other multidisciplinary modalities, the patient achieved partial response (PR).

Conclusion:
In this clinical case, we have observed that the OSB technique, which employs an increased per-fraction radiotherapy dose without the need to match the single-fraction doses typical of conventional SBRT, effectively enhances the therapeutic impact on leiomyosarcoma without an increase in radiotherapy-related side effects. By integrating the OSB technique with a multidisciplinary array of antineoplastic strategies, we can more effectively manage sarcomas in clinical practice.