bluuebunny/crossref_metadata_2025_split huggingface dataset:
MODL-15. ESTABLISHMENT OF ORGANOID MODELS OF PATIENT-DERIVED GH-PRODUCING PITUITARY ADENOMA
Authors: Maeda Sachi , Ohka Fumiharu , Kanamori Fumiaki , Okumura Yuka , Takeuchi Kazuhito , Nagata Yuichi , Motomura Kazuya , Yamaguchi Junya , Kibe Yuji , Harada Hideyuki , Shimizu Hiroki , Takido Yuhei , Saito Ryuta 
Published: November 2023

Abstract

BACKGROUND
Growth hormone-producing pituitary adenomas (GHomas) reveal unfavorable clinical course due to systemic complications such as excessive sweating, impaired glucose tolerance, and hypertension, in addition to its characteristic facial appearance. For GHoma, pharmacological treatments including somatostatin analogs and dopamine agonists are widely performed, however, a subset of case reveals dismal prognosis. We need to elucidate molecular mechanisms contributing to GHoma growth, however, experimental models of GHoma such as cell line and animal model are quietly limited.

OBJECTIVE
In recent years, organoid models using 3D-culture technologies have gained attention as useful research models for various types of cancers. This study aims to establish a novel organoid model derived from GHoma patients. Using established GHoma organoid model, we analyzed their histological characteristics.

METHODS
Surgical specimens from five cases of GHoma were finely dissected to approximately 1mm and embedded in Matrigel basement membrane matrix. The specimens were then cultured under 37°C conditions in a 5% CO2 incubator using a medium supplemented with various growth factors. After 28 days of culture, formalin-fixed paraffin-embedded sections were prepared, and the histological similarity with patient tumors was examined.

RESULTS
Hematoxylin and eosin staining showed that organoid models consisted of acidophilic, granular cytoplasm and small round nuclei, maintaining a cell morphology similar with the original tumor. Immunohistochemical staining revealed positive expression of growth hormone, Pit-1, and CAM5.2, which are specific markers for GHoma.

CONCLUSIONS
We successfully established a patient-derived organoid model of GHoma that retains histological and endocrinological characteristics. We believe that this model could be a valuable research model for elucidating the molecular mechanisms of GHoma and developing novel treatment approaches targeting important molecular abnormalities. Additionally, in clinical settings, this model might be useful for predicting the responsiveness to drug treatment and selecting appropriate therapies for individual patients.
MODL-22. DEVELOPMENT OF A PATIENT-DERIVED MODEL BIOBANK TO PROVIDE AN ACCURATE TOOL DECIPHERING BRAIN TUMOR INITIATION, PROGRESSION, AND THERAPEUTIC RESISTANCE
Authors: Deschuyter Marlène , Wolf Thibaut , Lhermitte Benoit , Reita Damien , Fuchs Quentin , Pierrevelcin Marina , Foppolo Sophie , Dontenwill Monique , Entz-Werlé Natacha 
Published: November 2023

Abstract
Brain cancers are the most incident and deadliest tumor types in pediatric and young adult populations. Among them, several histotypes are characterized by their molecular drivers and co-alterations currently guiding our therapeutic strategies. Due to inter- and intra-tumoral heterogeneity, those tumors are becoming rapidly chemo- and radioresistant. To encompass all their intrinsic and extrinsic mechanisms of therapeutic resistances, there is an urgent need to generate accurate brain tumors’ modeling to predict therapeutic responses. Patient-derived cell lines (PDCL) remain for now the most reliable model to estimate and mimic evolutive situation. Main difficulties rely on the derivation methods themselves (2D vs. 3D, in vitro vs. in vivo), but also on the methods to validate their molecular similarities comparatively to the primary tumors. Here we collected, through the PEDIAMODECAN program, 104 fresh brain tumors (e.g., 23 pilocytic astrocytomas (PA), 3 low-grade gliomas (LGG), 13 supra-tentorial high-grade gliomas and 10 DIPG/DMGs, 19 ependymomas, 19 medulloblastomas, 17 other rare entities) to generate PDCL and patient-derived xenografts (PDX). Using Next-Generation Sequencing (NGS), methylome assay and RNA sequencing, we were in capacity to underline similarities with initiated samples. Looking to derivation itself, we successfully maintained 80% samples in 2D cultures and 54% were derived in PDX. As expected, the PA/LGG group shows the higher percentage of failure of PDX generation (90%) and all established PA/LGG PDCLs were limited to a low number of passages. Nevertheless, for high-grade subtypes, PDX generation rate increased to 85,7%. No correlation was observed between derivation success and time between surgical removal and dissociation process. Whereas PDX histology was reproducing the same microscopic features than the primary tumors, methylome assay proves to be a good method to confirm original histotype group. Furthermore, those primary models afford a large biobank reproducing the diversity of pediatric brain tumors and were easily drug screened.
MODL-24. NEUROIMMUNE-COMPETENT HUMAN BRAIN ORGANOID MODEL FOR STUDYING BRAIN TUMOR INVASION
Authors: Sarnow Katharina , Majercak Emma , Haque Ishraq , Tang Xin 
Published: November 2023

Abstract

INTRODUCTION
Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brain tumor with a very poor prognosis (&lt; 12 months survival). There is currently no effective treatment for DIPG. Complete surgical resection of DIPG is difficult due to its skull base location and infiltrative growth pattern. Gaining insights into the invasion process of the DIPG cells and their interaction with brain cells in the tumor microenvironment, such as microglia - the brain's primary immune cells, may guide the development of effective treatment strategies to halt or even reverse disease progression. To build a clinically relevant model for studying the microglia/tumor interaction in a 3D human tissue context, we developed a neuroimmune-competent brain organoid/DIPG fusion model system.

METHODS
Human embryonic stem cell derived-neural progenitor cells (NPCs) and -GFP-labelled human myeloid precursor cells were combined to form microglia-containing organoids (MiCBOs) through self-assembly and co-development over two months. Using two-photon live imaging, we characterized the distribution and motility of microglia in MiCBOs and corroborated these results with immunofluorescence staining and single-cell RNA-Sequencing (scRNA-Seq). Tumor cell invasion and interaction with microglia in the brain organoids were assessed by confocal microscopy as well as immunofluorescence stainings.

RESULTS
The human microglia in MiCBOs are viable, widely distributed, actively motile, and highly resemble those in the human brain. Confrontation experiments of the MiCBO with DIPG spheroids enable quantitative characterization of the invasion patterns for different cell lines under various conditions.

CONCLUSION
Our MiCBOs represent a valuable model for studying tumor cell invasion within a neuroimmune-competent human tissue context. Ongoing experiments with different primary DIPG cell lines as well as genetically engineered microglia will deliver more detailed insights into the invasion patterns of tumor cells into brain tissue and shed light on tumor cell/microglia interplay during the DIPG invasion process.
MODL-28. LIVING EX VIVO ORGANOTYPIC BRAIN SLICE CULTURES AS A COMPREHENSIVE SUBSTRATE FOR TUMOR ENGRAFTMENT AND ANALYSIS
Authors: Adefolaju Adebimpe , Mann Breanna , Zhang Xiaopei , Bell Noah , Thang Morrent , Dasari Rajaneekar , Kanchi Krishna , Valdivia Alain , Yang Yang , Buckley Andrew , Lettry Vivien , Quinsey Carolyn , Rauf Yasmeen , Kram David , Cassidy Noah , Vaziri Cyrus , Corcoran David L , Rego Stephen , Jiang Yuchao , Graves Lee M , Dunn Denise , Floyd Scott , Baldwin Albert , Hingtgen Shawn , Satterlee Andrew B 
Published: November 2023

Abstract
Heterogeneity, drug resistance, tumor infiltration, and invasiveness significantly contribute to the poor prognosis often associated with brain cancers. To enhance drug development, it is crucial to have models that accurately replicate human responses. Standard in vitro methods to culture, treat and analyze brain tumors often lack resemblance to the original tumor and provide limited insight. To address these challenges, we developed an organotypic brain slice culture (OBSC) model that recapitulates in vivo tumor characteristics within a functional tumor microenvironment (TME) and provides rapid results. OBSCs effectively measure engrafted tumor growth, morphology, and invasion rates. Furthermore, engrafted tumors can undergo relevant therapeutic treatments and be analyzed for drug outcomes. In a 4-day assay, we successfully engrafted a diverse range of brain cancer cell lines, including low-passage lines that struggle to establish in vivo. These cell lines maintain tumor-specific invasion patterns, interact with the OBSC microenvironment, and display killing patterns consistent with in vivo tumor responses. Notably, invasive, metastatic, and diffuse tumor cell lines migrate outward on OBSCs, while densely growing lines contract inward. To further validate OBSCs as a model for the TME, we treated MB231BR, LN229, and U373 tumor lines with TR107, an experimental ClpP inhibitor derived from ONC201. This therapeutic family maximizes tumor elimination by targeting normal cells within the TME. In vitro experiments showed TR107 achieving incomplete tumor kill on cell lines grown in vitro, whereas treatment on OBSCs led to complete tumor kill, suggesting OBSCs' contribution to TME-based tumor elimination. Conclusively, OBSCs provide a valuable platform for studying brain cancers and accurately replicating tumor behavior and responses to therapies within the TME. This model has the potential to advance drug development and deepen our understanding of brain cancer biology, ultimately improving prognoses and treatment outcomes for patients.
MODL-39. ELUCIDATING THE TRANSCRIPTOMIC LANDSCAPE OF METASTATIC PEDIATRIC MEDULLOBLASTOMA
Authors: Orozco Ana Isabel Castillo , Aghababazadeh Masoumeh , Khatami Marjan , Danieau Geoffroy , Jawhar Wajih , Khazaei Niusha , Garzia Livia 
Published: November 2023

Abstract
Medulloblastoma (MB) is a highly aggressive and the most common brain tumor in childhood. MB presents a high intertumoral heterogeneity, with at least four molecular subgroups (SHH, WNT, Group 3, and Group 4) identified. MB can metastasize to the leptomeningeal space, known as Leptomeningeal Disease (LMD) and its presence is a universal predictor of poor outcome among MB patients. Metastatic MB is predominantly found in the MB Group 3 type. Although LMD represents a main clinical challenge, its molecular mechanisms remain poorly characterized. Recent research has shown that primary and MB metastasis diverge dramatically. Our work has focused on establishing therapy naïve Group 3 Patient-Derived Xenografts that faithfully replicate the nature of primary and metastatic Medulloblastoma with the aim to perform comparative genomic and transcriptomic analyses between these models to identify genetic drivers/pathways that sustain metastatic MB or leptomeningeal disease. Our results show various signaling pathways enriched across LMD models, such as protein secretion and oxidative phosphorylation. We also have identified differentially expressed genes, where sets of genes have shown to be present in more than one PDX model, such as members of the Solute Carriers family (SLC44A3 and SLC17A9) and FCGBP. Retrieval of short variants from RNAseq data has not revealed thus far mutations enriched in LMD, suggesting these changes could be attributed to epigenetic disruption rather than genetic changes. In conclusion, our results support the notion that primary and LMD are transcriptionally different, with various enriched pathways and sets of DEG among LMD Group 3 PDX models. These findings are in progress for functional validation. Work is currently being done to profile the epigenome of LMD by correlating transcriptomic data with active chromatin markers such as H3K27ac and H3K4me1. Through these approaches, we aim to elucidate the genetic dependencies of metastatic Medulloblastoma that will help for targeted therapies.
Trifluridine/Tipiracil Plus Bevacizumab for Vulnerable Patients With Pretreated Metastatic Colorectal Cancer: A Retrospective Study (WJOG14520G)
Authors: Kito Yosuke , Kawakami Hisato , Mitani Seiichiro , Nishina Shinichi , Matsumoto Toshihiko , Tsuzuki Takao , Shinohara Yudai , Shimokawa Hozumi , Kumanishi Ryosuke , Ohta Takashi , Katsuya Hiroo , Kawakami Takeshi , Nishina Tomohiro , Hasegawa Hiroko , Akiyoshi Kohei , Chiba Yasutaka , Yamazaki Kentaro , Hironaka Shuichi , Muro Kei 
Published: November 2023

Abstract

Background
Trifluridine/tipiracil (FTD/TPI) plus bevacizumab has shown clinical benefit for metastatic colorectal cancer (mCRC) refractory to standard therapy. However, few data have been available for patients with pretreated mCRC who are intolerant of intensive therapy (vulnerable).

Methods
We performed a multicenter retrospective study (WJOG14520G; TWILIGHT) of FTD/TPI plus bevacizumab for vulnerable patients with pretreated mCRC. Eligibility criteria included previous chemotherapy (although patients treated with all key cytotoxic agents, a fluoropyrimidine, oxaliplatin, and irinotecan, were excluded) and intolerance of full-dose combination therapy with oxaliplatin or irinotecan at the start of FTD/TPI plus bevacizumab.

Results
The median age of 93 evaluable patients was 79 years (range, 21-90). Intolerance of intensive therapy was attributable to an older age in 60 (65%) patients, serious concomitant disease in 24 (26%) patients, and a poor performance status in 19 (20%) patients. FTD/TPI plus bevacizumab was administered as second-line treatment in 74 (80%) patients and as third- or fourth-line treatment in 19 (20%) patients. The objective response rate was 4.9% (95% confidence interval [CI], 1.4%-12.2%), and the disease control rate was 67.9% (95% CI, 56.6%-77.8%). With a median follow-up time of 21.6 months, median overall survival and progression-free survival were 18.6 months (95% CI, 12.1-23.2) and 6.3 months (95% CI, 5.0-8.3), respectively. Neutropenia of grade ≥3 developed in 50 (54%) patients, whereas 2 (2%) patients experienced febrile neutropenia, and no treatment-related death was observed.

Conclusion
Our data show the potential efficacy and acceptable safety profile of FTD/TPI plus bevacizumab for vulnerable patients with pretreated mCRC.
early maturity 7 promotes early flowering by controlling the light input into the circadian clock in barley
Authors: Helmsorig Gesa , Walla Agatha , Rütjes Thea , Buchmann Gabriele , Schüller Rebekka , Hensel Götz , von Korff Maria 
Published: November 2023

Abstract
Breeding for variation in photoperiod response is crucial to adapt crop plants to various environments. Plants measure changes in day length by the circadian clock, an endogenous timekeeper that allows plants to anticipate changes in diurnal and seasonal light–dark cycles. Here, we describe the early maturity 7 (eam7) locus in barley (Hordeum vulgare), which interacts with PHOTOPERIOD 1 (Ppd-H1) to cause early flowering under non-inductive short days. We identify LIGHT-REGULATED WD 1 (LWD1) as a putative candidate to underlie the eam7 locus in barley as supported by genetic mapping and CRISPR-Cas9-generated lwd1 mutants. Mutations in eam7 cause a significant phase advance and a misregulation of core clock and clock output genes under diurnal conditions. Early flowering was linked to an upregulation of Ppd-H1 during the night and consequent induction of the florigen FLOWERING LOCUS T1 under short days. We propose that EAM7 controls photoperiodic flowering in barley by controlling the light input into the clock and diurnal expression patterns of the major photoperiod response gene Ppd-H1.
Constraining the cosmological model of modified f(Q) gravity: Phantom dark energy and observational insights
Authors: Koussour M , Myrzakulov N , Alfedeel Alnadhief H A , Abebe Amare 
Published: November 2023

Abstract
Despite the significant accomplishments of general relativity, numerous unresolved issues persist in our understanding of the cosmos. One of the most perplexing challenges is the ongoing accelerated expansion of the Universe, which continues to elude a complete explanation. Consequently, scientists have proposed various alternative theories to general relativity in pursuit of a deeper understanding. In our analysis, we delve into the recently proposed modified f(Q) gravity, where Q represents the nonmetricity scalar responsible for gravitational effects. Specifically, we investigate a cosmological model characterized by the functional form f(Q) = Q + αQn, where α (with α ≠ 0) and n serve as free parameters. Utilizing this functional form, we construct our Hubble rate, incorporating a specific equation of state to describe the cosmic fluid. Furthermore, we leverage a dataset consisting of 31 data points from Hubble measurements and an additional 1048 data points from the Pantheon dataset. These data serve as crucial constraints for our model parameters, and we employ the Markov Chain Monte Carlo (MCMC) method to explore the parameter space and derive meaningful results. With our parameter values constrained, our analysis yields several noteworthy findings. The deceleration parameter suggests a recent accelerated phase in the cosmic expansion. In addition, the EoS parameter paints a portrait of dark energy exhibiting phantom-like characteristics. Furthermore, we delve into the application of cosmological diagnostic tools, specifically the statefinder and the Om(z) diagnostics. Both of these tools align with our previous conclusions, confirming the phantom-like behavior exhibited by our cosmological model. These results collectively contribute to our understanding of the dynamic interplay between gravity, dark energy, and the expanding cosmos.
Association of the triglyceride-glucose index variability with blood pressure and hypertension: a cohort study
Authors: Wang D , Li W , Zhou M , Ma J , Guo Y , Yuan J , He M , Zhang X , Chen W 
Published: November 2023

Summary

Background
Several studies have indicated that the triglyceride-glucose index (TyG) index is associated with hypertension; however, evidence on the association of change in the TyG index with blood pressure and hypertension is limited.

Aims
To assess the association of the TyG index with blood pressure and hypertension.

Design
A cohort study.

Methods
We included 17 977 individuals with a mean age of 60.5 years from the Dongfeng–Tongji cohort. The TyG index was calculated as ln [fasting triglyceride (mg/dl)×fasting glucose (mg/dl)/2]. Hypertension was defined as blood pressure ≥140/90 mmHg, self-reported current use of antihypertensive medication or self-reported physician diagnosis of hypertension.

Results
In the longitudinal analyses, we found a linear dose–response relationship between changes in the TyG index and change in blood pressure. Each one-unit change in the TyG index was associated with a 1.93 (1.23–2.63) mmHg increase in systolic blood pressure (SBP) and a 1.78 (1.42–2.16) mmHg increase in diastolic blood pressure (DBP). During a median follow-up of 9.37 years, a total of 3594 individuals were newly diagnosed with hypertension. We also found a linear dose–response relationship between the TyG index and the incidence of hypertension. The hazard ratio (HR) of hypertension for each one-unit increase in the TyG index was 1.21 (1.13–1.29). In addition, the best cut-off point of TyG for predicting hypertension was 8.4797, with sensitivity, and specificity of 57.85% and 55.40%, respectively.

Conclusions
The TyG index had a positive dose–response relationship with blood pressure and could be used to predict the risk of hypertension.
Survey on reference dosimetry practice in Hokuriku region, Japan
Authors: Kinoshita Naoki , Takemura Akihiro , Oosaka Akitane , Shirosaki Nobuyuki , Tsujikawa Tetsuya 
Published: November 2023

Abstract
This study aimed to obtain reference dosimetry practices for flattened photon and electron beams. A questionnaire survey on these practices was sent to 37 facilities that performed radiotherapy using these beams in Fukui, Ishikawa, Niigata and Toyama, Japan. The survey comprised equipment (dosemeters, water phantoms, thermometers, barometers and hygrometers) and procedures for reference dosimetry (water used as the phantoms, verification of chamber placement, periodic checks of ion recombination- and polarity-corrections, pre-irradiation and relative humidity monitoring). Responses were received from 19 institutions. In the 19 institutions, a reference-class dosemeter was used for the reference dosimetry. In 6 of the 19 institutions, a 10-year-old or older dosemeter was used. Any barometers, thermometers and hygrometers were not recalibrated. Dosimetry equipment necessitates regular maintenance. Moreover, it is necessary to have a backup dosimetry system in clinics to account for potential malfunctions or instances when the primary system is sent for calibration.
Corollary Discharge Dysfunction as a Possible Substrate of Anomalous Self-experiences in Schizophrenia
Authors: Beño-Ruiz-de-la-Sierra Rosa M , Arjona-Valladares Antonio , Hernández-García Marta , Fernández-Linsenbarth Inés , Díez Álvaro , Fondevila Estevez Sabela , Castaño Carolina , Muñoz Francisco , Sanz-Fuentenebro Javier , Roig-Herrero Alejandro , Molina Vicente 
Published: November 2023

Abstract

Background and Hypothesis
Corollary discharge mechanism suppresses the conscious auditory sensory perception of self-generated speech and attenuates electrophysiological markers such as the auditory N1 Event-Related Potential (ERP) during Electroencephalographic (EEG) recordings. This phenomenon contributes to self-identification and seems to be altered in people with schizophrenia. Therefore, its alteration could be related to the anomalous self-experiences (ASEs) frequently found in these patients.

Study Design
To analyze corollary discharge dysfunction as a possible substrate of ASEs, we recorded EEG ERP from 43 participants with schizophrenia and 43 healthy controls and scored ASEs with the ‘Inventory of Psychotic-Like Anomalous Self-Experiences’ (IPASE). Positive and negative symptoms were also scored with the ‘Positive and Negative Syndrome Scale for Schizophrenia’ (PANSS) and with the ‘Brief Negative Symptom Scale’ (BNSS) respectively. The N1 components were elicited by two task conditions: (1) concurrent listening to self-pronounced vowels (talk condition) and (2) subsequent non-concurrent listening to the same previously self-uttered vowels (listen condition).

Study Results
The amplitude of the N1 component elicited by the talk condition was lower compared to the listen condition in people with schizophrenia and healthy controls. However, the difference in N1 amplitude between both conditions was significantly higher in controls than in schizophrenia patients. The values of these differences in patients correlated significantly and negatively with the IPASE, PANSS, and BNSS scores.

Conclusions
These results corroborate previous data relating auditory N1 ERP amplitude with altered corollary discharge mechanisms in schizophrenia and support corollary discharge dysfunction as a possible underpinning of ASEs in this illness.