bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical features of CDK4/6 inhibitor-related interstitial lung disease in patients with breast cancer: a case series study
Authors: Funasaka Chikako , Naito Yoichi , Kusuhara Shota , Nakao Takehiro , Nakajima Hiromichi , Kawamoto Megumi , Baba Kaede , Mamishin Kanako , Kondoh Chihiro , Harano Kenichi , Matsubara Nobuaki , Hosono Ako , Sasaki Tomoaki , Kawasaki Toshikatsu , Mukohara Toru 
Published: November 2022

AbstractBackgroundCyclin-dependent kinase 4/6 (CDK4/6) inhibitors are the standard treatment for advanced hormone receptor-positive breast cancer. Although interstitial lung disease is a rare (1–3.3%) but serious adverse event associated with CDK4/6 inhibitors, the incidence of interstitial lung disease in Japanese patients in the real world and the risk factors of interstitial lung disease are not clear.MethodsWe retrospectively investigated the incidence of interstitial lung disease in 224 patients with advanced breast cancer who received CDK4/6 inhibitors at our hospital between 31 January 2017 and 31 January 2021. The correlation of age (&gt;50 vs ≤50 years), presence or absence of previous history of interstitial lung disease, lung metastasis, smoking history and chest radiation with the development of interstitial lung disease was evaluated.ResultsIn total, 177 cases received palbociclib, 39 cases received abemaciclib and 8 cases received both palbociclib and abemaciclib, constituting a palbociclib group (n = 185) and an abemaciclib group (n = 47). At a median observation period of 607 days, 8.0% (18/224) cases (13 definite and 5 probable cases) had interstitial lung disease; 6.5% (12/185) of palbociclib-treated and 13% (6/47) of abemaciclib-treated cases. The median time to interstitial lung disease onset was 178 (range, 14–750) days. There was no significant correlation between the background factors studied and the development of interstitial lung disease.ConclusionThe frequency of CDK4/6 inhibitor-induced interstitial lung disease was higher than that reported in clinical trials. We did not identify any risk factors for the development of interstitial lung disease in this study, and thus, larger studies that include patient predisposition are required.
Osmoelectric siphon models for signal and water dispersal in wounded plants
Authors: Gao Yong-Qiang , Farmer Edward E 
Published: November 2022

AbstractWhen attacked by herbivores, plants produce electrical signals which can activate the synthesis of the defense mediator jasmonate. These wound-induced membrane potential changes can occur in response to elicitors that are released from damaged plant cells. We list plant-derived elicitors of membrane depolarization. These compounds include the amino acid l-glutamate (Glu), a potential ligand for GLUTAMATE RECEPTOR-LIKE (GLR) proteins that play roles in herbivore-activated electrical signaling. How are membrane depolarization elicitors dispersed in wounded plants? In analogy with widespread turgor-driven cell and organ movements, we propose osmoelectric siphon mechanisms for elicitor transport. These mechanisms are based on membrane depolarization leading to cell water shedding into the apoplast followed by membrane repolarization and water uptake. We discuss two related mechanisms likely to occur in response to small wounds and large wounds that trigger leaf-to-leaf electrical signal propagation. To reduce jasmonate pathway activation, a feeding insect must cut through tissues cleanly. If their mandibles become worn, the herbivore is converted into a robust plant defense activator. Our models may therefore help to explain why numerous plants produce abrasives which can blunt herbivore mouthparts. Finally, if verified, the models we propose may be generalizable for cell to cell transport of water and pathogen-derived regulators.
Ecological Speciation Promoted by Divergent Regulation of Functional Genes Within African Cichlid Fishes
Authors: Carruthers Madeleine , Edgley Duncan E , Saxon Andrew D , Gabagambi Nestory P , Shechonge Asilatu , Miska Eric A , Durbin Richard , Bridle Jon R , Turner George F , Genner Martin J 
Published: November 2022

AbstractRapid ecological speciation along depth gradients has taken place repeatedly in freshwater fishes, yet molecular mechanisms facilitating such diversification are typically unclear. In Lake Masoko, an African crater lake, the cichlid Astatotilapia calliptera has diverged into shallow-littoral and deep-benthic ecomorphs with strikingly different jaw structures within the last 1,000 years. Using genome-wide transcriptome data, we explore two major regulatory transcriptional mechanisms, expression and splicing-QTL variants, and examine their contributions to differential gene expression underpinning functional phenotypes. We identified 7,550 genes with significant differential expression between ecomorphs, of which 5.4% were regulated by cis-regulatory expression QTLs, and 9.2% were regulated by cis-regulatory splicing QTLs. We also found strong signals of divergent selection on differentially expressed genes associated with craniofacial development. These results suggest that large-scale transcriptome modification plays an important role during early-stage speciation. We conclude that regulatory variants are important targets of selection driving ecologically relevant divergence in gene expression during adaptive diversification.
ANGI-03. TARGETING ANGIOGENIC PATHWAYS IN COMBINATION WITH OHSV THERAPY IN GBM
Authors: Vazquez-Arreguin Karina , Otani Yoshihiro , Rivera-Caraballo Kimberly , Guangsheng Pei , Zhongming Zhao , Kaur Balveen 
Published: November 2022

Abstract
Glioblastoma (GBM) is the most aggressive brain malignancy, which despite continuing worldwide efforts to develop new therapies, remains a deadly disease with limited treatment options. The asparagine hydroxylase factor inhibiting HIF (FIH1) is located in chromosome 10q24, a region often deleted in GBM, suggesting a tumor protective role. FIH1 has been implicated in GBM as an inhibitor of HIF1α-mediated transcription of VEGF-A, leading to decreased angiogenesis. We previously showed that oncolytic HSV (oHSV) infection reduces the expression FIH1 via a virus encoded miRNA. Furthermore, we have found that FIH1 also negatively regulates NOTCH signaling, which is elevated following oHSV treatment. Thus, we hypothesize that FIH1 reconstitution in tumors will block pro-tumorigenic NOTCH and HIF1α signaling. Using FIH1-overexpressing GBM cells we observed a reduction in vascular permeability, measured by intravital imaging, and decreased expression of angiogenesis markers. In vivo, combination of FIH1 overexpression with oHSV treatment resulted in enhanced survival in mice bearing intracranial GBM tumors. Furthermore, FIH1 overexpression correlated with the enrichment of genes associated with oxidative phosphorylation and ROS pathways, suggesting the potential for multi-modality therapeutic strategies.
BIOM-03. COMPREHENSIVE GENOMIC AND IMMUNE PROFILING OF NON-SMALL CELL LUNG CANCER BRAIN METASTASES REVEALS LOW TUMOR INFLAMMATION AND ELEVATED CANCER TESTIS ANTIGEN BURDEN
Authors: Seager R J , Pabla Sarabjot , Achyut B R , Nesline Mary , Kannan Geoffrey , Chenn Anjen , Zhang Shengle , Klein Roger , Conroy Jeffrey , Sausen Mark , Saini Kamal , Jensen Taylor , Reddy Prasanth , Severson Eric , Ramkissoon Shakti 
Published: November 2022

Abstract

BACKGROUND
Non-small cell lung cancer (NSCLC) accounts for ~50% of brain metastases. We present the genomic and immune biomarker landscape for a cohort with metastatic NSCLC to the brain.

METHODS
We analyzed brain metastases FFPE tissue (n=137; ages 40-85y (mean 65y), 52% female, 48% male) vs. primary sites (n=5533; ages 24-100+y (mean 71y), 51% female, 49% male) for advanced or metastatic NSCLC patients with comprehensive genomic and immune biomarker profiling, including PD-L1 IHC, tumor mutational burden (TMB), Tumor Immunogenic Signature (TIGS), Cell Proliferation (CP), and Cancer Testis Antigen Burden (CTAB).

RESULTS
Genomic alteration (GA) frequency for NSCLC brain metastasis versus primary sites were similar among the most frequently mutated genes except for KRAS which was significantly higher among brain metastases (39.9% vs 25.5%, p&lt; 0.0005). No significant differences were observed for TP53 (50.7% vs 50.2%), STK11 (11.5% vs 10.9%), CDKN2A (10.1% vs 7%), or EGFR (8.0% vs 11.5%). PD-L1 expression for all cases by IHC was not significantly different (mean TPS 29.9% vs 26.3%); however, brain metastases were more likely to be PD-L1 negative (TPS&lt; 1%) (46.3% vs 33.3%, p&lt; 0.005). Conversely, TMB was higher in brain metastases versus primary sites (12.9 vs 10.2 muts/MB, p&lt; 8x10-10), with more TMB-high cases (10 muts/Mb) (57.0% vs 33.5%, p&lt; 3x10-8). Similarly, brain metastases had a higher proportion of CTAB-high cases (68.6% vs 57.6%, p=0.01). The immune response biomarker score, TIGS, was more often weak in brain metastases (52.6% vs 34.0%, p&lt; 9x10-6).

CONCLUSION
In NSCLC, metastatic brain lesions have a larger antigen burden, with increased TMB and CTAB, likely due to the immune privileged nature of the brain, which is reflected in the lower TIGS scores and PD-L1 positivity. Despite lower PD-L1 positivity, NSCLC brain metastases with negative PD-L1 IHC may potentially benefit from immunotherapy strategies given the high TMB and CTAB.
BIOM-05. THE HER2 FLIP: HER2 AMPLIFICATION OF TUMOR CELLS IN THE CEREBROSPINAL FLUID (CSF-TCS) OF PATIENTS WITH SOLID TUMOR LEPTOMENINGEAL METASTASIS
Authors: Kumthekar Priya , Youssef Michael , Blondin Nicholas , Azadi Amir , Piccioni David , Glantz Michael , Carillo Jose , Sharma Akanksha , Avgeropoulos Nicholas , Makar Sherif , Blouw Barbara , Natasha Anna , Fisher Deanna , Huynh Lan , Peters John , Matsutani Mariko , Sales Edgar , Sweed Nathan , Dugan Michael , Kesari Santosh 
Published: November 2022

Abstract

INTRODUCTION
Patients with leptomeningeal metastasis (LM) have limited treatment options and a poor outcome. However, they may benefit from targeted therapy. LM patients with HER2-positive primary breast cancer treated with IT trastuzumab demonstrated clinical benefit (Malani, 2020), and improved PFS (Figura, 2019). HER2 amplification in the primary and metastatic tumors can be divergent. Biocept’s CNSideTM is a CLIA validated test that can detect CSF tumor cells (CSF-TCs) and interrogate those cells with FISH and NGS. We analyzed HER2 amplification on CSF-TCs in LM patients with breast cancer, non-small cell lung cancer (NSCLC) and upper GI cancer.

METHODS
CSF was collected from patients with suspected or confirmed LM with breast cancer (N =134 patients), NSCLC (Nf28 patients) or upper GI cancer (Nf2 patients). CSF TCs were tested for HER2 amplification by FISH using CNSide.

RESULTS
HER2 amplification in CSF-TCs was detected in 46% (76/164) of all patients. Of the breast cancer patients, 37% (49/134) flipped HER2 status in the LM tumor, 38% (41/108) switched from a HER2 negative or equivocal primary tumor to HER2 positive CSF-TCs, and 27% (7/26) from a HER2 positive primary tumor to HER2 negative CSF-TCs. For the NSCLC patients, 50% (14/28) showed HER2 amplification on the CSF-TCs. For the upper GI cancer patients, HER2 amplification in CSF-TCs was detected in both patients, one patient had an equivocal HER2 primary tumor and HER2 positive CSF-TCs.

CONCLUSION
HER2 amplification was detected in a substantial fraction of CSF-TCs from patients with LM from breast, upper GI, and NSCL cancers. This finding may have important therapeutic (justifying the use of intra-CSF trastuzumab), prognostic (HER2 positivity in NSCLC is associated with poorer prognosis and a higher frequency of CNS metastases) and pathophysiologic implications (a potential role of HER2 amplification in the genesis of CNS metastases). Additional investigations are underway.
BIOM-34. MULTIPLEX PHENOTYPING OF EXTRACELLULAR VESICLES FOR ANALYSIS OF POTENTIAL BIOMARKERS IN GLIOBLASTOMA PATIENTS
Authors: Salviano-Silva Amanda , Wollmann Kathrin , Maire Cecile , Kolbe Katharina , Dührsen Lasse , Lamszus Katrin , Ricklefs Franz 
Published: November 2022

Abstract

INTRODUCTION
Extracellular vesicles (EVs) carry biological information from their cell of origin that is useful for non-invasive detection of tumor biomarkers and disease monitoring. In glioblastoma (GBM), blood circulating EVs are elevated and carry GBM-associated proteins. However, it is still challenging to analyze tumor derived EVs for translational purposes. Here, we used imaging flow cytometry (IFCM) as a robust strategy to perform phenotyping of EVs with GBM related surface markers in human plasma.

METHODS
EVs were isolated via differential ultracentrifugation from plasma of (a) 40 GBM patients, pre- and post-surgery, (b) 11matched GBM relapses and (c) 12 healthy donors (HD). EV sizes and concentrations were evaluated by NTA. EV markers (CD9,CD63 and CD81) together with glioma-related markers (integrin beta-1 [ITGB1], tenascin C [TNC], Profilin-1 [PFN1], CD44,GPNMB, SPARC, HLA-II or CD133) were analyzed by IFCM. EV percentages and objects/mL plasma were compared among the groups and correlated with clinical parameters.

RESULTS
CD9 was the predominant tetraspanin in all groups (15-96%), while CD63 had the lowest levels (0-33%) and the strongestdecrease in GBM patients after surgery (fold change [FC]=-5.4, p&lt;0.01). Among the glioma-related markers, ITGB1 and TNC displayed the most significant differences between the analyzed groups, especially the double positives ITGB1+/CD63+and TNC+/CD63+, which decreased in patients after tumor removal (FC=-3.5 and -12, respectively; p&lt;0.001). Meanwhile,ITGB1+/CD9+and TNC+/CD9+EVs exhibited the highest levels in GBM when compared to HD subjects (FC=8.6 and 17.4;p&lt;0.001) and upon tumor recurrence (FC=3.7 and 10.9, respectively; p&lt;0.01).

SUMMARY/CONCLUSION
We identified EV surface antigens with potential clinical utility as GBM biomarkers. Among them, we highlight ITGB1 and TNC as the most promising markers.
CNSC-14. ROLE OF A COLLAGEN RECEPTOR, LAIR-1, IN GLIOMA CELLS: A POTENTIAL THERAPEUTIC TARGET
Authors: Varela Maria Luisa , Comba Andrea , Syed Mohammad Faisal , Murthy Bhuvna R , Barissi Marcus N , Castro Maria , Lowenstein Pedro 
Published: November 2022

Abstract
Most primary brain tumors are gliomas, among which Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. GBM has a median survival of 15-18 months, and despite extensive research remains incurable. Previous work in our lab has shown the importance of Collagen I, expressed by glioma cells, in glioma growth. Employing genetically engineered mouse models (GEMM) of glioma, NPA (NRas, shP53, shATRX), we identified that Collagen 1α1 (Col1A1) plays a key role in tumor malignancy. Molecular ablation of Col1A1 extends median survival, with a reduction in migration and proliferation. However, the mechanisms underlining these changes in survival, and the receptors mediating these effects remain unknown. Several collagen receptors are present in glioma cells. LAIR-1 is a collagen receptor that was originally described as an inhibitory receptor in hematopoietic cells. Since then, it has been demonstrated that LAIR-1 plays critical roles in the immune imbalance of autoimmune diseases and cancers. There have been several studies postulating the expression of LAIR-1 in tumor cells, including non-hematopoietic tumors. These studies suggest that LAIR-1 may constitute a novel receptor that tumor cells exploit to promote tumor growth and achieve immune evasion, yet its role in glioma remains unclear. Here we describe that glioma cells express LAIR-1, and that its molecular ablation in vitro showed reduced cell proliferation. In addition, GEMM lacking LAIR-1 (NRas, shP53, shATRX, shLAIR-1) exhibit improved median survival. Our preliminary data suggest that LAIR-1 expressed in glioma cells has a role in glioma aggressiveness. Currently we are further characterizing the role of LAIR-1 in high grade gliomas, as well as its potential as a therapeutic target. We hypothesize that blocking the interaction between LAIR-1 and collagen in the tumor microenvironment may improve median survival by reducing tumor proliferation.
TMET-06. METABOLIC FATE OF OXALOACETATE IN GLIOBLASTOMA
Authors: Ijare Omkar , Baskin David , Conway David , Cash Alan , Pichumani Kumar 
Published: November 2022

Abstract
Oxaloacetate (OAA) inhibits the Warburg effect by reducing the glucose-derived lactate levels in human cancer cell lines. In dose ranging IC50 experiments with human hepatocellular carcinoma (HCC) cell lines, OAA inhibited cell growth in the concentration range 1.7 - 2.4 mM. Previously, we showed that in the presence of OAA, [U-13C]glucose derived lactate was reduced by 48.8% in GBM cells. OAA also increased survival in mouse models of GBM. Here, we are showing an evidence for the direct utilization of OAA by Glioblastoma (GBM) cells, using uniformly 13C-labeled oxaloacetate ([U-13C]OAA) as a metabolic tracer. Patient-derived GBM cells were grown in DMEM medium containing 11.0 mM glucose and 2.0 mM glutamine. When cells reached confluency, were treated with 4.0 mM [U-13C]OAA in the above DMEM medium. GC-MS based 13C isotopomer analysis showed that [U-13C]OAA entered the cells and get metabolized to generate distinct 13C-labeled isotopomers of aspartate, citrate, glutamate, malate and fumarate. Upon entering TCA cycle, [U-13C]OAA generated M+4 aspartate (3.0%) and citrate (3.2%), and M+3 glutamate (4.1%). During the first turn of the TCA cycle, it produced M+2 aspartate (13.9%), malate (10.5%), and fumarate (8.8%), and after multiple turns, [U-13C]OAA led to the production of the following 13C-labeled isotopomers: M+2 citrate (21.5%), M+2 glutamate (17.2%), M+1 glutamate (5.6%) and M+4 glutamate (2.2%). In addition, [U-13C]OAA also produced [U-13C]pyruvate (17.0%) through PEPCK/PK/ or malic enzyme which further generated similar amount of [U-13C]lactate (17.0%) and [U-13C]alanine (12%). These data demonstrate that GBM cells utilize [U-13C]OAA to perturb TCA cycle and glycolytic pathways, and support our previous observation that OAA-derived pyruvate lead to an increase in the total pyruvate pool and associated decrease in glycolytic flux including the glucose-derived lactate. OAA may metabolically reduce tumor growth in difficult to treat cancers.
TMET-17. NOX2-INDUCED HIGH GLYCOLYTIC ACTIVITY CONTRIBUTES TO THE GAIN OF COL5A1-MEDIATED MESENCHYMAL PHENOTYPE IN GBM
Authors: Park Youngjoon , Park Minwoo , Kim Junhyung , Ahn Juwon , Sim Jeongmin , Bang Ji-In , Heo Jinhyung , Choi Hyejeong , Cho Kyunggi , Lee Mihye , Moon Jong-Seok , Lim Jaejoon 
Published: November 2022

Abstract
Glioblastoma multiforme (GBM) is the most aggressive type of glioma and exhibits extensive heterogeneity and poor prognosis with a high recurrence rate. Among the genetic alterations in GBM with different phenotypic states, a mesenchymal subtype has been associated with a worse outcome in patients with GBM. The mechanisms for the gain of the mesenchymal subtype in GBM remain unclear. Our aim was to investigate whether NOX2-induced high glycolytic activity could contribute to the gain of the mesenchymal phenotype in GBM. We revealed that NOX2-induced high glycolytic activity can induce the gain of the COL5A1-mediated mesenchymal phenotype inGBM. Our findings will provide the molecular mechanism by which NOX2 contributes to the gain of mesenchymal phenotype in GBM.
TMIC-01. STAT3 EXPRESSION IN BRAIN METASTASES FROM BREAST CANCER: CORRELATIONS WITH DIFFERENT MOLECULAR SUBTYPES AND CLINICAL OUTCOME
Authors: Pellerino Alessia , Bruno Francesco , Bertero Luca , Bellini Elisa , Beano Alessandra , Montemurro Filippo , Valiente Manuel , Rudà Roberta , Soffietti Riccardo 
Published: November 2022

Abstract

BACKGROUND
STAT3 expression in peritumoral reactive astrocytes (RA) of brain metastases (BM) from breast cancer (BC) may favor a pro-metastatic environment.

MATERIAL AND METHODS
Eighty-five BM specimens from BC were identified from the biobank of Pathology Unit of University of Turin and Spanish national BrM network (RENACER). pSTAT3 expression was scored in RA of peritumoral tissue according to Priego et al. (Nat Med 2018). Clinical, molecular data, and intracranial progression (i-PFS) were retrospectively retrieved.

RESULTS
Median age was of 54 years (range 30–81). Immunohistochemistry for GFAP and pSTAT3 was feasible in 68/85 (80%). 15/68 patients (21.1%) had BM from luminal BC, 27/68 (39.7%) from HER2-positive BC, and 26/68 (39.2%) from TNBC. 56/68 (82.4%) showed positive staining of pSTAT3, of which 9/68 (13.3%) scored with 3, 26/68 (38.2%) with 2, 21/68 (30.9%%) with 1, and 12/68 (17.6%) with 0 (negative). High pSTAT3 expression (score 2-3) was observed in 17/27 (62.9%) BM from HER2-positive BC and in 15/26 (57.7%) BM from TNBC, while most of BM from luminal BC (12/15 – 80%) had low or absent pSTAT3 (score 0-1) (p=0.021). Overall i-PFS was 16 months (range 7-41): low pSTAT3 BM (score 0-1) had a median i-PFS of 21 months versus 12 months for high pSTAT3 BM (score 2-3). A shorter median i-PFS was observed in high pSTAT3 BM from TNBC (4 months) as compared with low pSTAT3 BM (11 months). Conversely, i-PFS of high pSTAT3 BM (7 months) was similar to low pSTAT3 BM (6 months) in HER2-positive BC.

CONCLUSION
pSTAT3 expression in RA of peritumoral tissue of BM from TNBC and HER2-positive BC is higher than in BM from luminal BC. Of note, patients with high pSTAT3 BM from TNBC progressed earlier in comparison with those with low pSTAT3, suggesting that pSTAT3 expression has an influence on the outcome.
TMIC-11. ASSOCIATION OF TIM-3/GAL-9 AXIS WITHNLRC4 INFLAMMASOME IN GLIOMA MALIGNANCY: TIM-3/GAL-9 INDUCE THE NLRC4 INFLAMMASOME
Authors: Sim Jeongmin , Park JeongMan , Kim Suwan , Hwang Sojung , Sung KyoungSu , Lee Jung-Eun , Yang SeungHo , Cho Kyunggi , Lee SungHwan , Moon Jong-Seok , Ahn Juwon , Lim Jaejoon 
Published: November 2022

Abstract
Tim-3/Gal-9 and the NLRC4 inflammasome contribute to glioma progression. However, the underlying mechanisms involved are unclear. Here, we observed that Tim-3/Gal-9 expression increased with glioma malignancy and found that Tim-3/Gal-9 regulate NLRC4 inflammasome formation and activation. Tim-3/Gal-9 and NLRC4 inflammasome-related molecule expression levels increased with WHO glioma grade, and this association was correlated with low survival. We investigated NLRC4 inflammasome formation by genetically regulating Tim-3 and its ligand Gal-9. Tim-3/Gal-9 regulation was positively correlated with the NLRC4 inflammasome, NLRC4, and caspase-1 expression. Tim-3/Gal-9 did not trigger IL-1  secretion but were strongly positively correlated with caspase-1 activity as they induced programmed cell death in glioma cells. A protein– protein interaction analysis revealed that the FYN-JAK1-ZNF384 pathways are bridges in NLRC4 inflammasome regulation by Tim-3/Gal-9. The present study showed that Tim-3/Gal-9 are associated with poor prognosis in glioma patients and induce NLRC4 inflammasome formation and activation. We proposed that a Tim-3/Gal-9 blockade could be beneficial in glioma therapy as it would reduce the inflammatory microenvironment by downregulating the NLRC4 inflammasome.