Aggressive Group Research Articles

Correlation of magnetic resonance imaging and computed tomography with biological factor expression and lymph node metastasis in aggressive prostate cancer.

This paper focused on probing the correlation of magnetic resonance imaging (MRI) and computed tomography (CT) manifestations with biological factor expression and lymph node metastasis (LNM) in aggressive prostate cancer (PCa). A total of 136 PCa patients underwent surgical treatment, and received CT and MRI examinations before surgery, whereby the apparent diffusion coefficient (ADC) values of quantitative MRI (qMRI) parameters were obtained. Patients were categorized into the non-aggressive PCa group and aggressive PCa group according to the postoperative pathological results and Gleason scores. The expression of biological factors [prostate-specific antigen (PSA), proliferating cell nuclear antigen (PCNA), p27, and ki-67] in both groups was tested. CT and MRI manifestations of aggressive PCa patients were analyzed. The qMRI parameters, biological factors levels and LNM were compared in two groups; the relationships between CT and MRI manifestations, qMRI parameters and positive expression of biological factors and LNM were probed in two groups. In the aggressive PCa group, MRI and CT presented different degrees of abnormal prostate changes. In the aggressive PCa group, PSA and p27 expression and ADC values were lower, and PCNA and ki-67, and LNM rates were higher. Patients' LNM rate was higher than that of ≤ 2 cm when the tumor diameter was > 2 cm. ADC values were positively correlated with PSA and p27 positive expression, and negatively correlated with PCNA, ki-67 and LNM in the aggressive PCa group. MRI and CT manifestations of aggressive PCa had certain characteristics; MRI manifestations and qMRI possessed a correlation with biological factors and LNM; ADC could be employed to assess the aggressiveness of PCa.

Diagnostic value of baseline 18F-FDG PET/CT and peripheral blood inflammatory markers for aggressive lymphoma in non-Hodgkin's lymphoma.

This study aims to investigate the diagnostic value of baseline F18 fluorodeoxyglucose (FDG) PET/computed tomography (CT) parameters and peripheral blood inflammatory markers in aggressive lymphoma of non-Hodgkin lymphoma (NHL) and the correlation between peripheral blood inflammatory markers and maximum standardized uptake value (SUVmax). We conducted a retrospective analysis including 121 patients with NHL. Patients were divided into aggressive lymphoma group and indolent lymphoma group. Mann-Whitney U test, chi-square test and multivariate stepwise logistic regression were used to analyse. Subsequently, receiver operating characteristic (ROC) curve analysis was conducted to evaluate the diagnostic performance. Additionally, Spearman correlation analysis was utilized to explore the correlation between peripheral blood inflammatory markers and SUVmax. Leptin mass criterion uptake value (SUL)max, SUVmax, SUVavg, SUVpeak, focal SUVmax/liver SUVmax, focal SUVmax/ mediastinal SUVmax, SULavg, SULpeak, systemic immune-inflammation, neutrophil ratio, total lesion glycolysis, neutrophils versus lymphocyte ratio, platelet-to-lymphocyte ratio, hemoglobin-to-white blood cell ratio, lactate dehydrogenase and lymphocyte ratio between two groups were statistically significant (P < 0.05). SUVmax was an independent influencing factor, and the area under the ROC curve was 0.862. There was a positive correlation between the platelet-to-lymphocyte ratio and SUVmax (r = 0.239; P = 0.008). PET/CT parameters and peripheral blood inflammatory markers have certain value in the diagnosis of aggressive lymphoma in NHL, among which SUVmax is an independent influencing marker and is positively correlated with PLR.

Long-term Outcomes and Prognostic Factors of Gastric MALT Lymphoma.

This study aimed to evaluate the long-term prognosis of patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma, including overall survival (OS), remission, and factors associated with an aggressive disease course. Medical records of 153 patients diagnosed with gastric MALT lymphoma between 2013 and 2020 were retrospectively reviewed. Patients experiencing relapse, progression, high-grade transformation, or residual diseasewere included in the aggressive group and were compared with those in the indolent group. Additionally, the endoscopic findings of Helicobacter pylori-negative patients were reviewed. Patient characteristics were as follows: mean age (56.9±11.2 years), sex (male, 51.0%), H. pylori infection (positive, 79.7%), endoscopic location (distal, 89.5%), endoscopic feature (superficial, 89.5%), clinical stage (stage I, 92.8%), invasion depth by endoscopic ultrasound (mucosa, n=115, 75.7%), and bone marrow result (no involvement, n=77, 100.0%). The median follow-up period was 59 months (mean, 61; range, 36-124) and the continuous remission period (n=149) was 51 months (mean, 50; range, 3-112). The 5-year survival rate was 97.7% while the 5-year continuous remission was 88.3%. Factors associated with the patients in the aggressive group were old age, sex(male), and clinical stage II or higher. H. pylori-negative patients' endoscopy revealed a high incidence of atrophic gastritis in the antrum. The long-term prognosis of gastric MALT lymphoma appears indolent and is indicated by the 5-year OS and continuous remission rates. Aggressive disease courses are associated with old age, sex (male), and clinical stage II or higher, but are not related to OS.

Value of miR-31 and miR-150-3p as diagnostic and prognostic biomarkers for breast cancer.

The most prevalent malignancy among women is breast cancer (BC). MicroRNAs (miRNAs) play a role in the initiation and progression of BC by influencing breast cancer stem cells (BCSCs) but the diagnostic and prognostic roles of those miRNAs on BC patients are still unknown. It was aimed to investigate expression profiles, diagnostic and prognostic potentials of BCSC-related miRNAs in different subtypes (Luminal A and B, HER2 + and TNBC) of BC patients. Expression analysis of 15 BCSC-related miRNAs was performed in 50 breast tumor tissues and 20 adjacent non-tumor tissues obtained from BC patients using the qRT-PCR method. The expression levels of miR-31 and miR-150-3p were significantly upregulated in the tumor tissues compared to the adjacent non-tumor tissues (p < 0.05). miR-31 expression upregulated in the Luminal A and Luminal B group compared to non-tumor tissue (p < 0.05). miR-31 expression was determined to be significantly higher in the Luminal group (Luminal A and B) compared to the aggressive group (HER2 + and TNBC) (p < 0.05). According to the ROC analysis, the area under the curve (AUC) of miR-31 and miR-150-3p were 0.66 with a sensitivity of 68% and a specificity of 70%. A significant inverse correlation was observed between miR-31 expression with metastatic carcinoma status, in situ component, and Ki67 value in tumors, and high miR-150-3p expression was correlated with p63 expression (p < 0.05). miR-31 and miR-150-3p have the potential to serve as biomarkers for guiding diagnosis, evaluating prognosis, and metastatic process in patients with BC.

Abstract A040: Multiplex fluorescent immunohistochemistry reveals immunosuppressive tumor microenvironment in COMPASS-like complex gene mutated pancreatic cancer

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to chemoradiation and immune therapies. There is limited biomarker to identify subsets of PDAC that responds to immunotherapy or targeted therapy. We have identified a subset of PDACs (approximately 25%) carrying COMPASS-like complex (CLC) gene mutations. Analysis of the clinicopathologic and molecular features of this PDAC subset revealed that these tumors are an aggressive group of PDACs with poor or squamous histologic differentiation, increased rates of TP53 mutations, and poor patient survival compared to control PDACs. Our preliminary data showed that PDACs carrying mutations in two members of the CLC genes (KDM6A and KMT2D) have immunosuppressive tumor microenvironment (TME), suggesting that CLC genes are candidate biomarkers for immunotherapy. However, a comprehensive analysis of the immune composition, immune checkpoint expression, and the relationship between tumor cells and immune cells in CLC gene mutated PDACs compared to controls has not been performed. In this study, we characterized the immune composition in CLC gene mutated PDACs compared to paired control PDACs using tyramide signal amplification multiplex fluorescent immunohistochemistry (mfIHC). Methods: Human PDAC tissue slides were stained with 2 mfIHC panels and cell types were defined by different markers: panel 1 (PanCK, CD163, PD-L1, CD3, CD8, FoxP3) and panel 2 (PanCK, CD163, CD3, CD8, TIGIT, TIM3). Random image sections were selected in each sample (5∼8 sections per sample) and divided into wild-type (WT) group (n=57) and mutant group (n=41) and analyzed using InForm Cell Analysis software. Tissue segmentation training was performed to separate stromal and epithelial elements. Cell percentage, cell density, and nearest neighbor distance of each cell type were calculated using R program. Results: The CLC gene mutation is associated with elevated epithelial cells (ECs) and PDL1+ ECs and increased infiltration of exhausted cytotoxic T cells (TIGIT+/TIM3+ CD8 T cells). CLC gene mutated PDACs are characterized by spatial proximity between exhausted T cells (TIGIT+) and epithelial cells/antigen presenting cells (APCs). Higher number of epithelial cells is associated with reduced infiltration of helper T cells in the mutant PDAC tissue. We also observed that high numbers of APC in proximity to CD4 T cells were positively correlated with the proximity of EC and CD8 cytotoxic T cells as well as the proximity of CD4 T cells and cytotoxic T cells in the WT group but not in the CLC gene mutant group. Conclusion: Our results provide insight into the effects of CLC gene mutations on shaping the immune microenvironment of PDAC and suggest that CLC gene mutated PDACs have an immunosuppressive immune microenvironment than other PDACs and may respond differently to immunotherapy. Citation Format: Shungang Zhang, Elaina Daniels, Jake McGue, Hong Sun Kim, Dafydd Thomas, Timothy Frankel, Jiaqi Shi. Multiplex fluorescent immunohistochemistry reveals immunosuppressive tumor microenvironment in COMPASS-like complex gene mutated pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A040.

Towards Digital Quantification of Ploidy from Pan-Cancer Digital Pathology Slides using Deep Learning.

Abnormal DNA ploidy, found in numerous cancers, is increasingly being recognized as a contributor in driving chromosomal instability, genome evolution, and the heterogeneity that fuels cancer cell progression. Furthermore, it has been linked with poor prognosis of cancer patients. While next-generation sequencing can be used to approximate tumor ploidy, it has a high error rate for near-euploid states, a high cost and is time consuming, motivating alternative rapid quantification methods. We introduce PloiViT, a transformer-based model for tumor ploidy quantification that outperforms traditional machine learning models, enabling rapid and cost-effective quantification directly from pathology slides. We trained PloiViT on a dataset of fifteen cancer types from The Cancer Genome Atlas and validated its performance in multiple independent cohorts. Additionally, we explored the impact of self-supervised feature extraction on performance. PloiViT, using self-supervised features, achieved the lowest prediction error in multiple independent cohorts, exhibiting better generalization capabilities. Our findings demonstrate that PloiViT predicts higher ploidy values in aggressive cancer groups and patients with specific mutations, validating PloiViT potential as complementary for ploidy assessment to next-generation sequencing data. To further promote its use, we release our models as a user-friendly inference application and a Python package for easy adoption and use.

The effect of aggressive group norms on young adults’ conformity behavior in WhatsApp chats: a vignette-based experiment

Social networking and messaging applications, such as WhatsApp, have become an essential social environment for adolescents and young adults (AYA). While facilitating connectivity, they also bear hazards, including cyber-aggression. This study investigates the impact of (aggressive) group norms on AYA's propensity to expect cyberaggressive behaviors within different group chats. Based on a vignette scenario, realistically simulated WhatsApp group chats enabled scrutinizing, if and how exemplary reactions (funny, aggressive, friendly) of group members influence AYA's conformity to cyber-aggression (N = 500, aged 16 to 29). Additionally, we examined the effect of chat group type—close friends versus fellow students—on the anticipation of aggressive reactions. Sociodemographic, social, and developmental-psychological factors were evaluated for potential effects. Multilevel logistic regression analyses indicated that aggressive group norms significantly predict cyber-aggression anticipation, while no effect of chat group type was observed. Controlling for the size and vivacity of participant’s friend group, gender, age, and educational status were significant predictors: males, younger participants, and non-university students expected higher levels of cyber-aggression conformity. This study underlines the importance of group dynamics on perceptions of cyber-aggression and hints at individual risk factors for AYA's digital communication behavior.

Efficacy of first-line chemotherapy based on primary site of tumor versus etoposide-platinum in advanced gastroenteropancreatic neuroendocrine carcinoma.

Gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs) constitute a rare and aggressive group of malignancies usually with widespread disease. There are limited studies on GEP-NECs, and therefore, we aim to acquire more information on the clinical features, treatment regimens, and prognosis. Data from advanced GEP-NECs patients who had not previously received systemic treatment for advanced disease at The First Affiliated Hospital of Nanjing Medical University from 2010 to 2022 were retrospectively collected. Relationships between clinical-pathological features, treatment regimens, and prognosis were investigated using Kaplan-Meier curves and cox regression models. A total of fifty-four patients were enrolled in the study. The median age was 65.5 years and 79.6% were male. At diagnosis, 51.9% and 3.7% of patients developed liver and brain metastasis respectively. Sixteen (29.6%) patients received chemotherapy according to primary site of tumor (PST), while thirty-eight (70.4%) were treated with etoposide-platinum (EP) regimen, which based on the first-line treatment of advanced small cell lung cancer (SCLC). No significant differences on progression-free survival (PFS) and response rate were observed between these two groups. Univariate survival analysis showed that liver metastasis, elevated baseline serum carcinoembryonic antigen, elevated baseline serum neuron-specific enolase, elevated baseline serum lactate dehydrogenase, and elevated baseline serum neutrophil-to-lymphocyte ratio (NLR) were associated with shorter PFS. After multivariate analysis, elevated NLR was the only factor that remained significantly associated with shorter PFS (P=0.01). GEP-NECs are aggressive neoplasms, of which elevated NLR is proven to be an independent negative predictor. Treatment regimens based on PST are not inferior to regiments based on SCLC (EP) for GEP-NECs patients. Large-scale, prospective randomized controlled trials are required to establish the standard of care.

EPEN-11. CHARACTERIZING EPIGENETIC MODULATIONS AND EZHIP DOWNSTREAM TARGETS IN PFA EPENDYMOMA

Abstract BACKGROUND Ependymomas can arise from all compartments of the central nervous system and ten distinct molecular groups have been identified in children and adults. In children, the most aggressive group is posterior fossa group A ependymoma (PFA). In PFA ependymomas, the aberrant overexpression of EZHIP (EZH inhibitory protein) has been implicated as a relevant driver of the disease. EZHIP suppresses the installing and spreading of the repressive epigenetic mark H3K27me3 via disturbing PRC2 (polycomb repressive complex 2) activity through inhibiting EZH2 (enhancer of zeste 2), which causes overall low levels of H3K27me3 in PFA. METHODS To get a better understanding how EZHIP may drive the disease, how it affects the epigenetic landscape and what the downstream targets of EZHIP are, we performed DNA sequencing, RNA expression profiling and ChIP-seq experiments of H3K27me3, H3K27ac, EZH2, and EZHIP in PFA, PFB, and ST-ZFTA ependymomas (n = 3 tumor cases each). RESULTS After validating the high levels of EZHIP and global reduction of H3K27me3 in PFA, we characterized the epigenetic landscape and EZHIP chromatin binding characteristics in PFA compared to PFB and ST-ZFTA ependymoma. Transcriptome analysis showed that overall more genes are up-regulated in PFA compared with PFB and ZFTA, which might be caused by its relatively high accessibility with a global loss of H3K27me3. EZHIP knockdown experiments confirmed direct changes on H3K27me3, H3K27ac and gene expression. We also found that PLAG1 (pleomorphic adenoma gene 1) expression linearly correlated with EZHIP expression in PFA tumors. ChIP-seq data indeed showed the PLAG1 locus to be bound by EZHIP and marked with increased H3K27ac and decreased H3K27me3 signals in PFA. CONCLUSIONS We identified PLAG1 as a potential downstream target of EZHIP in PFA tumors. Currently, more experiments on PLAG1 are being performed to further explore its role as a potential vulnerability in PFA ependymoma.

BIOM-13. THE MIR-17/92 CO-EXPRESSED NETWORK IS ENRICHED IN AGGRESSIVE PEDIATRIC BRAIN TUMORS

Abstract BACKGROUND Over the past two decades, the understanding of miRNA biology has drastically increased as miRNAs have been found to pervade most aspects of molecular biology–from cellular growth to apoptosis. Nevertheless, there has been little understanding of the role of miRNAs in pediatric brain tumors. In this study, we sought to correlate miRNA expression with pediatric brain tumor histologies. METHODS Weighted gene co-expression network analysis (WGCNA) was performed to determine co-expressed miRNA networks that correlated with distinct brain tumor histologies. Our study cohort consisted of miRNA-sequencing of 262 pediatric brain tumor histologies consisting of Atypical Teratoid/Rhabdoid tumors, Craniopharyngioma, Ependymomas, Ganglioglioma, Low-grade astrocytic tumors, High-grade astrocytic tumors, and Medulloblastoma. We utilized associated multi-omics data from the Open Pediatric Brain Tumor Atlas to validate the results. RESULTS WGCNA analysis revealed a distinct miRNA network consisting of 32 miRNAs with miR-17-5p as the hub miRNA that was markedly upregulated in the aggressive brain tumor group (p&amp;lt;0.001). Interestingly, the majority of the miRNA network consisted of the miR-17/92 family of miRNAs, which are known for their oncogenic role in various cancers. To determine the transcriptional regulatory mechanism of miR-17/92 miRNAs, we first looked at sample-matched RNA-sequencing data. The gene encoding for the miR-17/92 miRNAs, MIR17HG, was significantly overexpressed (p&amp;lt;0.001). Further upstream, we observed that E2F1/2/3, known transcriptional regulators of MIR17HG, gene and protein expressions were significantly overexpressed (p&amp;lt;0.01). Sample-matched phospho-proteomics data indicated the E2F regulator, RB1, being hyperphosphorylated–additionally supporting the E2F activity in these samples. CONCLUSION These findings reveal a network of oncogenic miRNAs consisting of the miR-17/92 family that are distinctly overexpressed in aggressive pediatric brain tumors. Moreover, we suggest that the E2F-RB1 axis is the upstream regulator of the miR-17/92 family of miRNAs.

Acetaminophen and Ibuprofen in Pediatric Central Nervous System Malaria

A third of children who survive malaria with neurological involvement (central nervous system [CNS] malaria) develop sequelae. A higher maximum temperature (Tmax) and seizures are risk factors for sequelae. To compare aggressive antipyretic therapy using scheduled acetaminophen and ibuprofen vs usual care with acetaminophen alone given only for a temperature of 38.5 °C or higher. This randomized clinical trial was conducted at inpatient pediatric services of 1 tertiary care and 1 district hospital in Zambia and a tertiary care center in Malawi. Included were children aged 2 to 11 years with CNS malaria (excluding those with creatinine >1.2 mg/dL), who were enrolled from 2019 to 2022. Data analysis took place from December 2022 to April 2023. The aggressive antipyretic group received acetaminophen (30 mg/kg load, then 15 mg/kg) plus ibuprofen, 10 mg/kg, every 6 hours, regardless of clinical temperature for 72 hours. The usual care group received 15 mg/kg of acetaminophen as needed every 6 hours for a temperature of 38.5 °C or higher. The primary outcome variable was Tmax over 72 hours, the total duration of follow-up. Secondary outcomes included seizures and parasite clearance. Five hundred fifty-three patients were screened, 226 (40.9%) were ineligible, and 57 (10.3%) declined. A total 256 participants (n = 128/group) had a mean (SD) age of 4.3 (2.1) years; 115 (45%) were female, and 141 (55%) were male. The aggressive antipyretic group had a lower Tmax, 38.6 vs 39.2 °C (difference, -0.62 °C; 95% CI, -0.82 to -0.42; P < .001) and lower odds of experiencing multiple or prolonged seizures, 10 (8%) vs 34 children (27%) in the usual care group (odds ratio [OR], 0.26; 95% CI, 0.12 to 0.56). No group difference in parasite clearance time was detected. Severe adverse events occurred in 40 children (15%), 25 (20%) in the usual care group and 15 (12%) in the aggressive antipyretic group, including 13 deaths (10 [8%] and 3 [2%], respectively). Increased creatinine resulted in study drug discontinuation in 8 children (6%) in the usual care group and 13 children (10%) in the aggressive antipyretic group (OR, 1.74; 95% CI, 0.63 to 5.07). This study found that aggressive antipyretic therapy reduced mean Tmax to temperature levels comparable with the Tmax among children without neurological impairments in prior observational studies and improved acute seizure outcomes with no prolongation of parasitemia. ClinicalTrials.gov Identifier: NCT03399318.

A phase 3, randomized study of adjuvant rilvegostomig plus chemotherapy in resected biliary tract cancer: ARTEMIDE-Biliary01.

TPS4199 Background: Biliary tract cancer (BTC) is a rare but aggressive heterogenous group of gastrointestinal cancers that arise from the intra- or extrahepatic bile ducts (cholangiocarcinoma [CCA]) or the gallbladder (GBC). In early-stage disease following curative resection, adjuvant chemotherapy with a fluoropyrimidine- or gemcitabine-based regimen is usually recommended, however, recurrence rates remain high (e.g. in the BILCAP study, 5-year recurrence-free survival with adjuvant capecitabine was 34%). Immunotherapy is efficacious as adjuvant therapy in other cancer types. Results from the TOPAZ-1 and KEYNOTE-966 studies support combining immunotherapy and chemotherapy in advanced BTC, including in locally advanced non-metastatic disease. Furthermore, dual inhibition of programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) and the novel immune checkpoint, T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), has shown promising results across multiple tumor types without major increases in high-grade toxicity compared with PD-1 or PD-L1 inhibition alone. Rilvegostomig is an anti-PD-1/-TIGIT bi-specific monoclonal antibody that appears active and well tolerated in non-small-cell lung cancer. ARTEMIDE-Biliary01 will investigate the efficacy of rilvegostomig plus standard of care adjuvant chemotherapy in patients with BTC after curative intent resection. Methods: ARTEMIDE-Biliary01 (NCT06109779) is a Phase 3, randomized, double-blind, placebo-controlled, multicenter, global study to assess the efficacy and tolerability of rilvegostomig IV every three weeks versus placebo in combination with investigator's choice of chemotherapy (capecitabine, S-1 [tegafur/gimeracil/oteracil] or gemcitabine/cisplatin) as adjuvant treatment in patients with BTC after curative intent resection. This study will enroll approximately 750 adults with histologically confirmed adenocarcinoma of the biliary tract (intrahepatic or extrahepatic CCA or muscle-invasive GBC) after macroscopically complete resection (R0 or R1) and an ECOG PS of 0–1. Key exclusion criteria include locally advanced, unresectable, or metastatic disease at initial diagnosis and any anti-cancer therapy for BTC prior to surgery. The primary endpoint is recurrence-free survival, and the key secondary endpoint is overall survival. Additional endpoints include progression-free survival following recurrence, patient-reported tolerability, and safety. Enrollment has begun, and approximately 200 sites will be recruiting globally across Asia, Australia, Europe, North America, and South America. Clinical trial information: NCT06109779 .

Boko Haram-Induced Forced Migration: Implications for Social and Economic Development in the Lake Chad Basin

In Africa, and notably the Lake Chad Basin (LCB), Boko Haram is a major threat to human security. The region, which spans 427,500 km2 and contains large ungoverned areas, is made up of Nigeria, Cameroon, Chad, and Niger. Boko Haram has been responsible for several attacks in Northeast Nigeria since 2003 and is also the leading cause of forced migration in the Lake Chad Basin. In northeastern Nigeria and other LCB countries, this insurgency has caused widespread migration and increased the humanitarian crisis, socio-economic, and environmental consequences. This research aims to examine the developmental challenges emerging from Boko Haram-induced forced displacement in the LCB. Empirical evidence suggests that the Lake Chad Basin countries’ governments have failed to contain this group's aggression. However, there are still gaps in the literature regarding how this insurgency has affected social and economic lives of displaced people in the region. The study utilized a case study design, documentary method of data collection, and content analysis as the analytical technique. The study applies the Human Security Theory and Regional Security Complex Theory (RSCT) as the theoretical framework. Ultimately, the findings of this study revealed that forced migration severs social ties, leading to economic, social, and psychological impacts, including family separation and loss, with families often split up abruptly due to attacks and evacuation. In Addition, negative economic impacts disproportionately affect impoverished individuals, exacerbating chronic poverty and hindering their ability to escape poverty due to price volatility and wage declines. It was recommended that the governments of Lake Chad Basin countries should develop and implement policies that support the economic integration of refugees and displaced individuals, including measures to facilitate access to employment and promoting self-reliance and resilience. They should also foster initiatives that strengthen social ties and networks among displaced populations to facilitate integration into host communities and mitigate the negative impacts of social disconnection.

Does a cautious driving style reduce the crash risk of older drivers? An analysis using a novel driving style recognition method

Older drivers who are aware of their declining functions tend to adopt a cautious driving style to compensate for their declining driving abilities. However, whether cautious older drivers are associated with a reduced crash risk has not been well studied. In this study, we examined the association between older drivers’ cautious driving style and crash risk using a novel driving style recognition method. We proposed a driving style recognition method that does not require predefined thresholds and applied it to the driving data of 71 drivers comprising 59 drivers aged 65 years or older (mean age 72.4; 67.8 % male) and 12 drivers aged 51–64 years (mean age 58.3; 66.7 % male). Drivers were classified into cautious and relatively aggressive groups based on the classification results of their speed, acceleration, and braking styles. The results showed that cautious drivers were characterized by older age, poorer Trail Making Test Part B performance, less frequent night driving, and lower driving exposure, indicating that older drivers may adopt multiple compensatory strategies. Although the crash involvement rate of cautious older drivers was approximately half that of relatively aggressive drivers, the difference was not statistically significant. Furthermore, this difference was expected to decrease when driving exposure was considered. Older drivers who adopted a cautious driving style but were involved in traffic crashes had poorer visual acuity and contrast sensitivity. The results of this study indicate that a cautious driving style alone may not be sufficient to compensate for older drivers’ declining functions, particularly the loss of two visual functions observed in the present study.

Exaggerated sensitivity to threat and reduced medial prefrontal engagement during threat generalization in reactive aggressive adolescents

Aggressive adolescents tend to exhibit abnormal fear acquisition and extinction, and reactive aggressive adolescents are often more anxious. However, the relationship between fear generalization and reactive aggression (RA) remains unknown. According to Reactive-Proactive Aggression Questionnaire (RPQ) scores, 61 adolescents were divided into two groups, namely, a high RA group (N = 30) and a low aggression (LA) group (N = 31). All participants underwent three consecutive phases of the Pavlovian conditioning paradigm (i.e., habituation, acquisition, and generalization), and neural activation of the medial prefrontal cortex (mPFC) was assessed by functional near-infrared spectroscopy (fNIRS). The stimuli were ten circles with varying sizes, including two conditioned stimuli (CSs) and eight generalization stimuli (GSs). A scream at 85 dB served as the auditory unconditioned stimulus (US). The US expectancy ratings of both CSs and GSs were higher in the RA group than in the LA group. The fNIRS results showed that CSs and GSs evoked lower mPFC activation in the RA group compared to the LA group during fear generalization. These findings suggest that abnormalities in fear acquisition and generalization are prototypical dysregulations in adolescents with RA. They provide neurocognitive evidence for dysregulated fear learning in the mechanisms underlying adolescents with RA, highlighting the need to develop emotional regulation interventions for these individuals.

The OTX2 Gene Induces Tumor Growth and Triggers Leptomeningeal Metastasis by Regulating the mTORC2 Signaling Pathway in Group 3 Medulloblastomas.

Medulloblastoma (MB) encompasses diverse subgroups, and leptomeningeal disease/metastasis (LMD) plays a substantial role in associated fatalities. Despite extensive exploration of canonical genes in MB, the molecular mechanisms underlying LMD and the involvement of the orthodenticle homeobox 2 (OTX2) gene, a key driver in aggressive MB Group 3, remain insufficiently understood. Recognizing OTX2's pivotal role, we investigated its potential as a catalyst for aggressive cellular behaviors, including migration, invasion, and metastasis. OTX2 overexpression heightened cell growth, motility, and polarization in Group 3 MB cells. Orthotopic implantation of OTX2-overexpressing cells in mice led to reduced median survival, accompanied by the development of spinal cord and brain metastases. Mechanistically, OTX2 acted as a transcriptional activator of the Mechanistic Target of Rapamycin (mTOR) gene's promoter and the mTORC2 signaling pathway, correlating with upregulated downstream genes that orchestrate cell motility and migration. Knockdown of mTOR mRNA mitigated OTX2-mediated enhancements in cell motility and polarization. Analysis of human MB tumor samples (N = 952) revealed a positive correlation between OTX2 and mTOR mRNA expression, emphasizing the clinical significance of OTX2's role in the mTORC2 pathway. Our results reveal that OTX2 governs the mTORC2 signaling pathway, instigating LMD in Group 3 MBs and offering insights into potential therapeutic avenues through mTORC2 inhibition.

NRF2 activation by cysteine as a survival mechanism for triple-negative breast cancer cells

Triple-negative breast cancer (TNBC) is a very aggressive and heterogeneous group of tumors. In order to develop effective therapeutic strategies, it is therefore essential to identify the subtype-specific molecular mechanisms underlying disease progression and resistance to chemotherapy. TNBC cells are highly dependent on exogenous cystine, provided by overexpression of the cystine/glutamate antiporter SLC7A11/xCT, to fuel glutathione synthesis and promote an oxidative stress response consistent with their high metabolic demands. Here we show that TNBC cells of the mesenchymal stem-like subtype (MSL) utilize forced cystine uptake to induce activation of the transcription factor NRF2 and promote a glutathione-independent mechanism to defend against oxidative stress. Mechanistically, we demonstrate that NRF2 activation is mediated by direct cysteinylation of the inhibitor KEAP1. Furthermore, we show that cystine-mediated NRF2 activation induces the expression of important genes involved in oxidative stress response, but also in epithelial-to-mesenchymal transition and stem-like phenotype. Remarkably, in survival analysis, four upregulated genes (OSGIN1, RGS17, SRXN1, AKR1B10) are negative prognostic markers for TNBC. Finally, expression of exogenous OSGIN1, similarly to expression of exogenous NRF2, can prevent cystine depletion-dependent death of MSL TNBC cells. The results suggest that the cystine/NRF2/OSGIN1 axis is a potential target for effective treatment of MSL TNBCs.

Cortical volume alterations in the limbic network in adolescents with high reactive aggression.

Previous studies show aggression-related structural alterations in frontal and limbic brain regions. Most studies have focused on overall aggression, instead of its subtypes, and on specific regions instead of networks. This study aims to identify both brain networks and regions that are associated with reactive and proactive subtypes of aggression. Structural MRI data were collected from 340 adolescents (125 F/215 M) with a mean age of 16.29 (SD = 1.20). Aggression symptomology was indexed via the Reactive Proactive Aggression Questionnaire (RPQ). Freesurfer was used to estimate Cortical Volume (CV) from seven networks and regions within specific networks associated with aggression. Two multivariate analyses of covariance (MANCOVAs) were conducted on groups for low versus higher reactive and proactive RPQ scores. Our reactive aggression MANCOVA showed a main effect in CV [F(14,321) = 1.935, p = 0.022,ηp2 = 0.078] across all the 7-Networks. Unpacking this main effect revealed significant volumetric differences in the right Limbic Network (LN) (p = 0.029) and the Temporal Pole (p = 0.011), where adolescents in the higher reactive aggression group showed higher cortical volumes. Such findings are consistent with region/voxel-specific analyses that have associated atypical structure within the LN and reactive aggression. Moreover, the temporal pole is highly interconnected with regions important in the regulation and initiation of reactive aggression.

301 Even Heterozygous Loss of CDKN2A B Greatly Accelerates Recurrence in Aggressive Meningioma

INTRODUCTION: In the WHO 2021 criteria, homozygous deletion of cyclin-dependent kinase-inhibitor 2A and/or B (CDKN2A/B) qualifies meningiomas as Grade 3. We assessed the effect of heterozygous CDKN2A/B loss, which was not addressed by the WHO, on recurrence-free survival (RFS), and evaluated the relationship of CDKN2A/B losses with our MenG classification. METHODS: Methylation and RNA-profiling were used to assign MenG. Methylation data identified heterozygous or homozygous loss of CDKN2A/B in 776 meningiomas. Clinical data for 659 tumors were used for survival analysis. RESULTS: Of the 776 tumors, 738 (95.1%) had intact CDKN2A/B, 20 (2.5%) had heterozygous loss of both CDKN2A/B, 3 (0.4%) had homozygous CDKN2A and heterozygous CDKN2B loss, and 15 (1.9%) had homozygous loss of both CDKN2A/B. Of the 659 tumors with clinical data, 28 (4.2%) showed any CDKN2A/B loss. RFS was based on concordant CDKN2A/B status. Tumors with intact CDKN2A/B (n = 631, mRFS not reached) had improved RFS compared to those with heterozygous loss (n = 15, mRFS = 29.1 mo) and homozygous loss (n = 11, mRFS = 10.5mo; p &lt; 0.0001 all groups, homozygous vs. heterozygous p = 0.4, Log-rank). Nearly all tumors with CDKN2A/B loss (27/28) were MenG C, the most aggressive group. Among MenG C tumors, presence of either homozygous (n = 11, mRFS 10.5mo) or heterozygous (n = 14, mRFS 25.1 mo) CDKN2A/B loss led to shortened RFS than those with intact CDKN2A/B (n = 198, mRFS 61.4 mo; p &lt; 0.0001 Log-rank). Median RFS was not reached in MenG A (n = 173) or MenG B (n = 259). Tumors with any CDKN2A/B loss had worse survival when controlling for WHO Grade (Grade: 2 p &lt; 0.0001, 3 p = 0.035, Log-rank). CONCLUSIONS: Heterozygous CDKN2A/B loss (not addressed in the 2021 WHO criteria) leads to poor outcome in meningioma even when controlling for molecular subgroup (MenG C) or WHO grade (2/3). All but 1 tumor (27/28) with any type of CDKN2A/B loss were MenG C.

TRADE CREDIT POLICY AND THE FINANCIAL SITUATION OF DAIRY COOPERATIVES

Aim: The aim of the study is to examine the financial health of dairy cooperatives in relation to their credit position and trade credit strategy. Methods: Using the author’s synthetic indicator, the position and strategy for granting trade credit were determined, and the levels of profitability, liquidity, debt, and management efficiency were assessed in separate groups of entities: conservative, moderate, and aggressive recipients, versus conservative, moderate, and aggressive providers. The research carried out in the field of trade credit management at dairy cooperatives allowed us to establish that the financial position of the analyzed entities varied depending on their credit position and trade credit strategy. Results: The highest level of ROE was found in the group of entities categorized as conservative recipients, where this indicator was 11.1%. Simi­larly, the group of moderate providers also had a high level of 7.1%. On the other hand, the lowest level was found in the return on sales indicator, which was 0.3% and 0.4% in the moderate recipient and aggressive provider groups, respectively. Additionally, cooperatives following a conservative trade credit strategy had a higher level of return on sales compared to the cooperatives classified in the aggressive provider group. Conclusions: The profitability of assets, funds, and sales, as well as the level of liquidity, varied among the distinguished group of cooperatives based on their position and commercial credit strategy. However, there was no variation observed in terms of the level of indebtedness.