STEM-20. THE ROLE OF HUMAN BETA DEFENSINS IN THE CLONOGENICITY OF GLIOBLASTOMA MULTIFORME

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi25-vi25
Author(s):  
Peggy Harris ◽  
Amber Kerstetter-Fogle ◽  
Anthony Sloan ◽  
Alankrita Raghavan ◽  
Harry Hoffman ◽  
...  
Keyword(s):  
Median Overall Survival ◽  
Poor Response ◽  
Small Population ◽  
Response To Treatment ◽  
Lower Grade ◽  
Cancer Type ◽  
Mrna Levels ◽  
Self Renewal ◽  
Beta Defensins

Abstract INTRODUCTION Glioblastoma (GBM) is the most common primary malignant brain tumor with a median overall survival of 12-15months. GBM aggressiveness and poor response to treatment are often attributed to a small population of stem-like cells referred to as glioma stem cells (GSCs). Human Beta-Defensins (HBDs), a family of small molecules initially thought to function as anti-microbials, have been implicated in various cancers with functions that are cancer type specific, including proinflammatory and immunosuppressive roles. GOAL: This study aimed to elucidate HBDs expression in GSCs and differentiated gioma cells (DGSs). METHODS We identified HBD2 and HBD3 in glioma and GSCs and DGSs by immunofluorescence (IF) and immunohistochemistry (IHC). We also assessed the role HBD2/3 play in GBM oncogenesis by investigating their effects on the self-renewal capacity of GSCs. RESULTS HBD2 and HBD3 are found in both bulk tumor and GSCs by IHC and IF. Expression of HBD2 and HBD3 mRNA levels are elevated in GBM patient tissue in comparison to lower grade gliomas by 16.2 & 1.9 fold (respectively; p < 0.0001). Additionally, transcriptional expression of HBD2 and HBD3 are increased by 0.68 and 1.15 fold respectively in GSCs versus autologous DGCs (p < 0.05; p< 0.005 respectively), suggesting a role for HBD 2/3 in oncogenesis. Interestingly however, HBD2 and HBD3 pretreatment of GSC cell lines showed decreased self-renewal capacity by 34.2 and 66.4% (p < 0.001), determined by the reduced number of large neurospheres ( >250mm). CONCLUSIONS Our results demonstrate the presence of HBD2/3 in GBM samples by IHC and IF with increased HBD2/3 mRNA expression in GBM samples. Interestingly DGCs contain less HBD2/3 than their GCS counterparts, and clonogenicity assays demonstrate a decrease in oncogenesis, suggesting that HBD’s role in proliferation and clonogenicity of DGCs and GSCs may be context dependent, leading to additional questions and future studies.

scholarly journals Mettl14 inhibits bladder TIC self-renewal and bladder tumorigenesis through N6-methyladenosine of Notch1

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Chaohui Gu ◽  
Zhiyu Wang ◽  
Naichun Zhou ◽  
Guanru Li ◽  
Yiping Kou ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Rna Stability ◽  
Developed Countries ◽  
Small Population ◽  
Clinical Severity ◽  
Cancer Type ◽  
Tumor Initiating Cells ◽  
Self Renewal ◽  
Common Cancer Type

Abstract Background N6-methyladenosine (m6A) emerges as one of the most important modification of RNA. Bladder cancer is a common cancer type in developed countries, and hundreds of thousands of bladder cancer patients die every year. Materials and methods There are various cells in bladder tumor bulk, and a small population cells defined as tumor initiating cells (TIC) have self-renewal and differentiation capacities. Bladder TICs drive bladder tumorigenesis and metastasis, and their activities are fine regulated. However, the role of N6-methyladenosine in bladder TIC self-renewal is unknown. Results Here, we found a decrease of N6-methyladenosine in bladder tumors and bladder TICs. N6-methyladenosine levels are related to clinical severity and outcome. Mettl14 is lowly expressed in bladder cancer and bladder TICs. Mettl14 knockout promotes the proliferation, self-renewal, metastasis and tumor initiating capacity of bladder TICs, and Mettl14 overexpression exerts an opposite role. Mettl14 and m6A modification participate in the RNA stability of Notch1 mRNA. Notch1 m6A modification inhibits its RNA stability. Notch1 plays an essential role in bladder tumorigenesis and bladder TIC self-renewal. Conclusion This work reveals a novel role of Mettl14 and N6-methyladenosine in bladder tumorigenesis and bladder TICs, adding new layers for bladder TIC regulation and N6-methyladenosine function.

The role of mTOR and hypoxia pathway activation in promoting tumorigenesis of intrahepatic cholangiocarcinoma.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 218-218
Author(s):  
A. J. McRee ◽  
S. Chen ◽  
B. H. O'Neil ◽  
K. Rathmell
Keyword(s):  
Mouse Model ◽  
Liver Tumors ◽  
Molecular Subtype ◽  
Hypoxia Inducible Factor ◽  
Poor Response ◽  
Normal Liver ◽  
Response To Treatment ◽  
Pten Gene ◽  
Clinicopathologic Characteristics

218 Background: Cholangiocarcinoma (CC) is an aggressive malignancy that often presents in advanced stages with poor response rates to conventional chemotherapy. Recent studies of CC have uncovered several oncogenes and tumor suppressors implicated in the transition from biliary hyperplasia to malignancy. We have developed a mouse model of intrahepatic CC that results from deletion of the phosphatase and tensin homolog (PTEN) gene and the von Hippel Lindau (VHL) gene, a tumor suppressor that regulates hypoxia inducible factor (HIF) expression. Immunohistochemical (IHC) analysis of the liver tumors revealed strong staining of p-AKT and HIF-1α. This study aims to determine the expression of the same downstream targets p-AKT and HIF1α in a dataset of human CC tumors. Methods: Archived samples from 33 CC patients were sectioned and stained via IHC for p-AKT and HIF1α expression. Samples were evaluated using a proportion score (PS) for neoplastic cells on a scale of 0 to 5, and an intensity score (IS) expressed on a scale of 0 to 3. Normal liver samples were used as controls. Results: Using a combined score of at least 5 to determine positive expression, 18% of the 33 evaluated samples displayed positive p-AKT expression and 61% displayed positive HIF1α expression. 15% of cases displayed concomitant expression of both p-AKT and HIF1α, while 39% of evaluated samples had expression of neither protein. Conclusions: Delineating the molecular pathways that lead to CC formation is crucial in developing novel therapeutics for a disease in drastic need of more effective therapies. Our group has developed a mouse model of intrahepatic CC that suggests a synergistic role of PTEN and VHL in the tumorigenesis of CC with upregulation of p-AKT and HIF1α. A modest percentage of a cohort of human samples demonstrates a similar expression pattern, potentially defining a distinct molecular subtype of this cancer with implications for tumor behavior and response to treatment. Future studies will correlate these molecularly-defined subtypes to the clinicopathologic characteristics of the tumors with the ultimate aim of establishing biomarkers of disease prognosis as well as potential predictive indicators of treatment activity. No significant financial relationships to disclose.

scholarly journals Information Processing in Mood Disorders

2016 ◽  
pp. 178-189 ◽  
Author(s):  
Jonathan Roiser ◽  
Barbara J. Sahakian
Keyword(s):  
Information Processing ◽  
Mood Disorders ◽  
Poor Response ◽  
Good Evidence ◽  
Reward Processing ◽  
Response To Treatment ◽  
Consistent Finding ◽  
Fundamental Information ◽  
Cognitive Neuropsychological

This article discusses the central role of information processing in mood disorders, distinguishing “cold” (emotion-independent) from “hot” (emotional-dependent) cognition. Impaired cold cognition, which appears in the core diagnostic criteria for both depressive and manic episodes, is a reliable finding in mood disorders. There is good evidence that cold cognitive abnormalities remain in remission, predict poor response to treatment, and are present in unaffected first-degree relatives of patients with mood disorders, suggesting that they are not simply epiphenomena of extreme mood states. Abnormal hot cognition is also a consistent finding in mood disorders. Mood-congruent affective biases and disrupted reward-processing have commonly been reported; the latter is especially relevant for understanding anhedonia. This pattern of disrupted hot and cold cognition is consistent with a cognitive neuropsychological model of depression, which proposes a central role for fundamental information-processing abnormalities in generating symptoms.

scholarly journals Starting from the Influence of Tobacco: AKR1C3 and COVID-19 Receptor ACE2 Are Potential Pprognostic Biomarkers for Brain Lower Grade Glioma, Evidence from Bioinformatics Analyses

2020 ◽  
Author(s):  
Heng-Yi Yang ◽  
Tian-Ni Mao
Keyword(s):  
Host Cells ◽  
Expression Level ◽  
Lower Grade ◽  
Cancer Type ◽  
Survival Curves ◽  
Hub Genes ◽  
Bioinformatics Analyses ◽  
Clinical Model ◽  
Lower Grade Glioma

Background: Coronavirus disease (COVID-19) related pneumonia is leaded by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which infects host cells through receptors named Angiotensin-converting enzyme 2 (ACE2). Smoking is thought to be related to poor disease prognosis, as a large amount of evidence highlights the negative effects of smoking on lung health and its causal relationship with various respiratory diseases. Methods: We first evaluated the role of ACE2 expression level with tobacco effect. And correlation analyses were used to identify the related genes of ACE2 both in smoker trait and human normal multi-tissues. After intersections, hub genes were later used to further GSEA and co-regulated mechanisms were explored by GeneMANIA. We used UALCAN to perform survival curves of pan-cancers included 33 types of cancers. New clinical model of top co-occurrence cancer type was constructed and validated. Results: Effected by cigarette smoking, the expression level of ACE2 expressed statistically upwards in current smokers compared with never smokers, upwards in groups after acute smoke exposed compared with normal control. But no strong evidence detected in third-hand smoke, as poor amounts of samples, only 4. A little trend of expressing upwards became in groups after third-hand smoke compared with groups after clean air exposing. 4 genes included PIR, ADH7, AKR1C2 and AKR1C3 were identified as ACE2 related genes in smoker trait and human normal multi-tissues. Then, we made the survival curves of pan-cancers in 4 genes. Brain lower grade glioma was the co-occurrence type as both ACE2, PIR and AKR1C3 had the significantly prognostic situation. Later, we made the new clinical prediction model as the C-index was 0.827 and the Area Under Curves (AUCs) of 1-year survival, 2-year survival and 3-year survival were 0.921(95%CI, 0.882-0.961), 0.911(95%CI, 0.860-0.962) and 0.878(95%CI, 0.818-0.939). In inner validation, the AUCs of 1-year survival, 2-year survival and 3-year survival were 0.777(95%CI, 0.640-0.914), 0.916(95%CI, 0.842-0.990) and 0.888(95%CI, 0.768-1.000). In outer validation one, the AUCs of 1-year survival, 2-year survival and 3-year survival were 0.764(95%CI, 0.672-0.856), 0.848(95%CI, 0.783-0.913) and 0.748(95%CI, 0.656-0.841). And in outer validation two the AUCs of 1-year survival, 2-year survival and 3-year survival were 0.740(95%CI, 0.654-0.826), 0.766(95%CI, 0.688-0.843) and 0.794(95%CI, 0.721-0.866). Conclusions: In our study, we compared the ACE2 expression level between smokers and non-smokers crowds and identified associated hub genes. Then we explored the further role of hub genes in tumor fields to identify the correlation and influence between the avoidable host factors such as smoking on COVID-19 contamination and tumor. ACE2 and AKR1C3 are potential prognostic genes for brain lower grade glioma, and we created the web dynamic nomogram and encapsulation app through validations.

Criteria positive and criteria negative anaphylaxis, with a focus on undifferentiated somatoform idiopathic anaphylaxis: A review and case series

2020 ◽  
Vol 41 (6) ◽  
pp. 436-441 ◽  
Author(s):  
Daniel A. Rosloff ◽  
Kunal Patel ◽  
Paul J. Feustel ◽  
Jocelyn Celestin
Keyword(s):  
Diagnostic Criteria ◽  
Statistical Significance ◽  
Case Series ◽  
Poor Response ◽  
Response To Treatment ◽  
Fisher Exact Test ◽  
Subjective Symptoms ◽  
Significant Difference ◽  
Physical Findings ◽  
Idiopathic Anaphylaxis

Background: Undifferentiated somatoform (US) idiopathic anaphylaxis (IA) is considered a psychogenic disorder characterized by a lack of observable physical findings and poor response to treatment. Although failure to diagnose true anaphylaxis can have disastrous consequences, identification of US-IA is crucial to limit unnecessary expenses and use of health care resources. Objective: To better define the presentation and understand the potential relationship between US-IA and underlying psychiatric comorbidities. Methods: We retrospectively reviewed 110 visits by 107 patients to our institution for evaluation and management of anaphylaxis over a 1-year period. The patients were classified as having either criteria positive (CP) or criteria negative (CN) anaphylaxis based on whether they met Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network Symposium criteria for the clinical diagnosis of anaphylaxis. Patient characteristics, including objective and subjective signs and symptoms, and the presence of psychiatric diagnoses were collected and analyzed. Statistical significance was assessed by using the Fisher exact test. A literature review of US-IA and other psychogenic forms of anaphylaxis was performed. Results: Patients with CP anaphylaxis were more likely to present with hypotension, wheezing, urticaria, and vomiting than were patients with CN anaphylaxis. The patients with CN anaphylaxis were more likely to present with subjective symptoms of sensory throat tightness or swelling compared with patients with CP anaphylaxis. No significant difference was detected in the prevalence of psychiatric conditions between the two groups. Conclusion: Patients who met previously established diagnostic criteria for anaphylaxis were more likely to present with objective physical findings than those who did not meet criteria for true anaphylaxis. CN patients who presented for treatment of anaphylaxis were more likely to present with subjective symptoms. Formal diagnostic criteria should be used by clinicians when evaluating patients with suspected anaphylaxis.

Juvenile xanthogranuloma of the subdural spaces mimicking chronic hematoma with positive FDG uptake on PET: case report

2020 ◽  
Vol 26 (4) ◽  
pp. 449-453
Author(s):  
Jacob A. Kahn ◽  
Jeffrey T. Waltz ◽  
Ramin M. Eskandari ◽  
Cynthia T. Welsh ◽  
Michael U. Antonucci
Keyword(s):  
Potential Role ◽  
Response To Treatment ◽  
Juvenile Xanthogranuloma ◽  
Imaging Features ◽  
Limited Information ◽  
Advanced Imaging ◽  
Systemic Involvement ◽  
The Central Nervous System ◽  
Infancy And Early Childhood

The authors report an unusual presentation of juvenile xanthogranuloma (JXG), a non–Langerhans cell histiocytosis of infancy and early childhood. This entity typically presents as a cutaneous head or neck nodule but can manifest with more systemic involvement including in the central nervous system. However, currently there is limited information regarding specific imaging features differentiating JXG from other neuropathological entities, with diagnosis typically made only after tissue sampling. The authors reviewed the initial images of a young patient with shunt-treated hydrocephalus and enlarging, chronic, extraaxial processes presumed to reflect subdural collections from overshunting, and they examine the operative discovery of a mass lesion that was pathologically proven to be JXG. Their results incorporate the important associated histological and advanced imaging features, including previously unreported metabolic activity on FDG PET. Ultimately, the case underscores the need to consider JXG in differential diagnoses of pediatric intracranial masses and highlights the potential role of PET in the initial diagnosis and response to treatment.

Potential of Mesenchymal Stem Cells in Anti-Cancer Therapies

2020 ◽  
Vol 15 (6) ◽  
pp. 482-491 ◽  
Author(s):  
Milena Kostadinova ◽  
Milena Mourdjeva
Keyword(s):  
Cancer Cells ◽  
Small Population ◽  
Tumor Formation ◽  
Bioactive Molecules ◽  
Cancer Therapies ◽  
New Methods ◽  
Cycle Arrest ◽  
Anti Cancer ◽  
Blocking Mechanisms

Mesenchymal stem/stromal cells (MSCs) are localized throughout the adult body as a small population in the stroma of the tissue concerned. In injury, tissue damage, or tumor formation, they are activated and leave their niche to migrate to the site of injury, where they release a plethora of growth factors, cytokines, and other bioactive molecules. With the accumulation of data about the interaction between MSCs and tumor cells, the dualistic role of MSCs remains unclear. However, a large number of studies have demonstrated the natural anti-tumor properties inherent in MSCs, so this is the basis for intensive research for new methods using MSCs as a tool to suppress cancer cell development. This review focuses specifically on advanced approaches in modifying MSCs to become a powerful, precision- targeted tool for killing cancer cells, but not normal healthy cells. Suppression of tumor growth by MSCs can be accomplished by inducing apoptosis or cell cycle arrest, suppressing tumor angiogenesis, or blocking mechanisms mediating metastasis. In addition, the chemosensitivity of cancer cells may be increased so that the dose of the chemotherapeutic agent used could be significantly reduced.

scholarly journals POS0677 THE ROLE OF MUSCULOSKELETAL ULTRASOUND IN PREDICTING THE RESPONSE TO JAK INHIBITORS: RESULTS FROM A LARGE MONOCENTRIC COHORT

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 583-583
Author(s):  
C. Garufi ◽  
F. Ceccarelli ◽  
F. R. Spinelli ◽  
S. Mancuso ◽  
C. Pirone ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Structural Damage ◽  
Power Doppler ◽  
Response To Treatment ◽  
Jak Inhibitors ◽  
Inflammatory Score ◽  
Inflammatory Status

Background:In the management of chronic arthritis, such as Rheumatoid Arthritis (RA), Ultrasound (US) assessment can provide relevant information about the joint inflammatory status in the diagnostic phase and even more in the monitoring of disease activity and structural damage1,2.Objectives:In this longitudinal study, we aimed to assesse the role of US in predicting the efficacy of JAK-inhibitors (JAKi) in RA patients.Methods:We enrolled RA patients starting baricitinib or tofacitinib. All patients were evaluated at baseline and after 4, 12, 24, 48 weeks. Disease activity was calculated by DAS28CRP. US examination in 22 joints (I–V MCPs and PIPs, wrists) aimed at evaluating inflammatory features (synovial effusion and hypertrophy, power Doppler-PD), through a semi-quantitative scale (0-3). The total US (0-198) and PD (0-66) scores were calculated. We scanned bilateral flexor (I–V fingers of hands) and extensor compartments (1-6) tendons: tenosynovitis was scored as absent/present (0/1), resulting in a total score (0-22).Results:We studied 102 patients (M/F 15/87; median age 59.2 years, IQR 17.75; median disease duration 144 months, IQR 126), 61 treated with baricitinib and 41 with tofacitinib. At baseline, the median total US score was 18 (IQR 19) and the median PD score 2 (4). We observed a significant reduction in both total and PD US scores at all time-points (p<0.0001) (Figure 1). At baseline, 75.4% of patients showed tenosynovitis involving at least one tendon, with a median score of 2 (IQR 3.5) significantly decreasing after 24 weeks (p=0.02). Multivariate analysis, adjusted for baseline DAS28CRP and other concomitant treatments (including glucocorticoids and methotrexate treatment), confirmed the independent association between baseline US (PD and tenosynovitis) scores and the reduction of disease activity at follow-up evaluations.Conclusion:The present study confirmed the early efficacy of JAKi in RA patients by using US evaluation. Furthermore, power doppler and tenosynovitis scores could play a predictive role in response to treatment.References:[1]MUELLER RB, HASLER C, POPP F, et al. Effectiveness, Tolerability, and Safety of Tofacitinib in Rheumatoid Arthritis: A Retrospective Analysis of Real-World Data from the St. Gallen and Aarau Cohorts. J Clin Med. 2019;8(10):1548.[2]COLEBATCH AN, EDWARDS CJ, ØSTERGAARD M, et al. EULAR recommendations for the use of imaging of the joints in the clinical management of rheumatoid arthritis. Ann Rheum Dis. 2013;72(6):804-14.Figure 1.Ultrasound inflammatory score (a) and Ultrasound Power Doppler (PD) score (b) at baseline and follow-up.Table 1.Baseline characteristics of 414 RA patients.WEEKS04122448US inflammatory score18 (19)11 (15.5)9.5 (11.7)7.5 (8)6 (11)US PD score2 (4)0 (2)0 (1)0 (1)0 (0.7)Disclosure of Interests:Cristina Garufi: None declared, Fulvia Ceccarelli: None declared, Francesca Romana Spinelli Speakers bureau: Abbvie, Eli Lilly, Consultant of: Gilead/Galapagos, Eli Lilly, Grant/research support from: Pfizer, Silvia Mancuso: None declared, Carmelo Pirone: None declared, Fabrizio Conti Speakers bureau: Abbvie, Eli Lilly, Sanofi, Pfizer, Consultant of: Gilead/Galapagos

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