scholarly journals CircSMARCA5 Regulates VEGFA mRNA Splicing and Angiogenesis in Glioblastoma Multiforme Through the Binding of SRSF1

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 194 ◽  
Author(s):  
Davide Barbagallo ◽  
Angela Caponnetto ◽  
Duilia Brex ◽  
Federica Mirabella ◽  
Cristina Barbagallo ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Survival Rates ◽  
Progression Free Survival ◽  
Negative Control ◽  
Splicing Factor ◽  
Circular Rnas ◽  
P Value ◽  
Physical Interaction ◽  
Mrna Isoforms ◽  
R Value

Circular RNAs are a large group of RNAs whose cellular functions are still being investigated. We recently proposed that circSMARCA5 acts as sponge for the splicing factor Serine and Arginine Rich Splicing Factor 1 (SRSF1) in glioblastoma multiforme (GBM). After demonstrating by RNA immunoprecipitation a physical interaction between SRFS1 and circSMARCA5, we assayed by real-time PCR in a cohort of 31 GBM biopsies and 20 unaffected brain parenchyma controls (UC) the expression of total, pro-angiogenic (Iso8a) and anti-angiogenic (Iso8b) mRNA isoforms of Vascular Endothelial Growth Factor A (VEGFA), a known splicing target of SRSF1. The Iso8a to Iso8b ratio: (i) increased in GBM biopsies with respect to UC (p-value < 0.00001); (ii) negatively correlated with the expression of circSMARCA5 (r-value = −0.46, p-value = 0.006); (iii) decreased in U87-MG overexpressing circSMARCA5 with respect to negative control (p-value = 0.0055). Blood vascular microvessel density, estimated within the same biopsies, negatively correlated with the expression of circSMARCA5 (r-value = −0.59, p-value = 0.00001), while positively correlated with that of SRSF1 (r-value = 0.38, p-value = 0.00663) and the Iso8a to Iso8b ratio (r-value = 0.41, p-value = 0.0259). Kaplan-Meier survival analysis showed that GBM patients with low circSMARCA5 expression had lower overall and progression free survival rates than those with higher circSMARCA5 expression (p-values = 0.033, 0.012, respectively). Our data convincingly suggest that circSMARCA5 is an upstream regulator of pro- to anti-angiogenic VEGFA isoforms ratio within GBM cells and a highly promising GBM prognostic and prospective anti-angiogenic molecule.

scholarly journals circSMARCA5-SRSF1 interaction is functionally involved in GBM pathogenesis

2021 ◽  
Vol 54 (384) ◽  
pp. MISC3-MISC4
Author(s):  
Angela Caponnetto
Keyword(s):  
Alternative Splicing ◽  
Survival Rates ◽  
Progression Free Survival ◽  
Splicing Factor ◽  
Circular Rnas ◽  
Physical Interaction ◽  
Human Brain Tumor ◽  
Molecular Features ◽  
Upstream Regulator ◽  
Grade Malignancy

Glioblastoma multiforme (GBM) is the most aggressive human brain tumor with a median survival of 15 months. The standard treatments of GBM and the total medical resection are unable to contrast this mortal cancer. For these reason new diagnostic approaches and therapies are needed. The identification of molecular features of this cancer may allow to create a personalized therapy. Circular RNAs (circRNAs) are a new class of non-coding RNAs (ncRNAs) highly enriched in brain, stable within the cells, detectable in body fluids and having a potential role and biological importance still object of debate. This thesis investigated the putative involvement of circRNAs in GBM pathogenesis. It has been demonstrated that circSMARCA5 is downregulated in GBM biopsies, its expression is associated to the glioma grade malignancy and it negatively regulates migration of U87MG cells. Moreover, it has been proved the physical interaction between circSMARCA5 and one of its predicted interactor Serine/arginine-rich splicing factor 1 (SRSF1). Interesting splicing targets of SRSF1 are the serine and arginine rich splicing factor 3 (SRSF3) and the vascular endothelial growth factor A (VEGFA). It has been proposed that circSMARCA5 may regulate the alternative splicing of SRSF3 in favor of the formation of a stable oncoprotein in GBM. It also regulates the alternative splicing of VEGFA mRNA through the binding to SRSF1. In addition, blood vascular microvessel density evaluated in GBM negatively correlates with the expression of circSMARCA5, while positively correlates with that of SRSF1 and pro-to-anti-angiogenic VEGFA isoform ratio. GBM patients with low circSMARCA5 expression have lower overall and progression free survival rates. Based on these findings, CircSMARCA5 could be considered a promising druggable tumor suppressor in GBM. Moreover, its interaction with SRSF1 makes circSMARCA5 an upstream regulator of pro- to anti-angiogenic VEGFA isoforms ratio within GBM cells and a highly promising GBM prospective anti-angiogenic molecule.

Hypofractionated therapy versus conventional fractionated radiotherapy in elderly patients with glioblastoma multiforme

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 12529-12529
Author(s):  
H. Elshenshawy ◽  
A. Abd El-Razek ◽  
H. Bader
Keyword(s):  
Glioblastoma Multiforme ◽  
Elderly Patients ◽  
Performance Status ◽  
Survival Rates ◽  
Progression Free Survival ◽  
Fractionated Radiotherapy ◽  
Treatment Groups ◽  
Short Course ◽  
Short Course Radiotherapy ◽  
Better Than

12529 Background: To evaluate efficacy of short- course radiotherapy(RT) in elderly (>60years) patients with glioblastoma multiforme(GBM), and compare this biological similar short -course radiotherapy with a standard radiotherapy Methods: Forty-four elderly patients with GBM were randomly assigned after surgery to receive either a short-course of radiotherapy (45 Gy in 15 fractions over 3 weeks ) or standard radiotherapy (60 Gy in 30 fractions over 6weeks) to a target volume described as tumor visible on CT scan and a 2- cm margin . The primary end point was overall survival. Results: The overall response rate and median duration of response were 60%and 8.5 months in short- course RT versus 65% and 8 months in standard RT . Improvement in pretreatment performance status and increase in post- treatment corticosteroid dosage were observed in 50% and 25% in short- course RT versus 40% and 50% in standard RT (P=0.09, P=0.031) respectively. Median survival time was 5.9 months in short-course RT versus 5.6 months in standard RT . Six months, 1-year survival and progression-free survival rates were 40%, 15% and 30% ,10% in short- course RT versus 45%, 10% and 35% , 5% in standard RT , respectively. In both treatment groups, females did significantly better than males, patients with KPS 60–70 did significantly better than those with KPS 50 , patients having tumors 4–5 cm did significantly better than those with tumors 6–8 cm as well as did those with more radical surgery when compared to those with biopsy only. On multivariate analysis , only tumor size and extent of surgery were found to independently influence survival. Acute toxicity was generally assessed as mild in the two treatment groups. While RT -induced brain necrosis appeared only in one patient received short- course RT, but this patient died from tumor recurrence. Conclusions: Hypofractionated RT is feasible and safe treatment for elderly patients with GBM. No significant financial relationships to disclose.

Hypofractionated radiotherapy versus conventional fractionated radiotherapy in elderly patients with glioblastoma multiforme

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2042-2042
Author(s):  
H. M. El-Shenshawy ◽  
A. Abd El-Razek ◽  
H. Bader
Keyword(s):  
Glioblastoma Multiforme ◽  
Elderly Patients ◽  
Performance Status ◽  
Survival Rates ◽  
Progression Free Survival ◽  
Fractionated Radiotherapy ◽  
Treatment Groups ◽  
Short Course ◽  
Short Course Radiotherapy ◽  
Better Than

2042 Background: To evaluate efficacy of short- course radiotherapy(RT) in elderly (>60 years) patients with glioblastoma multiforme (GBM), and compare this biological similar short -course radiotherapy with a standard radiotherapy. Methods: Forty-four elderly patients with GBM were randomly assigned after surgery to receive either a short-course of radiotherapy (45 Gy in 15 fractions over 3 weeks) or standard radiotherapy (60 Gy in 30 fractions over 6 weeks) to a target volume described as tumor visible on CT scan and a 2 cm margin. The primary end point was overall survival. Results: The overall response rate and median duration of response were 60% and 8.5 months in short-course RT versus 65% and 8 months in standard RT. Improvement in pretreatment performance status and increase in post-treatment corticosteroid dosage were observed in 50% and 25% in short-course RT versus 40% and 50% in standard RT (P=0.09, P=0.031) respectively. Median survival time was 5.9 months in short-course RT versus 5.6 months in standard RT. Six months, 1-year survival and progression-free survival rates were 40%, 15% and 30% ,10% in short-course RT versus 45%, 10% and 35%, 5% in standard RT, respectively. In both treatment groups, females did significantly better than males, patients with KPS 60–70 did significantly better than those with KPS 50, patients having tumors 4–5 cm did significantly better than those with tumors 6–8 cm as well as did those with more radical surgery when compared to those with biopsy only. On multivariate analysis, only tumor size and extent of surgery were found to independently influence survival. Acute toxicity was generally assessed as mild in the two treatment groups. While RT-induced brain necrosis appeared only in one patient received short- course RT, but this patient died from tumor recurrence. Conclusions: Hypofractionated RT is feasible and safe treatment for elderly patients with GBM. No significant financial relationships to disclose.

SERUM PROLACTINE LEVEL IN PATIENTS OF PSORIASIS VULGARIS AND ITS CORRELATION WITH DISEASE SEVERITY: A CASE-CONTROL STUDY

2019 ◽  
Vol 3 (6) ◽  
Author(s):  
Pawan Kumar Saini ◽  
Devendra Yadav ◽  
Rozy Badyal ◽  
Suresh Jain ◽  
Arti Singh ◽  
...  
Keyword(s):  
Disease Severity ◽  
Prolactin Level ◽  
Case Control Study ◽  
Statistical Significance ◽  
Case Control ◽  
Serum Prolactin ◽  
P Value ◽  
Serum Prolactin Level ◽  
R Value ◽  
Control Study

Background: Psoriasis is an autoimmune chronic inflammatory disorder affecting the skin mediated by T-lymphocytes resulting in production of cytokines which cause hyperproliferation of keratinocytes.  Several factors and hormones like Prolactin have an action similar to these cytokines in promoting the multiplication of keratinocytes and other cells like lymphocytes and epithelial cells may have a role on the etiopathogenesis of psoriasis. Aim:-The aim of study is to compare the serum Prolactin levels in patients of psoriasis with a control group. Setting and study design: This is a case-control study conducted in the department of Dermatology, Venereology and Leprosy GMC, Kota over a period of 1year from July 2017 to June 2018 Material and method: The study included 100 cases of psoriasis (60 males and 40 females) and 100 controls similar for age and sex. Serum Prolactin levels were measured by ECLIA and results were obtained. Statistical analysis: Mean and standard deviation were calculated for each variable. Statistical significance of the results was analyzed using correlation analysis (Pearson correlation coefficient) and independent samples t-test. Statistical significance was assumed at p value<0.05. Result: Serum Prolactin level was significantly higher in cases of psoriasis compared to controls (p-value <0.001). PASI score and serum Prolactin levels were found to have a positive correlation (r value = 0.337; p-value: 0.001). No significant  correlation was found between serum levels of Prolactin and duration of disease r value= -0.034, P value =0.733). Serum Prolactin level was higher in male patients compared to females patients. Conclusion:- High serum Prolactin may be a biological marker of disease severity in psoriasis and may have a role in the pathogenesis of psoriasis. Further studies with large sample size are required to confirm this hypothesis.

scholarly journals Radiotherapy in nodal oligorecurrent prostate cancer

2021 ◽  
Author(s):  
Michael Pinkawa ◽  
Daniel M. Aebersold ◽  
Dirk Böhmer ◽  
Michael Flentje ◽  
Pirus Ghadjar ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Literature Review ◽  
Survival Rates ◽  
Local Treatment ◽  
Progression Free Survival ◽  
Nodal Metastasis ◽  
Stereotactic Ablative Radiotherapy ◽  
Current Standard ◽  
Free Survival ◽  
Systemic Treatments

Abstract Objective The current article encompasses a literature review and recommendations for radiotherapy in nodal oligorecurrent prostate cancer. Materials and methods A literature review focused on studies comparing metastasis-directed stereotactic ablative radiotherapy (SABR) vs. external elective nodal radiotherapy (ENRT) and studies analyzing recurrence patterns after local nodal treatment was performed. The DEGRO Prostate Cancer Expert Panel discussed the results and developed treatment recommendations. Results Metastasis-directed radiotherapy results in high local control (often > 90% within a follow-up of 1–2 years) and can be used to improve progression-free survival or defer androgen deprivation therapy (ADT) according to prospective randomized phase II data. Distant progression after involved-node SABR only occurs within a few months in the majority of patients. ENRT improves metastases-free survival rates with increased toxicity in comparison to SABR according to retrospective comparative studies. The majority of nodal recurrences after initial local treatment of pelvic nodal metastasis are detected within the true pelvis and common iliac vessels. Conclusion ENRT with or without a boost should be preferred to SABR in pelvic nodal recurrences. In oligometastatic prostate cancer with distant (extrapelvic) nodal recurrences, SABR alone can be performed in selected cases. Application of additional systemic treatments should be based on current guidelines, with ADT as first-line treatment for hormone-sensitive prostate cancer. Only in carefully selected patients can radiotherapy be initially used without additional ADT outside of the current standard recommendations. Results of (randomized) prospective studies are needed for definitive recommendations.

scholarly journals Serum Extracellular Vesicle-Derived circHIPK3 and circSMARCA5 Are Two Novel Diagnostic Biomarkers for Glioblastoma Multiforme

2021 ◽  
Vol 14 (7) ◽  
pp. 618
Author(s):  
Michele Stella ◽  
Luca Falzone ◽  
Angela Caponnetto ◽  
Giuseppe Gattuso ◽  
Cristina Barbagallo ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Roc Analysis ◽  
Characteristic Curve ◽  
Area Under The Curve ◽  
Digital Pcr ◽  
Extracellular Vesicle ◽  
Size Exclusion ◽  
Circular Rnas ◽  
Diagnostic Biomarkers ◽  
Exclusion Chromatography

Glioblastoma multiforme (GBM) is the most frequent and deadly human brain cancer. Early diagnosis through non-invasive biomarkers may render GBM more easily treatable, improving the prognosis of this currently incurable disease. We suggest the use of serum extracellular vesicle (sEV)-derived circular RNAs (circRNAs) as highly stable minimally invasive diagnostic biomarkers for GBM diagnosis. EVs were isolated by size exclusion chromatography from sera of 23 GBM and 5 grade 3 glioma (GIII) patients, and 10 unaffected controls (UC). The expression of two candidate circRNAs (circSMARCA5 and circHIPK3) was assayed by droplet digital PCR. CircSMARCA5 and circHIPK3 were significantly less abundant in sEVs from GBM patients with respect to UC (fold-change (FC) of −2.15 and −1.92, respectively) and GIII (FC of −1.75 and −1.4, respectively). Receiver operating characteristic curve (ROC) analysis, based on the expression of sEV-derived circSMARCA5 and circHIPK3, allowed us to distinguish GBM from UC (area under the curve (AUC) 0.823 (0.667–0.979) and 0.855 (0.704 to 1.000), with a 95% confidence interval (CI), respectively). Multivariable ROC analysis, performed by combining the expression of sEV-derived circSMARCA5 and circHIPK3 with preoperative neutrophil to lymphocyte (NLR), platelet to lymphocyte (PLR) and lymphocyte to monocyte (LMR) ratios, three known diagnostic and prognostic GBM markers, allowed an improvement in the GBM diagnostic accuracy (AUC 0.901 (0.7912 to 1.000), 95% CI). Our data suggest sEV-derived circSMARCA5 and circHIPK3 as good diagnostic biomarkers for GBM, especially when associated with preoperative NLR, PLR and LMR.

scholarly journals FEN1 Blockade for Platinum Chemo-Sensitization and Synthetic Lethality in Epithelial Ovarian Cancers

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1866
Author(s):  
Katia A. Mesquita ◽  
Reem Ali ◽  
Rachel Doherty ◽  
Michael S. Toss ◽  
Islam Miligy ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
High Throughput Screening ◽  
Nuclear Translocation ◽  
Synthetic Lethality ◽  
Excision Repair ◽  
Progression Free Survival ◽  
Ovarian Cancer Cells ◽  
Physical Interaction ◽  
Base Excision

FEN1 plays critical roles in long patch base excision repair (LP-BER), Okazaki fragment maturation, and rescue of stalled replication forks. In a clinical cohort, FEN1 overexpression is associated with aggressive phenotype and poor progression-free survival after platinum chemotherapy. Pre-clinically, FEN1 is induced upon cisplatin treatment, and nuclear translocation of FEN1 is dependent on physical interaction with importin β. FEN1 depletion, gene inactivation, or inhibition re-sensitizes platinum-resistant ovarian cancer cells to cisplatin. BRCA2 deficient cells exhibited synthetic lethality upon treatment with a FEN1 inhibitor. FEN1 inhibitor-resistant PEO1R cells were generated, and these reactivated BRCA2 and overexpressed the key repair proteins, POLβ and XRCC1. FEN1i treatment was selectively toxic to POLβ deficient but not XRCC1 deficient ovarian cancer cells. High throughput screening of 391,275 compounds identified several FEN1 inhibitor hits that are suitable for further drug development. We conclude that FEN1 is a valid target for ovarian cancer therapy.

scholarly journals Frequency and Prognosis of Epidermal Growth Factor Receptor Variant III Mutations in Glioblastoma Multiforme among Indian Patients: A Single-Institution Study

2020 ◽  
Vol 09 (03) ◽  
pp. 126-129
Author(s):  
Wesley Mannirathil Jose ◽  
Vinayak Munirathnam ◽  
V. Narendranath ◽  
Arun Philip ◽  
Pavithran Keechilat
Keyword(s):  
Growth Factor ◽  
Glioblastoma Multiforme ◽  
Epidermal Growth Factor ◽  
World Literature ◽  
Mutational Analysis ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Rank Test ◽  
Cancer Center ◽  
Epidermal Growth

Abstract Background Glioblastoma multiforme (GBM) is a disease with poor outcome. Alterations or mutations in epidermal growth factor receptors (EGFRs) are found in GBM and may be targeted to improve outcomes. Aims We analyzed the frequency of EGFR variant III (vIII) mutations in patients with GBM and their outcomes after standard treatment. Materials and Methods This is a retrospective study conducted in a single tertiary cancer center in south India. Forty patients with GBM who had their entire treatment done at this center were identified, and their primary tumor tissue blocks were retrieved. Genomic DNA was extracted, and molecular analysis was performed and analyzed. The results of mutational analysis were correlated with treatment outcome of the patients. Statistical Analysis Survival outcome was analyzed using the Kaplan–Meier method. The log-rank test was used to assess the association between the groups and various parameters. Results Our study showed a similar incidence of EGFR vIII alterations as published in world literature, but we did not find any difference in overall survival (OS) and progression-free survival (PFS) in patients with EGFR vIII mutation compared with nonmutant cohort. Conclusions Contrary to the existing literature which indicated EGFR vIII alterations to be a negative prognostic indicator, our study did not find it to be an independent predictor of prognosis among Indian GBM patients treated with present standard of care.

scholarly journals Lorlatinib in pretreated ALK- or ROS1-positive lung cancer and impact of TP53 co-mutations: results from the German early access program

2021 ◽  
Vol 13 ◽  
pp. 175883592098055 ◽  
Author(s):  
Nikolaj Frost ◽  
Petros Christopoulos ◽  
Diego Kauffmann-Guerrero ◽  
Jan Stratmann ◽  
Richard Riedel ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Survival Rates ◽  
Real Life ◽  
Progression Free Survival ◽  
Leptomeningeal Carcinomatosis ◽  
Resistance Mutations ◽  
Duration Of Treatment ◽  
Tp53 Mutations ◽  
Early Access ◽  
Access Program

Introduction: We report on the results of the German early access program (EAP) with the third-generation ALK- and ROS1-inhibitor lorlatinib. Patients and Methods: Patients with documented treatment failure of all approved ALK/ROS1-specific therapies or with resistance mutations not covered by approved inhibitors or leptomeningeal carcinomatosis were enrolled and analyzed. Results: In total, 52 patients were included [median age 57 years (range 32–81), 54% female, 62% never smokers, 98% adenocarcinoma]; 71% and 29% were ALK- and ROS1-positive, respectively. G1202R and G2032R resistance mutations prior to treatment with lorlatinib were observed in 10 of 26 evaluable patients (39%), 11 of 39 patients showed TP53 mutations (28%). Thirty-six patients (69%) had active brain metastases (BM) and nine (17%) leptomeningeal carcinomatosis when entering the EAP. Median number of prior specific TKIs was 3 (range 1–4). Median duration of treatment, progression-free survival (PFS), response rate and time to treatment failure were 10.4 months, 8.0 months, 54% and 13.0 months. Calculated 12-, 18- and 24-months survival rates were 65, 54 and 47%, overall survival since primary diagnosis (OS2) reached 79.6 months. TP53 mutations were associated with a substantially reduced PFS (3.7 versus 10.8 month, HR 3.3, p = 0.003) and were also identified as a strong prognostic biomarker (HR for OS2 3.0 p = 0.02). Neither prior treatments with second-generation TKIs nor BM had a significant influence on PFS and OS. Conclusions: Our data from real-life practice demonstrate the efficacy of lorlatinib in mostly heavily pretreated patients, providing a clinically meaningful option for patients with resistance mutations not covered by other targeted therapies and those with BM or leptomeningeal carcinomatosis.

scholarly journals 1-Year Evaluation of OT Bridge Abutments for Immediately Loaded Maxillary Fixed Restorations: A Multicenter Study

2021 ◽  
Author(s):  
Rosario Acampora ◽  
Marco Montanari ◽  
Roberto Scrascia ◽  
Emiliano Ferrari ◽  
Massimo Pasi ◽  
...  
Keyword(s):  
Survival Rates ◽  
Health Impact ◽  
P Value ◽  
Success Rates ◽  
Marginal Bone Loss ◽  
Bridge Abutments ◽  
Bleeding On Probing ◽  
Fixed Dental Prosthesis ◽  
Low Profile ◽  
One Year

Abstract Objective  Preliminary data on survival and success rates of immediately loaded, maxillary, screw-retained, implant-supported, fixed restorations delivered on narrow and low-profile OT Equator abutments (OT Bridge, Rhein’83) were evaluated. Materials and Methods This retrospective study evaluated data collected from patients rehabilitated with OT Bridge prosthetic concept between November 2017 and February 2019 in six different centers. Outcome measures were implant and prosthetic survival rates, biological and technical complications, marginal bone loss (MBL), oral health impact profile (OHIP), bleeding on probing, and plaque index. Results A total of 76 implants were inserted in 14 patients. Patients were followed for a mean period of 15.8 months (range = 12–24). All the patients receive OT Equator (Rhein'83) as intermediate abutments. One year after loading, one implant failed (1.3%). None of the prosthesis failed. One prosthetic complication was experienced in one patient. Three out of 76 implants were connected to the prosthetic framework using only the Seeger system, without screw. Difference in OHIP values was statistically significant (71.9 ± 8.5; p = 0.000). One year after loading, MBL was 0.21 ± 0.11 mm and p-value was 0.000. One year after loading, 8.7% of the examined implant sites present positive bleeding on probing, while 6.4% of the implant sites presented plaque. Conclusion The OT Equator abutments (Rhein'83) showed successful results when used to support maxillary fixed dental prosthesis delivered on four to six implants. High implant and prosthetic survival rates, very low complications, high patient satisfaction, and good biological parameters, including only 0.2 mm of bone remodeling were experienced one year after function. Further studies are needed to confirm these preliminary results.

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