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Technology in Cancer Research &... 2021The purpose of this meta-analysis was to study the prognostic effects of androgen receptor splicing variant 7 (AR-V7) on metastatic castration-resistant prostate cancer... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The purpose of this meta-analysis was to study the prognostic effects of androgen receptor splicing variant 7 (AR-V7) on metastatic castration-resistant prostate cancer (mCRPC) under different treatment options (chemotherapy, hormone therapy).
METHODS
We conducted a systematic search of PubMed, EMBASE and Cochrane databases for clinical studies up to June 4, 2021, and used prostate-specific antigen (PSA) progression free-survival (PSA-PFS), radiologic PFS (r-PFS), overall survival (OS) and PSA response rate (PSA RR) as the main endpoints. Subgroup analyses were conducted based on the source of the specimens. STATA v.15 software was used for data analysis.
RESULTS
Twenty-one studies were included in this meta-analysis, with a total of 1578 samples. In the abiraterone (AA)/enzalutamide (E) treatment group, AR-V7 positive patients had worse PSA-PFS (hazard ratio [HR] = 3.40; 95% confidence interval [95%CI] 2.56-4.51; < 0.05) and worse r-PFS (HR = 2.69; 95%CI 1.70-4.24; < 0.05) and OS (HR = 3.02; 95%CI 1.73-5.30; < 0.05). Multivariate Cox regression results showed that AR-V7 positive status was an independent risk factor for OS in the AA/E treatment group. In the taxane treatment group, AR-V7-positive and negative patients had similar PSA-PFS (HR = 0.87; 95%CI 0.46-1.63; = 0.657), r-PFS (HR = 1.01; 95%CI 0.53-1.96; = 0.965) and OS (HR = 1.50; 95%CI 0.89-2.52; = 0.127). For AR-V7-positive patients, the difference in OS between taxane and AA/E treatment was not statistically significant (HR = 1.03; 95%CI 0.52-2.06; = 0.930). However, multivariate Cox regression results suggested that for AR-V7-positive patients, taxane therapy was a protective factor for OS (HR = 0.35; 95%CI 0.20-0.60; < 0.05).
CONCLUSION
The expression of AR-V7 indicates a poor prognosis and is an independent risk factor for OS in AA/E-treated mCRPC patients. However, AR-V7 positive status does not play the same role in taxane-treated patients. In addition, compared to AA/E, taxane treatment is a protective factor for OS in AR-V7-positive patients. AR-V7 may thus be an effective biomarker for treatment prognosis in patients with mCRPC.
Topics: Alternative Splicing; Biomarkers, Tumor; Humans; Male; Prognosis; Proportional Hazards Models; Prostatic Neoplasms, Castration-Resistant; RNA Isoforms; Receptors, Androgen
PubMed: 34313171
DOI: 10.1177/15330338211035260 -
Iranian Journal of Pathology 2018Acute myeloid leukemia (AML) as a distortion of blood cells involves the differ entiation of hematopoietic stem cells. Several studies established the irregular over... (Review)
Review
Acute myeloid leukemia (AML) as a distortion of blood cells involves the differ entiation of hematopoietic stem cells. Several studies established the irregular over expression of specific genes is a common finding in patients with AML. The ectopic viral integration site-1 () gene is a protooncogene subject to alternative splicing, and encodes a zincfinger protein that acts as a transcriptional regulator in early devel opment. Forced overexpression of in hematopoietic progenitors later induced a myeloid differentiation block. The current review aimed at determining the prognos tic value of expression in patients with AML in the age range of one month to fifteen years. The scientific databases including PubMed, Google Scholar, EMBASE, Scopus, and ISI published up to January 2016 were searched using the conformity keywords and a total of four articles were studied. Three articles declared higher overexpression of in patients with mixed-lineage leukemia (MLL) rearrangements. The percentage of overall survival (OS), reported in two articles, decreased in AML patients with high EVI1 expression. A study reported that the relationship between EVI1 expression and OS was negligible in cases with and without expression. Another study showed significant differences in event free survival (EFS) and OS in the group of patients with positive MLL-AF9 between + and patients. The current study revealed that high expression was not a poor prognostic factor in pediatric patients with AML. And this gene expression was mainly prognostic concomitantly by other factors such as MLL rearrangement, expression, and white blood cell (WBC) count.
PubMed: 30636951
DOI: No ID Found -
Biological Psychiatry Oct 2019Many polymorphisms in dopamine genes are reported to affect cognitive, imaging, or clinical phenotypes. It is often inferred or assumed that such associations are... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Many polymorphisms in dopamine genes are reported to affect cognitive, imaging, or clinical phenotypes. It is often inferred or assumed that such associations are causal, mediated by a direct effect of the polymorphism on the gene product itself. However, the supporting evidence is not always clear.
METHODS
We conducted systematic reviews and meta-analyses to assess the empirical evidence for functional polymorphisms in genes encoding dopaminergic enzymes (COMT, DBH, DDC, MAOA, MAOB, and TH), dopamine receptors (DRD1, DRD2, DRD3, DRD4, and DRD5), the dopamine transporter (DAT), and vesicular transporters (VMAT1 and VMAT2). We defined functionality as an effect of the polymorphism on the expression, abundance, activity, or affinity of the gene product.
RESULTS
We screened 22,728 articles and identified 255 eligible studies. We found robust and medium to large effects for polymorphisms in 4 genes. For catechol-O-methyltransferase (COMT), the ValMet polymorphism (rs4680) markedly affected enzyme activity, protein abundance, and protein stability. Dopamine β-hydroxylase (DBH) activity was associated with rs1611115, rs2519152, and the DBH-STR polymorphism. Monoamine oxidase A (MAOA) activity was associated with a 5' VNTR polymorphism. Dopamine D receptor (DRD2) binding was influenced by the Taq1A (rs1800497) polymorphism, and rs1076560 affected DRD2 splicing.
CONCLUSIONS
Some widely studied dopaminergic polymorphisms clearly and substantially affect the abundance or activity of the encoded gene product. However, for other polymorphisms, evidence of such an association is negative, inconclusive, or lacking. These findings are relevant when selecting polymorphisms as "markers" of dopamine function, and for interpreting the biological plausibility of associations between these polymorphisms and aspects of brain function or dysfunction.
Topics: Brain; Dopamine; Dopamine Plasma Membrane Transport Proteins; Humans; Polymorphism, Single Nucleotide; Receptors, Dopamine
PubMed: 31303260
DOI: 10.1016/j.biopsych.2019.05.014 -
Future Oncology (London, England) Dec 2018In September 2017, the US FDA announced re-approval of gemtuzumab ozogamicin (GO), a CD33-targeting immunoconjugate, for treatment of newly diagnosed and... (Meta-Analysis)
Meta-Analysis
In September 2017, the US FDA announced re-approval of gemtuzumab ozogamicin (GO), a CD33-targeting immunoconjugate, for treatment of newly diagnosed and relapsed/refractory acute myeloid leukemia (AML). This is a very significant step toward defining new treatment regimens in AML, as the treatment has essentially stayed unchanged with the '7 + 3 induction regimen' (7 days cytarabine and 3 days of anthracycline) since 1973. GO is the first antibody-drug conjugate to receive FDA approval for treating cancer. This review article discusses the challenges faced and lessons learned during the journey of GO for AML treatment. Selected trials that have made significant contribution in our understanding of the most efficacious and safe use of GO for treating AML patients as well as factors influencing GO response are highlighted in this article.
Topics: Age Factors; Aminoglycosides; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Biomarkers, Tumor; Drug Discovery; France; Gemtuzumab; Humans; Leukemia, Myeloid, Acute; Molecular Targeted Therapy; Randomized Controlled Trials as Topic; Sialic Acid Binding Ig-like Lectin 3; Treatment Outcome; United States
PubMed: 30039981
DOI: 10.2217/fon-2018-0325 -
European Journal of Human Genetics :... Apr 2017Fragile-X syndrome (FXS) is a frequent genetic form of intellectual disability (ID). The main recurrent mutagenic mechanism causing FXS is the expansion of a CGG repeat... (Meta-Analysis)
Meta-Analysis
Fragile-X syndrome (FXS) is a frequent genetic form of intellectual disability (ID). The main recurrent mutagenic mechanism causing FXS is the expansion of a CGG repeat sequence in the 5'-UTR of the FMR1 gene, therefore, routinely tested in ID patients. We report here three FMR1 intragenic pathogenic variants not affecting this sequence, identified using high-throughput sequencing (HTS): a previously reported hemizygous deletion encompassing the last exon of FMR1, too small to be detected by array-CGH and inducing decreased expression of a truncated form of FMRP protein, in three brothers with ID (family 1) and two splice variants in boys with sporadic ID: a de novo variant c.990+1G>A (family 2) and a maternally inherited c.420-8A>G variant (family 3). After clinical reevaluation, the five patients presented features consistent with FXS (mean Hagerman's scores=15). We conducted a systematic review of all rare non-synonymous variants previously reported in FMR1 in ID patients and showed that six of them are convincing pathogenic variants. This study suggests that intragenic FMR1 variants, although much less frequent than CGG expansions, are a significant mutational mechanism leading to FXS and demonstrates the interest of HTS approaches to detect them in ID patients with a negative standard work-up.
Topics: Female; Fragile X Mental Retardation Protein; Fragile X Syndrome; Humans; Male; Middle Aged; Mutation; Polymorphism, Single Nucleotide; RNA Splicing; Siblings
PubMed: 28176767
DOI: 10.1038/ejhg.2016.204