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BMC Pulmonary Medicine Sep 2021Dyskeratosis congenita (DC) is a rare genetic disorder of poor telomere maintenance. Pulmonary fibrosis (PF) related to DC is rarely reported.
BACKGROUND
Dyskeratosis congenita (DC) is a rare genetic disorder of poor telomere maintenance. Pulmonary fibrosis (PF) related to DC is rarely reported.
CASE PRESENTATION
A 23-year-old student presented with a four-year history of progressive cough and exertional dyspnea. Physical examination was remarkable for typical mucocutaneous abnormalities. Chest computerized tomography scan revealed interstitial fibrosis. Testing of peripheral blood leukocytes confirmed that his telomeres were 30th percentile of age-matched controls. A heterozygous missense mutation located in exon 22 of PARN gene was identified in the patient by whole exome sequencing. The patient refused danazol therapy and lung transplantation, and died of respiratory failure 2 years later. In addition, this case and 26 reported cases of DC-related PF identified through the comprehensive search of PubMed, Web of Science, WANFANG and CNKI were reviewed. Later-onset PF was observed in 11 patients (40.7%). Radiological usual interstitial pneumonia (UIP) pattern or possible UIP pattern was noted only in half of patients. However, histopathological UIP or probable UIP patterns were found in 63.6% of patients. Age at bone marrow failure (BMF) and the frequency of normal to mild thrombocytopenia in later-onset patients was significantly higher than in early-onset patients (p = 0.017 and p = 0.021, respectively). Age at PF and age at BMF in DC patients with TERC/TERT variants was significantly higher than in those with TINF2 variants or DKC1/NHP2 variants (p = 0.004 and p = 0.003, respectively). The patients with TERT/TERC/RTEL1/PARN variants had a significantly better transplant-free survival than those with TINF2 variants or DKC1/NHP2 variants (p < 0.05). Patients who underwent surgical lung biopsy had significantly worse transplant-free survival than those without lung biopsy (p = 0.042). Worse survival was found in patients with immunosuppression therapy than in those without (p = 0.012).
CONCLUSIONS
It is common for DC-associated PF to occur later in life without significant hematological manifestations. Mutations in the genes encoding different components of the telomere maintenance pathway were associated with clinical phenotypes and prognosis. PF caused by DC should be kept in mind by clinicians in the differential diagnosis of patients with unexplained PF and should be excluded before diagnostic surgical lung biopsy is undertaken or empirical immunosuppression therapy is prescribed.
Topics: Cell Cycle Proteins; DNA Helicases; Dyskeratosis Congenita; Fatal Outcome; Humans; Idiopathic Pulmonary Fibrosis; Male; Nuclear Proteins; Telomere-Binding Proteins; Young Adult
PubMed: 34479523
DOI: 10.1186/s12890-021-01645-w -
Cancer Control : Journal of the Moffitt... 2021Gliomas are the most prevalent brain tumors among children and adolescents. The occurrence and development of various malignant tumors is closely related with gene, but...
Gliomas are the most prevalent brain tumors among children and adolescents. The occurrence and development of various malignant tumors is closely related with gene, but its relationship with glioma susceptibility has not been widely discovered. In this case-control study, we conducted four single nucleotide polymorphisms (SNPs) (rs3811464 G>A, rs3811463 T>C, rs34787247 G>A, and rs11247957 G>A) of gene to investigate whether they increase the risk of glioma. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate their relationship. There was no significant correlation between four SNPs and glioma risk in single polymorphism and conjoint analysis. However, in stratification analysis, we found that rs3811463 TC/CC may add to the risk of glioma with clinical stage III (adjusted OR = 3.16, 95% CI = 1.15-8.70, P = .026) or stage III+IV patients (adjusted OR = 2.05, 95% CI = 1.02-4.13, P = .044). Our research suggested that four SNPs of gene have a weak relationship with the risk of glioma in Chinese children. rs3811463 TC/CC may increase the possibility of glioma in clinical stage III or stage III+IV patients which need larger samples and further confirmation.
Topics: Biomarkers, Tumor; Brain Neoplasms; Child; China; DNA, Neoplasm; Genetic Predisposition to Disease; Genotype; Glioma; Humans; Neoplasm Staging; Polymorphism, Single Nucleotide; RNA-Binding Proteins
PubMed: 34468231
DOI: 10.1177/10732748211040009 -
Drug Design, Development and Therapy 2021Various imidazole-containing compounds have been tested for their medical usefulness in clinical trials for several disease conditions. The rapid expansion of...
Various imidazole-containing compounds have been tested for their medical usefulness in clinical trials for several disease conditions. The rapid expansion of imidazole-based medicinal chemistry suggests the promising and potential therapeutic values of imidazole-derived compounds for treating incurable diseases. Imidazole core scaffold contains three carbon atoms, and two nitrogen with electronic-rich characteristics that are responsible for readily binding with a variety of enzymes, proteins, and receptors compared to the other heterocyclic rings. Herein, we provide a thorough overview of the current research status of imidazole-based compounds with a wide variety of biological activities including anti-cancer, anti-microbial, anti-inflammatory and their potential mechanisms including topoisomerase IIR catalytic inhibition, focal adhesion kinase (FAK) inhibition, c-MYC G-quadruplex DNA stabilization, and aurora kinase inhibition. Additionally, a great interest was reported in the discovery of novel imidazole compounds with anti-microbial properties that break DNA double-strand helix and inhibit protein kinase. Moreover, anti-inflammatory mechanisms of imidazole derivatives include inhibition of COX-2 enzyme, inhibit neutrophils degranulation, and generation of reactive oxygen species. This systemic review helps to design and discover more potent and efficacious imidazole compounds based on the reported derivatives, their ADME profiles, and bioavailability scores that together aid to advance this class of compounds.
Topics: Animals; Anti-Inflammatory Agents; Chemistry, Pharmaceutical; Humans; Imidazoles; Protein Kinase Inhibitors
PubMed: 34354342
DOI: 10.2147/DDDT.S307113 -
Acta Neuropathologica Communications Aug 2021Although the right temporal variant frontotemporal dementia (rtvFTD) is characterised by distinct clinical and radiological features, its underlying histopathology...
Although the right temporal variant frontotemporal dementia (rtvFTD) is characterised by distinct clinical and radiological features, its underlying histopathology remains elusive. Being considered a right-sided variant of semantic variant primary progressive aphasia (svPPA), TDP-43 type C pathology has been linked to the syndrome, but this has not been studied in detail in large cohorts. In this case report and systematic review, we report the autopsy results of five subjects diagnosed with rtvFTD from our cohort and 44 single rtvFTD subjects from the literature. Macroscopic pathological evaluation of the combined results revealed that rtvFTD demonstrated either a frontotemporal or temporal evolution, even if the degeneration started in the right temporal lobe initially. FTLD-TDP type C was the most common underlying pathology in rtvFTD, however, in 64% of rtvFTD, other underlying pathologies than FTLD-TDP type C were present, such as Tau-MAPT and FTLD-TDP type A and B. Additionally, accompanying motor neuron or corticospinal tract degeneration was observed in 28% of rtvFTD patients. Our results show that in contrast to the general assumption, rtvFTD might not be a pure FTLD-TDP type C disorder, unlike its left temporal counterpart svPPA. Large sample size pathological studies are warranted to understand the diverse pathologies of the right and left temporal variants of frontotemporal dementia.
Topics: Aged; Aphasia, Primary Progressive; DNA-Binding Proteins; Female; Frontotemporal Dementia; Functional Laterality; Humans; Male; Middle Aged; Neuropsychological Tests
PubMed: 34344452
DOI: 10.1186/s40478-021-01229-z -
Journal of Ovarian Research Jun 2021To explore the relationship between ERCC1 rs11615 polymorphism and chemosensitivity to platinum drugs in ovarian cancer by the method of meta-analysis. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To explore the relationship between ERCC1 rs11615 polymorphism and chemosensitivity to platinum drugs in ovarian cancer by the method of meta-analysis.
METHODS
Pubmed, Web of Science, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI), and China Wanfang databases were comprehensively searched up to September 2020, to identify the relationship between ERCC1 rs11615 polymorphism and chemosensitivity of ovarian cancer. The data was analyzed by Stata 15.0 statistic software.
RESULTS
A total of 10 published papers were included, including 1866 patients with ovarian cancer. The results showed that compared allele C at ERCC1 rs11615 locus with allele T, the pooled OR was 0.92 (95%CI:0.68 ~ 1.24, P > 0.05). There were no significant differences in recessive, dominant, homozygous, and heterozygous models. In accordance with a subgroup analysis of Ethnicity, all genotypes were statistically significant in the Asian population. In the allelic, dominant, recessive, homozygous and heterozygous models, the OR was 0.70 (95%CI:0.51 ~ 0.95), 0.20 (95%CI:0.07 ~ 0.56), 0.79 (95%CI:0.63 ~ 1.00), 0.21 (95%CI:0.07 ~ 0.59), 0.19 (95%CI:0.07 ~ 0.54), respectively, while in the Caucasian population, no statistically significant genotype was found.
CONCLUSION
The ERCC1 rs11615 polymorphism is associated with chemosensitivity in patients with ovarian cancer, especially in the Asian population, but not in the Caucasian population.
Topics: DNA-Binding Proteins; Endonucleases; Female; Humans; Ovarian Neoplasms; Platinum; Polymorphism, Genetic
PubMed: 34148553
DOI: 10.1186/s13048-021-00831-y -
Frontiers in Immunology 2021Bispecific antibodies (BsAbs) are antibodies with two binding sites directed at two different antigens or two different epitopes on the same antigen. The clinical...
Bispecific antibodies (BsAbs) are antibodies with two binding sites directed at two different antigens or two different epitopes on the same antigen. The clinical therapeutic effects of BsAbs are superior to those of monoclonal antibodies (MoAbs), with broad applications for tumor immunotherapy as well as for the treatment of other diseases. Recently, with progress in antibody or protein engineering and recombinant DNA technology, various platforms for generating different types of BsAbs based on novel strategies, for various uses, have been established. More than 30 mature commercial technology platforms have been used to create and develop BsAbs based on the heterologous recombination of heavy chains and matching of light chains. The detailed mechanisms of clinical/therapeutic action have been demonstrated with these different types of BsAbs. Three kinds of BsAbs have received market approval, and more than 110 types of BsAbs are at various stages of clinical trials. In this paper, we elaborate on the classic platforms, mechanisms, and applications of BsAbs. We hope that this review can stimulate new ideas for the development of BsAbs and improve current clinical strategies.
Topics: Animals; Antibodies, Bispecific; Antibody Specificity; Binding Sites, Antibody; Biotechnology; Drug Design; Epitopes; Humans; Immunotherapy; Protein Engineering; Recombinant Proteins; Translational Research, Biomedical
PubMed: 34025638
DOI: 10.3389/fimmu.2021.626616 -
Histopathology Oct 2021There has been an increased demand for mismatch repair (MMR) status testing in sarcoma patients after the success of immune checkpoint inhibition (ICI) in MMR deficient...
INTRODUCTION
There has been an increased demand for mismatch repair (MMR) status testing in sarcoma patients after the success of immune checkpoint inhibition (ICI) in MMR deficient tumors. However, data on MMR deficiency in bone and soft tissue tumors is sparse, rendering it unclear if routine screening should be applied. Hence, we aimed to study the frequency of MMR deficiency in bone and soft tissue tumors after we were prompted by two (potential) Lynch syndrome patients developing sarcomas.
METHODS
Immunohistochemical expression of MLH1, PMS2, MSH2 and MSH6 was assessed on tissue micro arrays (TMAs), and included 353 bone and 539 soft tissue tumors. Molecular data was either retrieved from reports or microsatellite instability (MSI) analysis was performed. In MLH1 negative cases, additional MLH1 promoter hypermethylation analysis followed. Furthermore, a systematic literature review on MMR deficiency in bone and soft tissue tumors was conducted.
RESULTS
Eight MMR deficient tumors were identified (1%), which included four leiomyosarcoma, two rhabdomyosarcoma, one malignant peripheral nerve sheath tumor and one radiation-associated sarcoma. Three patients were suspected for Lynch syndrome. Literature review revealed 30 MMR deficient sarcomas, of which 33% were undifferentiated/unclassifiable sarcomas. 57% of the patients were genetically predisposed.
CONCLUSION
MMR deficiency is rare in bone and soft tissue tumors. Screening focusing on tumors with myogenic differentiation, undifferentiated/unclassifiable sarcomas and in patients with a genetic predisposition / co-occurrence of other malignancies can be helpful in identifying patients potentially eligible for ICI.
Topics: Adult; Biomarkers, Tumor; Bone Neoplasms; Brain Neoplasms; Colorectal Neoplasms; DNA-Binding Proteins; Humans; Male; Middle Aged; Mismatch Repair Endonuclease PMS2; MutL Protein Homolog 1; MutS Homolog 2 Protein; Neoplastic Syndromes, Hereditary; Soft Tissue Neoplasms
PubMed: 33825202
DOI: 10.1111/his.14377 -
Archives of Gynecology and Obstetrics Jun 2021The Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) groups has identified four molecular prognostic groups of endometrial cancer (EC): POLE-mutated... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) groups has identified four molecular prognostic groups of endometrial cancer (EC): POLE-mutated (POLE-mt), mismatch repair-deficient (MMR-d), p53-abnormal (p53-abn), p53-wild-type (p53-wt). These groups might have different pathogenesis and risk factors, and might occur in different phenotypes of patients. However, these data are still lacking.
OBJECTIVE
To provide a clinical characterization of the ProMisE groups of EC.
METHODS
A systematic review and meta-analysis was performed by searching seven electronic databases from their inception to December 2020, for all studies reporting clinical characteristics of EC patients in each ProMisE group. Pooled means of age and BMI and pooled prevalence of FIGO stage I and adjuvant treatment in each ProMisE group were calculated.
RESULTS
Six studies with 1, 879 women were included in the systematic review. Pooled means (with standard error) and prevalence values were: in the MMR-d group, age = 66.5 ± 0.6; BMI = 30.6 ± 1.2; stage I = 72.6%; adjuvant treatment = 47.3%; in the POLE-mt group, age = 58.6 ± 2.7; BMI = 27.2 ± 0.9; stage I = 93.7%; adjuvant treatment = 53.6%; in the p53-wt group, age = 64.2 ± 1.9; BMI = 32.3 ± 1.4; stage I = 80.5%; adjuvant treatment = 45.3%; in the p53-abn group, age = 71.1 ± 0.5; BMI = 29.1 ± 0.5; stage I = 50.8%; adjuvant treatment = 64.4%.
CONCLUSION
The ProMisE groups identify different phenotypes of patients. The POLE-mt group included the youngest women, with the lower BMI and the highest prevalence of stage I. The p53-wt group included patients with the highest BMI. The p53-abn group included the oldest women, with the highest prevalence of adjuvant treatment and the lowest prevalence of stage I. The MMR-d group showed intermediate values among the ProMisE groups for all clinical features.
Topics: Aged; Biomarkers, Tumor; DNA Polymerase II; Endometrial Neoplasms; Female; Genes, p53; Humans; Middle Aged; Mutation; PTEN Phosphohydrolase; Phenotype; Poly-ADP-Ribose Binding Proteins; Prognosis; Risk Assessment; Tumor Suppressor Protein p53
PubMed: 33754186
DOI: 10.1007/s00404-021-06028-4 -
Medicine Mar 2021Chromodomain helicase DNA-binding protein 1-like (CHD1L) is an oncogene. It was cloned from 1q21 chromosome region of hepatocellular carcinoma in 1991. CHD1L is... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Chromodomain helicase DNA-binding protein 1-like (CHD1L) is an oncogene. It was cloned from 1q21 chromosome region of hepatocellular carcinoma in 1991. CHD1L is up-regulated in many kinds of cancers and is involved in the carcinogenesis and development of tumors. More and more studies have shown that over-expression of CHD1L is associated with poor prognosis of tumors. The purpose of this study was to evaluate the prognostic value of CHD1L in human solid tumors.
METHODS
The key words in the database of PubMed, Web of Science, Embase, Cochrane library, and TCGA were searched for systematic literature retrieval. We collected relevant articles and data about CHD1L and prognosis of cancer and screened them according to the eligible criteria to evaluate the prognostic value of CHD1L in cancer patients. Then Stata SE12.0 software is used to analyze the data.
RESULTS
In our meta-analysis, 2720 patients with a total of 15 articles involving multiple types of tumors showed that high expression levels of CHD1L were associated with shorter overall survival (OS) (hazard ratio = 2.21, 95% confidence interval [CI]: (1.49-3.30)] and (hazard ratio = 1.16, 95% CI: (1.01-1.32)] in the TCGA database, in addition, the pooled odds ratios (ORs) indicated high expression levels of CHD1L in tumors significantly are associated with TNM stage (OR = 1.61, 95% CI: 1.01-2.55, P < .05), tumor size (OR = 1.38, 95% CI: 1.07-1.78, P < .05), tumor differentiation (OR = 2.13, 95% CI: 1.43-3.16, P < .05), and distant metastasis (OR = 1.86, 95% CI: 1.45-2.39 P < .05). However, we did not observe a significant correlation between the high expression of CHD1L and age, gender.
CONCLUSION
The high expression of CHD1L is associated with poor OS as well as related to tumor differentiation, tumor size, and distant metastasis, which can be served as a prognostic marker and a potential predictor of clinical pathology in human solid tumors.
Topics: Biomarkers, Tumor; DNA Helicases; DNA-Binding Proteins; Humans; Neoplasm Metastasis; Neoplasms; Prognosis; Survival Analysis; Tumor Burden; Up-Regulation
PubMed: 33725840
DOI: 10.1097/MD.0000000000024851 -
International Journal of Rheumatic... May 2021To evaluate the diagnostic value of anti-citrullinated α-enolase peptide 1 (anti-CEP 1) antibody in patients with rheumatoid arthritis (RA) by conducting a systematic... (Meta-Analysis)
Meta-Analysis
AIM
To evaluate the diagnostic value of anti-citrullinated α-enolase peptide 1 (anti-CEP 1) antibody in patients with rheumatoid arthritis (RA) by conducting a systematic review and meta-analysis.
METHODS
The PubMed, Web of Science, Embase, Scopus, and Cochrane Library databases were searched for relevant studies published until September 23, 2020. A bivariate mixed-effects model was used to calculate the diagnostic indices from primary data of eligible studies. We performed meta-regression and subgroup analysis to explore the sources of heterogeneity.
RESULTS
Twenty-four articles, with a total of 17 380 patients with RA and 7505 control participants, met the criteria for inclusion in the meta-analysis. The pooled sensitivity, specificity, and positive and negative likelihood ratios for the anti-CEP 1 antibody were 44% (95% CI: 38%-51%), 97% (95% CI: 96%-98%), and 14.81 (95% CI: 10.66-20.57) and 0.57 (95% CI: 0.52-0.64), respectively. The pooled positive and negative predictive values were 0.96 (95% CI: 0.95-0.97) and 0.53 (95% CI: 0.43-0.63), respectively. The area under the summary receiver operating characteristic curve was 0.86. Meta-regression indicated that the anti-CEP 1 antibody detection method may be a source of heterogeneity. The subgroup analysis of the group in which the anti-CEP 1 antibody was detected by using a commercial enzyme-linked immunosorbent assay (ELISA) kit had a sensitivity of 59% (95% CI: 50%-68%) and a specificity of 93% (95% CI: 85%-97%).
CONCLUSIONS
The anti-CEP 1 antibody had moderate RA diagnostic value with relatively low sensitivity and high specificity. An ELISA may increase the RA diagnostic sensitivity.
Topics: Anti-Citrullinated Protein Antibodies; Antibodies; Arthritis, Rheumatoid; Biomarkers, Tumor; DNA-Binding Proteins; Enzyme-Linked Immunosorbent Assay; Genetic Predisposition to Disease; Humans; Peptides, Cyclic; Phosphopyruvate Hydratase; Sensitivity and Specificity; Tumor Suppressor Proteins
PubMed: 33713557
DOI: 10.1111/1756-185X.14093