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Diagnostics (Basel, Switzerland) Mar 2023Parkinson's disease is the second most common neurodegenerative disorder, affecting 2-3% of the population of patients >65 years. Although the standard diagnosis of PD... (Review)
Review
Parkinson's disease is the second most common neurodegenerative disorder, affecting 2-3% of the population of patients >65 years. Although the standard diagnosis of PD is clinical, neuroimaging plays a key role in the evaluation of patients who present symptoms related to neurodegenerative disorders. MRI, DAT-SPECT, and PET with [F]-FDG are routinely used in the diagnosis and focus on the investigation of morphological changes, nigrostriatal degeneration or shifts in glucose metabolism in patients with parkinsonian syndromes. The aim of this study is to review the current PET radiotracers targeting TSPO, a transmembrane protein that is overexpressed by microglia in another pathophysiological process associated with neurodegenerative disorders known as neuroinflammation. To the best of our knowledge, neuroinflammation is present not only in PD but in many other neurodegenerative disorders, including AD, DLB, and MSA, as well as atypical parkinsonian syndromes. Therefore, in this study, specific patterns of microglial activation in PD and the differences in distribution volumes of these radiotracers in patients with PD as compared to other neurodegenerative disorders are reviewed.
PubMed: 36980337
DOI: 10.3390/diagnostics13061029 -
Journal of Cellular Physiology May 2023Heparanase (HPSE; heparanase-1) is an endo-β-glucuronidase capable of degrading the carbohydrate moiety of heparan sulfate proteoglycans, thus modulating and... (Review)
Review
Heparanase (HPSE; heparanase-1) is an endo-β-glucuronidase capable of degrading the carbohydrate moiety of heparan sulfate proteoglycans, thus modulating and facilitating the remodeling of the extracellular matrix and basement membrane. HPSE activity is strongly associated with major human pathological complications, including but not limited to tumor progress and angiogenesis. Several lines of literature have shown that overexpression of HPSE leads to enhanced tumor growth and metastatic transmission, as well as poor prognosis. Gene silencing of HPSE or treatment of tumor with compounds that block HPSE activity are shown to remarkably attenuate tumor progression. Therefore, targeting HPSE is considered as a potential therapeutical strategy for the treatment of cancer. Intriguingly, recent findings disclose that heparanase-2 (HPSE-2), a close homolog of HPSE but lacking enzymatic activity, can also regulate antitumor mechanisms. Given the pleiotropic roles of HPSE, further investigation is in demand to determine the precise mechanism of regulating action of HPSE in different cancer settings. In this review, we first summarize the current understanding of HPSE, such as its structure, subcellular localization, and tissue distribution. Furthermore, we systematically review the pro- and antitumorigenic roles and mechanisms of HPSE in cancer progress. In addition, we delineate HPSE inhibitors that have entered clinical trials and their therapeutic potential.
Topics: Humans; Neoplasms; Heparan Sulfate Proteoglycans; Glucuronidase; Extracellular Matrix
PubMed: 36924082
DOI: 10.1002/jcp.30995 -
International Journal of Molecular... Feb 2023Anti-HER2 therapies have dramatically improved the prognosis of human epidermal growth factor receptor 2 (HER2)-overexpressing cancers. However, the correlation between... (Meta-Analysis)
Meta-Analysis Review
Anti-HER2 therapies have dramatically improved the prognosis of human epidermal growth factor receptor 2 (HER2)-overexpressing cancers. However, the correlation between the copy number and the response rate to anti-HER2 remains unclear. Here, following the PRISMA method, we performed a meta-analysis in the neoadjuvant setting in breast cancer to study the association between the amplification level and the pathological complete response (pCR) to anti-HER2 therapies. Nine articles (four clinical trials, five observational studies) were retrieved after full-text screening, involving 11,238 women with locally advanced breast cancer in the neoadjuvant setting. The median ratio cut-off value was 5.0 ± 5.0 (min-max = 1.0-14.0). For the overall population, the median pCR rate was 48% using the random effect model. The studies were categorized in quartiles as follows: ≤2 (Class 1); 2.1 to 5.0 (Class 2); 5.1 to 7.0 (Class 3); and >7.0 (Class 4). After grouping, the pCR rates were 33%, 49%, 57%, and 79%, respectively. When we excluded the study by Greenwell et al., which accounted for 90% of the patients, using the same quartiles, we still observed an increasing rate of pCR as the ratio increased. This is the first meta-analysis demonstrating the relationship between the amplification level and the percentage of pCR in the neoadjuvant setting among women with HER2-overexpressing breast cancer, with potential therapeutic applications.
Topics: Female; Humans; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Neoadjuvant Therapy; Receptor, ErbB-2
PubMed: 36834998
DOI: 10.3390/ijms24043590 -
Biomolecules Jan 2023The role of matrix metalloproteinases (MMPs) in routine cardiac operations including cardiopulmonary bypass (CPB) is still poorly explored. The purpose of this... (Review)
Review
The role of matrix metalloproteinases (MMPs) in routine cardiac operations including cardiopulmonary bypass (CPB) is still poorly explored. The purpose of this systematic review was to thoroughly summarize and discuss the existing knowledge of the MMP profile in cardiac surgery. All studies meeting the inclusion criteria (i.e., those reporting detailed data about MMP release during and after CPB) were selected after screening the literature published between July 1975 and August 2022. Fifteen trials that enrolled a total of 431 participants were included. MMP levels were found to be significantly correlated with CPB in all included studies. The gelatinases MMP-2 and MMP-9 were highly released in cardiac surgery with CPB. MMP-9 levels were found to be increased after CPB start and during the duration of CPB. Particularly, it is overexpressed both in the myocardial tissue and circulating in the bloodstream. Also, MMP-2 levels increased after CPB both in plasma and in myocardial tissue. MMP-7, MMP-8, and MMP-13 levels increased after CPB start and remained elevated up to 6 h later. Increased levels of MMPs were associated with adverse post-operative outcomes. Conversely, TIMP-1 decreased with CPB. Mechanical and pharmacological strategies were applied in two studies to analyze their effect on the inflammatory response to cardiac surgery and CPB and on postoperative outcomes. New targeted MMP inhibitor therapies could protect against systemic inflammatory response syndrome after CPB and should be the subject of future large prospective multicenter randomized clinical trials.
Topics: Humans; Matrix Metalloproteinase 9; Matrix Metalloproteinase 2; Prospective Studies; Cardiac Surgical Procedures; Myocardium; Multicenter Studies as Topic
PubMed: 36671498
DOI: 10.3390/biom13010113 -
Expert Review of Molecular Diagnostics Dec 2022Cell migration-inducing and hyaluronan-binding protein () is overexpressed in several cancers and is related to prognosis in cancer patients. Here, we conducted a... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Cell migration-inducing and hyaluronan-binding protein () is overexpressed in several cancers and is related to prognosis in cancer patients. Here, we conducted a meta-analysis to explore the prognostic effects of in cancer patients.
METHODS
Relevant published studies were systematically searched in four databases. The role of was evaluated using pooled hazard ratios (HRs), odd ratios (ORs), and 95% confidence intervals (95% CIs). The Cancer Genome Atlas (TCGA) was used to investigate the prognostic value of in various cancers.
RESULTS
11 literatures with 1355 patients were included in this meta-analysis. The results showed that overexpression of was significantly associated with poor OS (HR = 3.03; 95% CI: 2.00-4.59; < 0.001), DFS (HR = 3.38; 95% CI: 2.41-4.74; < 0.001). Elevated expression is associated with advanced clinical stage, lymph node metastasis, and poor histological grade. In addition, TCGA datasets were used to verify that was found highly expressed in multiple cancers and was associated with poorer survival.
CONCLUSION
The results demonstrated that could be a novel prognostic biomarker for cancer patients. However, because the included studies mainly focused on Asian populations, further research is needed to verify its applicability.
Topics: Humans; Biomarkers, Tumor; Lymphatic Metastasis; Neoplasms; Odds Ratio; Prognosis; RNA, Long Noncoding
PubMed: 36631437
DOI: 10.1080/14737159.2022.2168191 -
International Journal of Molecular... Dec 2022Endometriosis is a chronic inflammatory disorder, characterized by the presence of endometrial cells outside the uterine cavity. An increasing number of studies... (Review)
Review
Endometriosis is a chronic inflammatory disorder, characterized by the presence of endometrial cells outside the uterine cavity. An increasing number of studies correlate the immune system with endometriosis, particularly NK receptors (NKR), which have been suggested to play an essential role in the pathogenesis of the disease. This systematic review aims to enlighten the role of NKR in endometriosis. A literature search was performed independently by two reviewers, to identify studies assessing the role of NKR in endometriosis. In total, 18 studies were included. Endometriosis pathogenesis seems to be marked by the overexpression of NK inhibitor receptors (KIRS), namely, CD158a+, KIR2DL1, CD94/NKG2A, PD-1, NKB1, and EB6, and inhibiting ligands such as PD-L1, HLA-E, HLA-G, and HLA-I. Concurrently, there is a decrease in NK-activating receptors and natural cytotoxicity receptors (NCRs), such as NKp46, NKp30, and NKG2D. The immune shift from NK surveillance to NK suppression is also apparent in the greater relative number of ITIM domains compared with ITAM domains in NKRs. In conclusion, NK receptor activity seems to dictate the immunocompetency of women to clear endometriotic cells from the peritoneal cavity. Future research could explore NKRs as therapeutic targets, such as that which is now well established in cancer therapy through immunotherapy.
Topics: Humans; Female; Receptors, Natural Killer Cell; Killer Cells, Natural; Endometriosis; Endometrium
PubMed: 36613776
DOI: 10.3390/ijms24010331 -
The International Journal of Biological... Mar 2023The relationship between PLIN2 expression and prognosis, and clinicopathological significance of various cancers has been extensively studied, but the results are not... (Meta-Analysis)
Meta-Analysis Review
The relationship between PLIN2 expression and prognosis, and clinicopathological significance of various cancers has been extensively studied, but the results are not completely consistent. This review followed the guidelines for systematic reviews of prognostic factors studies and was reported under the Preferred Reporting Program for Systematic Reviews and Meta-Analysis (PRISMA). We searched PubMed, Embase, Cochrane Library, Web of Science, and Google Academia for relevant articles up to September 2, 2022, and calculated the pooled hazard ratios (HR) with 95% confidence intervals (CI) to determine the association between PLIN2 expression and the prognosis of various cancers. The meta-analysis ultimately included 17 studies. The quality of all included cohort studies was evaluated using the Quality in Prognosis Studies (QUIPS) tool, and an adaptation of Grading of Recommendations Assessment, Development and Evaluation (GRADE) method was used to assess the certainty of the results. High expression of PLIN2 was associated with poorer overall survival (HR = 1.65; 95% CI = 1.14, 2.38; = 0.008), metastasis-free survival (HR = 1.48; 95% CI = 1.12, 1.94; = 0.005), progression-free survival (HR = 2.11; 95% CI = 1.55, 2.87; < 0.0005) and recurrence-free survival/relapse-free survival (HR = 2.21; 95% CI = 1.64, 2.98; < 0.0005) in cancers. The clinicopathological parameters of digestive system malignancies suggested that high expression of PLIN2 was notably associated with distant metastasis ( + ) (odds ratio (OR) = 3.37; 95% CI = 1.31, 8.67; = 0.012), lymph node metastasis ( + ) (OR = 1.61; 95% CI = 1.01, 2.54; = 0.004), and tumor stage (III-IV) (OR = 1.96; 95% CI = 1.24, 3.09; = 0.006). In summary, overexpression of PLIN2 is significantly associated with a poor prognosis in various human cancers, especially in respiratory and digestive malignancies. Thus, PLIN2 expression may be a potential prognostic biomarker in cancer patients.
Topics: Humans; Prognosis; Lymphatic Metastasis; Progression-Free Survival; Proportional Hazards Models; Biomarkers, Tumor; Perilipin-2
PubMed: 36604990
DOI: 10.1177/03936155221147536 -
Oncogene Jan 2023Over the last 40 years osteosarcoma (OS) survival has stagnated with patients commonly resistant to neoadjuvant MAP chemotherapy involving high dose methotrexate,...
Over the last 40 years osteosarcoma (OS) survival has stagnated with patients commonly resistant to neoadjuvant MAP chemotherapy involving high dose methotrexate, adriamycin (doxorubicin) and platinum (cisplatin). Due to the rarity of OS, the generation of relevant cell models as tools for drug discovery is paramount to tackling this issue. Four literature databases were systematically searched using pre-determined search terms to identify MAP resistant OS cell lines and patients. Drug exposure strategies used to develop cell models of resistance and the impact of these on the differential expression of resistance associated genes, proteins and non-coding RNAs are reported. A comparison to clinical studies in relation to chemotherapy response, relapse and metastasis was then made. The search retrieved 1891 papers of which 52 were relevant. Commonly, cell lines were derived from Caucasian patients with epithelial or fibroblastic subtypes. The strategy for model development varied with most opting for continuous over pulsed chemotherapy exposure. A diverse resistance level was observed between models (2.2-338 fold) with 63% of models exceeding clinically reported resistance levels which may affect the expression of chemoresistance factors. In vitro p-glycoprotein overexpression is a key resistance mechanism; however, from the available literature to date this does not translate to innate resistance in patients. The selection of models with a lower fold resistance may better reflect the clinical situation. A comparison of standardised strategies in models and variants should be performed to determine their impact on resistance markers. Clinical studies are required to determine the impact of resistance markers identified in vitro in poor responders to MAP treatment, specifically with respect to innate and acquired resistance. A shift from seeking disputed and undruggable mechanisms to clinically relevant resistance mechanisms may identify key resistance markers that can be targeted for patient benefit after a 40-year wait.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cisplatin; Clinical Relevance; Doxorubicin; Neoplasm Recurrence, Local; Osteosarcoma; Drug Resistance, Neoplasm
PubMed: 36434179
DOI: 10.1038/s41388-022-02529-x -
Frontiers in Plant Science 2022The core particle represents the catalytic portions of the 26S proteasomal complex. The genes encoding α- and β-subunits play a crucial role in protecting plants...
The core particle represents the catalytic portions of the 26S proteasomal complex. The genes encoding α- and β-subunits play a crucial role in protecting plants against various environmental stresses by controlling the quality of newly produced proteins. The 20S proteasome gene family has already been reported in model plants such as Arabidopsis and rice; however, they have not been studied in oilseed crops such as rapeseed ( L.). In the present study, we identified 20S proteasome genes for α- (PA) and β-subunits (PB) in through systematically performed gene structure analysis, chromosomal location, conserved motif, phylogenetic relationship, and expression patterns. A total of 82 genes, comprising 35 and 47 of the 20S proteasome, were revealed in the genome. These genes were distributed on all 20 chromosomes of and most of these genes were duplicated on homoeologous chromosomes. The (α1-7) and (β1-7) genes were phylogenetically placed into seven clades. The pattern of expression of all the and genes was also studied using RNA-seq datasets under biotic and abiotic stress conditions. Out of 82 genes, three exhibited high expression under abiotic stresses, whereas two genes were overexpressed in response to biotic stresses at both the seedling and flowering stages. Moreover, an additional eighteen genes were expressed under normal conditions. Overall, the current findings developed our understanding of the organization of the 20S proteasome genes in , and provided specific genes for further functional research in response to abiotic and biotic stresses.
PubMed: 36388569
DOI: 10.3389/fpls.2022.1037206 -
Frontiers in Oncology 2022Dysregulation of the mesenchymal epithelial transition (MET) pathway contributes to poor clinical outcomes in patients with non-small cell lung cancer (NSCLC). Numerous... (Review)
Review
BACKGROUND
Dysregulation of the mesenchymal epithelial transition (MET) pathway contributes to poor clinical outcomes in patients with non-small cell lung cancer (NSCLC). Numerous clinical trials are currently investigating several therapies based on modulation of the MET pathway.
OBJECTIVES
This study aimed to systematically evaluate the activity and safety of MET inhibitors in patients with NSCLC.
METHODS
We searched PubMed, Embase, and the Cochrane Library from inception to June 02, 2022. The objective response rate (ORR) and disease control rate (DCR) were extracted as the main outcomes and pooled using the weighted mean proportion with fixed- or random-effects models in cases of significant heterogeneity ( >50%). Safety analysis was performed based on adverse events reported in all studies.
RESULTS
Eleven studies (882 patients) were included in the meta-analysis. The pooled ORR was 28.1% (95% confidence interval [CI], 0.223-0.354), while the pooled DCR was 69.1% (95% CI, 0.631-0.756). ORRs were higher for tepotinib (44.7% [95% CI, 0.365-0.530]) and savolitinib (42.9% [95% CI, 0.311-0.553]) than for other types of MET inhibitors. Patients with NSCLC with exon 14 skipping exhibited higher ORRs (39.3% (95% CI, 0.296-0.522)) and DCRs (77.8% (95% CI, 0.714-0.847)) than those with MET protein overexpression or amplification. Intracranial response rate and intracranial disease control rates were 40.1% (95% CI, 0.289-0.556) and 95.4% (95% CI, 0.892-0.100), respectively. Adverse events were mild (grade 1 to 2) in 87.2% of patients. Common adverse events above grade 3 included lower extremity edema (3.5% [95% CI, 0.027-0.044]), alanine aminotransferase (ALT) elevation (2.4% [95% CI, 0.014-0.033]), and lipase elevation (2.2% [95% CI, 0.016-0.031]).
CONCLUSION
MET inhibitors, which exhibited a satisfactory safety profile in the current study, may become a new standard of care for addressing MET dysregulation in patients with advanced or metastatic NSCLC, and even in those with brain metastases, particularly tepotinib, savolitinib and capmatinib. Further randomized trials are required to establish standard predictive biomarkers for MET therapies and to compare the effects of different MET inhibitors in NSCLC with MET dysregulation.
PubMed: 36387098
DOI: 10.3389/fonc.2022.1013299