-
Translational Neurodegeneration Apr 2022A growing amount of evidence has indicated contributions of variants in causative genes of Parkinson's disease (PD) to the development of sleep disturbance in PD and... (Meta-Analysis)
Meta-Analysis Review
A growing amount of evidence has indicated contributions of variants in causative genes of Parkinson's disease (PD) to the development of sleep disturbance in PD and prodromal PD stages. In this article, we aimed to investigate the role of genetics in sleep disorders in PD patients and asymptomatic carriers at prodromal stage of PD. A systematic review and meta-analysis of observational studies was conducted based on the MEDLINE, EMBASE and PsychINFO databases. A pooled effect size was calculated by odds ratio (OR) and standard mean difference (SMD). Forty studies were selected for quantitative analysis, including 17 studies on glucocerebrosidase (GBA), 25 studies on Leucine-rich repeat kinase 2 (LRRK2) and 7 on parkin (PRKN) genes, and 3 studies on alpha-synuclein gene (SNCA) were used for qualitative analysis. Patients with PD carrying GBA variants had a significantly higher risk for rapid-eye-movement behavior disorders (RBD) (OR, 1.82) and higher RBD Screening Questionnaire scores (SMD, 0.33). Asymptomatic carriers of GBA variants had higher severity of RBD during follow-up. Patients with PD carrying the LRRK2 G2019S variant had lower risk and severity of RBD compared with those without LRRK2 G2019S. Variants of GBA, LRRK2 and PRKN did not increase or decrease the risk and severity of excessive daytime sleepiness and restless legs syndrome in PD. Our findings suggest that the genetic heterogeneity plays a role in the development of sleep disorders, mainly RBD, in PD and the prodromal stage of PD.
Topics: Genetic Heterogeneity; Glucosylceramidase; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mutation; Parkinson Disease; Prodromal Symptoms; Sleep Wake Disorders; alpha-Synuclein
PubMed: 35395825
DOI: 10.1186/s40035-022-00294-1 -
The Journal of Maternal-fetal &... Jun 2020Multiple factors and pathways have been reported as critical machineries for cell differentiation and survival during pregnancy; a number of them involve glycogen...
Multiple factors and pathways have been reported as critical machineries for cell differentiation and survival during pregnancy; a number of them involve glycogen synthase kinase (GSK) 3a/β. Several reports on GSK3's functional role exist; however, the specific role of GSK3 in reproductive tissues and its contribution to normal or abnormal parturition are still unclear. To fill this knowledge gap, a systematic review of literature was conducted to better understand the functional role of GSK3 in various intrauterine tissues during implantation, pregnancy, and parturition. We conducted a systematic review of literature on GSK3's expression and function reported between 1980 and 2017 in reproductive tissues during pregnancy using three electronic databases (Web of Science, Medline, and ClinicalTrials.gov). Study selection, data extraction, quality assessment and analyses were performed in duplicate by two independent reviewers. A total of 738 citations were identified; 80 were selected for full text evaluation and 25 were included for final review. GSK3's regulation and function were mostly studied in tissues and cells from placentas (12), fetuses (8), uteruses (6), and ovaries (2). GSK3 is primarily reported as a downstream responder of protein kinase B (AKT)-, Wnt-, and reactive oxygen species (ROS)-related pathways where it plays a critical role in cell survival and growth in reproductive tissues. Though GSK3 has been functionally linked to a number of biological processes in reproductive tissues, it has primarily been studied as a secondary signaler of various conserved cell signaling pathways. Lack of scientific rigor in studying GSK3's role in reproductive tissues makes this molecule's function still obscure. No studies have reported GSK3 in the cervix, and very few reports exist in myometrium and decidua. This systematic review suggests more functional and mechanistic studies focusing on GSK3 need to be conducted in reproductive biology.
Topics: Biomarkers; Female; Glycogen Synthase Kinase 3; Humans; Parturition; Pregnancy
PubMed: 30278798
DOI: 10.1080/14767058.2018.1531843 -
Expert Opinion on Drug Metabolism &... Mar 2018Malignant melanoma (MM) is an aggressive disease with a rapidly rising incidence due to neoplasm of melanocytes. Molecular targeted therapies have demonstrated lower... (Review)
Review
Malignant melanoma (MM) is an aggressive disease with a rapidly rising incidence due to neoplasm of melanocytes. Molecular targeted therapies have demonstrated lower toxicity and improved overall survival versus conventional therapies of MM. The revealing of mutations in the BRAF/MEK/ERK pathway has led to the development of BRAF inhibitors such as vemurafenib and dabrafenib for the treatment of cutaneous MM. Though, progression of resistance to these agents has prompted attempts to target downstream proteins in this pathway. Trametinib, a MEK1/2 inhibitor, was approved in 2013 for the treatment of BRAF V600E/K mutation-positive unresectable or metastatic cutaneous melanoma patients. Areas covered: The aim of the current review is to present an update on the role of MEK in progressive melanomas and summarize latest results of clinical studies with innovative MEK inhibitors and/or combined approaches with other kinase inhibitors such as BRAF inhibitors in the treatment of MM. Expert opinion: Two combined treatments (i.e. trametinib plus dabrafenib and vemurafenib plus cobimetinib) target two different kinases in the BRAF/MEK/ERK pathway. The simultaneous prohibition of both MEK and BRAF is associated with more durable response rate than BRAF monotherapy and can overcome acquired resistance.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Humans; Melanoma; Mitogen-Activated Protein Kinases; Molecular Targeted Therapy; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms
PubMed: 29363351
DOI: 10.1080/17425255.2018.1432593 -
Scientific Reports Jun 2023Many studies report Liver kinase B1 (LKB1) plays a critical role in gastric cancer (GC). However, the relationship between LKB1 and the clinicopathological parameters of... (Meta-Analysis)
Meta-Analysis
Many studies report Liver kinase B1 (LKB1) plays a critical role in gastric cancer (GC). However, the relationship between LKB1 and the clinicopathological parameters of GC patients remains controversial. This meta-analysis aimed to investigate the above question and re-evaluate the prognostic significance of LKB1 in GC patients. We searched PubMed, Web of Science, Cochrane Library, Google Scholar, CNKI, and Wan Fang to identify relevant studies published before April 20, 2023. After careful screening, 11 studies involving 1767 patients were included. We found that LKB1 expression was significantly related to tumor size (OR 0.515; 95% CI 0.316-0.839; P < 0.01), differentiation (OR 0.643; 95% CI 0.521-0.794; P < 0.001), depth of invasion (OR 0.397; 95% CI 0.319-0.494; P < 0.001), lymph node metastasis (OR 0.487; 95% CI 0.397-0.598; P = 0.01), and TNM stage (OR 0.362; 95% CI 0.293-0.447; P = 0.006). However, LKB1 was unrelated to gender and age (P > 0.05). Moreover, low LKB1 expression was significant correlate with overall survival (OS) (HR = 1.59; 95% CI 1.29-1.96; P < 0.001). In conclusion, LKB1 expression is related to tumor size, differentiation, depth of invasion, lymph node metastasis, and TNM stage, and low LKB1 expression can predict a poor prognosis. LKB1 is a potentially valuable prognosis signature and therapeutic target in GC patients.
Topics: Humans; Biomarkers, Tumor; Lymphatic Metastasis; Prognosis; Protein Serine-Threonine Kinases; Stomach Neoplasms
PubMed: 37264076
DOI: 10.1038/s41598-023-36239-5 -
Molecular Biology Reports Oct 2022Neurodegenerative disorders are a diverse variety of diseases that can be distinguished from developing degeneration of neurons in the CNS. Several alkaloids have shown... (Review)
Review
INTRODUCTION
Neurodegenerative disorders are a diverse variety of diseases that can be distinguished from developing degeneration of neurons in the CNS. Several alkaloids have shown mounting effects in neurodegenerative disorders, and berberine is one of them. Demethyleneberberine is a metabolite of berberine that has better blood-brain barrier crossing capacity. Demethyleneberberine possesses anti-inflammatory, anti-oxidant, and mitochondrial targeting properties. However, neither the pharmacological action nor the molecular mechanism of action of demethyleneberberine on neurodegenerative disorders has been explored yet.
MATERIALS AND METHODS
A systematic literature review of PubMed, Medline, Bentham, Scopus, and EMBASE (Elseveier) databases was carried out with the help of keywords like "Demethyleneberberine; neuroinflammation; oxidative stress; Neuroprotective; Neurodegenerative disorders" till date.
CONCLUSION
This review focus on the neuroprotective potential of demethyleneberberine in neurodegenerative disorders by attenuating different pathways, i.e., NF-κB, MAPK, and AMPK signalling.
Topics: AMP-Activated Protein Kinases; Alkaloids; Anti-Inflammatory Agents; Antioxidants; Berberine; Humans; NF-kappa B; Neurodegenerative Diseases; Neuroprotective Agents
PubMed: 35657450
DOI: 10.1007/s11033-022-07594-9 -
Pulmonary Pharmacology & Therapeutics Aug 2023COPD pathogenesis is frequently associated with endoplasmic reticulum stress (ER stress) progression. Targeting the major unfolded protein response (UPR) branches in the... (Review)
Review
COPD pathogenesis is frequently associated with endoplasmic reticulum stress (ER stress) progression. Targeting the major unfolded protein response (UPR) branches in the ER stress pathway may provide pharmacotherapeutic selection strategies for treating COPD and enable relief from its symptoms. In this study, we aimed to systematically review the potential role of the ER stress inhibitors of major UPR branches (IRE1, PERK, and ATF6) in COPD-related studies and determine the current stage of knowledge in this field. The systematic review was carried out adhering to the PRISMA checklist based on published studies obtained from specific keyword searches of three databases, namely PubMed, ScienceDirect and Springer Database. The search was limited to the year 2000-2022 which includes all in vitro studies, in vivo studies and clinical trials related to the application of ER stress inhibitors toward COPD-induced models and disease. The risk of bias was evaluated using the QUIN, SYRCLE, revised Cochrane risk of bias tool for randomized trials (RoB 2.0) and NIH tool respectively. A total of 7828 articles were screened from three databases and a final total of 37 studies were included in the review. The ER stress and UPR pathways are potentially useful to prevent COPD progression and attenuate the exacerbation of COPD and related symptoms. Interestingly, the off-target effects from inhibition of the UPR pathway may be desirable or undesirable depending on context and therapeutic applications. Targeting the UPR pathway could have complex consequences as the production of ER molecules involved in folding may be impaired which could continuously provoke misfolding of proteins. Although several emerging compounds were noted to be potentially useful for targeted therapy against COPD, clinical studies have yet to be thoroughly explored.
Topics: Humans; eIF-2 Kinase; Endoplasmic Reticulum Stress; Unfolded Protein Response; Pulmonary Disease, Chronic Obstructive
PubMed: 37201652
DOI: 10.1016/j.pupt.2023.102218 -
Hematology (Amsterdam, Netherlands) Dec 2023Polycythemia vera (PV) is classically thought to be associated with low erythropoietin (EPO) levels. Here, we present a review of the utility of using EPO levels in...
OBJECTIVES
Polycythemia vera (PV) is classically thought to be associated with low erythropoietin (EPO) levels. Here, we present a review of the utility of using EPO levels in diagnosing polycythemia.
METHODS
We conducted a systematic literature review of the Medline data through Pubmed and Google Scholar. We included the articles which described confirmed PV associated with elevated EPO level. Our search strategy included the following terms in Pubmed (((polycythemia vera[MeSH Terms]) OR (jak2 protein tyrosine kinase[MeSH Terms])) OR (Myeloproliferative Disorders[MeSH Terms])) AND (Erythropoietin[MeSH Terms]), and 'polycythemia vera with erythropoietin' in Google Scholar.
RESULTS
Our research yielded four cases of PV with elevated EPO levels. The most common symptom was a headache. Thrombotic phenomena happened in a single case in the form of Budd-Chiari syndrome. The mean Hb level was 20.2 gm/dl, and the EPO level was 213 mlU/mL.
DISCUSSION
Although PV is usually associated with low EPO levels, high levels do not exclude this diagnosis. Workup should include testing for JAK2 mutation and bone marrow biopsy in the presence of suggestive signs and symptoms. Novel biomarkers are also being proposed to aid in the diagnosis.
CONCLUSION
Although elevated EPO levels suggest secondary causes of polycythemia, cases where elevated EPO levels were associated with an underlying PV are reported in the literature, and we have summarized a review of them. Workup for polycythemia should include JAK2 mutation testing if signs and symptoms suggest PV even if EPO is elevated.
Topics: Humans; Polycythemia; Polycythemia Vera; Janus Kinase 2; Bone Marrow; Erythropoietin
PubMed: 37843428
DOI: 10.1080/16078454.2023.2269510 -
Cancer Treatment Reviews Apr 2023The anti-tumor activity of WEE1 inhibitors (WEE1i) in gynecological malignancies has recently been demonstrated in clinical trials and its rationale is based on... (Review)
Review
INTRODUCTION
The anti-tumor activity of WEE1 inhibitors (WEE1i) in gynecological malignancies has recently been demonstrated in clinical trials and its rationale is based on biological/molecular features of gynecological cancers. With this systematic review, we aim to outline the clinical development and current evidence regarding the efficacy and safety of these targeted agents in in this patient group.
METHODS
Systematic literature review of trials including patients with gynecological cancers treated with a WEE1i. The primary objective was to summarize the efficacy of WEE1i in gynecological malignancies regarding objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS) and progression-free survival (PFS). Secondary objectives included toxicity profile, Maximum Tolerated Dose (MTD), pharmacokinetics, drug-drug interactions and exploratory objectives such as biomarkers for response.
RESULTS
26 records were included for data extraction. Almost all trials used the first-in-class WEE1i adavosertib; one conference abstract reported about Zn-c3. The majority of the trials included diverse solid tumors (n = 16). Six records reported efficacy results of WEE1i in gynecological malignancies (n = 6). Objective response rates of adavosertib monotherapy or in combination with chemotherapy ranged between 23% and 43% in these trials. Median PFS ranged from 3.0 to 9.9 months. The most common adverse events were bone marrow suppression, gastrointestinal toxicities and fatigue. Mainly alterations in cell cycle regulator genes TP53 and CCNE1 were potential predictors of response.
CONCLUSION
This report summarizes encouraging clinical development of WEE1i in gynecological cancers and considers its application in future studies. Biomarker-driven patient selection might be essential to increase the response rates.
Topics: Female; Humans; Genital Neoplasms, Female; Antineoplastic Agents; Protein-Tyrosine Kinases; Cell Cycle Proteins
PubMed: 36893690
DOI: 10.1016/j.ctrv.2023.102531 -
Experimental Cell Research Aug 2016In this review, we discuss the molecular mechanisms and prognostic implications of the protein kinase A (PKA) signaling pathway in human tumors, with special emphasis on... (Meta-Analysis)
Meta-Analysis Review
In this review, we discuss the molecular mechanisms and prognostic implications of the protein kinase A (PKA) signaling pathway in human tumors, with special emphasis on the malignant thyroid. The PKA signaling pathway is differentially activated by the expression of regulatory subunits 1 (R1) and 2 (R2), whose levels change during development, differentiation, and neoplastic transformation. Following the identification of gene mutations within the PKA regulatory subunit R1A (PRKAR1A) that cause Carney complex-associated neoplasms, several investigators have studied PRKAR1A expression in sporadic thyroid tumors. The PKA regulatory subunit R2B (PRKAR2B) is highly expressed in benign, as well as in malignant differentiated and undifferentiated lesions. PRKAR1A is highly expressed in follicular adenomas and malignant lesions with a statistically significant gradient between benign and malignant tumors; however, it is not expressed in hyperplastic nodules. Although the importance of PKA in human malignancy outcomes is not completely understood, PRKAR1A expression correlates with tumor dimension in malignant lesions. Additional studies are needed to determine whether a relationship exists between PKA subunit expression and clinical outcomes, particularly in undifferentiated tumors. In conclusion, the R1A subunit might be a good molecular candidate for the targeted treatment of malignant thyroid tumors.
Topics: Adult; Aged; Aged, 80 and over; Cell Differentiation; Cyclic AMP-Dependent Protein Kinases; Female; Humans; Hyperplasia; Male; Middle Aged; Prognosis; Protein Subunits; Thyroid Gland; Thyroid Neoplasms
PubMed: 27321957
DOI: 10.1016/j.yexcr.2016.06.004 -
Lung Cancer (Amsterdam, Netherlands) Nov 2021Anaplastic Lymphoma Kinase (ALK) inhibitors have revolutionized the treatment of advanced ALK-positive non-small cell lung cancer (NSCLC), improving progression-free... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Anaplastic Lymphoma Kinase (ALK) inhibitors have revolutionized the treatment of advanced ALK-positive non-small cell lung cancer (NSCLC), improving progression-free survival. Bradycardia is a potential adverse effect of these agents. We aimed to determine the risk of bradycardia associated with ALK inhibitors in patients with advanced NSCLC.
MATERIALS AND METHODS
We conducted a systematic search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, National clinical trial registry, and Web of Science Core Collection. We included all randomized controlled trials in which an ALK-inhibitor was compared with another ALK-inhibitor or standard chemotherapy. Meta-analyses were conducted to evaluate the pooled incidence rates of bradycardia and dizziness using fixed effect models.
RESULTS
The pooled incidence of bradycardia among 1737 individuals prescribed ALK inhibitors was 8% during a mean follow-up of 1.26 years. Crizotinib led to more bradycardia than standard chemotherapy (relative risk, RR 24.68, 95% CI 7.11-85.), while no difference was seen between crizotinib and alectinib (RR 1.12, 95% CI 0.79-1.59). The next-generation ALK inhibitors alectinib, brigatinib and lorlatinib combined resulted in a similar rate of bradycardia when compared to crizotinib (RR 0.77, 95% CI 0.57-1.04). All ALK inhibitors (as an aggregate) caused more dizziness (as a potential symptom of bradycardia) than standard chemotherapy (RR 1.88, 95% CI 1.44-2.44).
CONCLUSION
Crizotinib for the treatment of NSCLC is associated with a higher risk for bradycardia compared to standard chemotherapy. There is no evidence of a difference in bradycardia risk between crizotinib and newer ALK inhibitors.
Topics: Anaplastic Lymphoma Kinase; Bradycardia; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lung Neoplasms; Protein Kinase Inhibitors
PubMed: 34492553
DOI: 10.1016/j.lungcan.2021.08.014