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Pharmacological Research Jan 2023Cucurbitacin B (CuB, CHO), the most abundant and active member of cucurbitacins, which are highly oxidized tetracyclic triterpenoids. Cucurbitacins are widely... (Review)
Review
Cucurbitacin B (CuB, CHO), the most abundant and active member of cucurbitacins, which are highly oxidized tetracyclic triterpenoids. Cucurbitacins are widely distributed in a variety of plants and mainly isolated from plants in the Cucurbitaceae family. CuB is mostly obtained from the pedicel of Cucumis melo L. Modern pharmacological studies have confirmed that CuB has a broad range of pharmacological activities, with significant therapeutic effects on a variety of diseases including inflammatory diseases, neurodegenerative diseases, diabetes mellitus, and cancers. In this study the PubMed, Web of Science, Science Direct, and China National Knowledge Infrastructure (CNKI) databases were searched from 1986 to 2022. After inclusion and exclusion criteria were applied, 98 out of 2484 articles were selected for a systematic review to comprehensively summarize the pharmacological activity, toxicity, and pharmacokinetic properties of CuB. The results showed that CuB exhibits potent anti-inflammatory, antioxidant, antiviral, hypoglycemic, hepatoprotective, neuroprotective, and anti-cancer activities mainly via regulating various signaling pathways, such as the Janus kinase/signal transducer and activator of transcription-3 (JAK/STAT3), nuclear factor erythroid 2-related factor-2/antioxidant responsive element (Nrf2/ARE), nuclear factor (NF)-κB, AMP-activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)/Akt, cancerous inhibitor of protein phosphatase-2A/protein phosphatase-2A (CIP2A/PP2A), Wnt, focal adhesion kinase (FAK), Notch, and Hippo-Yes-associated protein (YAP) pathways. Studies of its toxicity and pharmacokinetic properties showed that CuB has non-specific toxicity and low bioavailability. In addition, derivatives and clinical applications of CuB are discussed in this paper.
Topics: Cucurbitacins; Protein Phosphatase 2; Antioxidants; Phosphatidylinositol 3-Kinases; Triterpenes; NF-kappa B
PubMed: 36460279
DOI: 10.1016/j.phrs.2022.106587 -
Frontiers in Endocrinology 2023Glucokinase activators (GKAs) promote the activity of glucokinase (GK) and is under development for the treatment of diabetes. The efficacy and safety of GKAs require... (Meta-Analysis)
Meta-Analysis
AIMS
Glucokinase activators (GKAs) promote the activity of glucokinase (GK) and is under development for the treatment of diabetes. The efficacy and safety of GKAs require evaluation.
METHODS
This meta-analysis included randomized controlled trials (RCTs) with a duration of at least 12 weeks conducted in patients with diabetes. The primary objective of this meta-analysis was the difference of hemoglobin A1c (HbA1c) change from baseline to study end between GKA groups and placebo groups. Risk of hypoglycemia and laboratory indicators were also evaluated. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated for the continuous outcomes, and odds ratios (ORs) and 95% CI were calculated for the risk of hypoglycemia.
RESULTS
Data from 13 RCTs with 2,748 participants treated with GKAs and 2,681 control participants were analyzed. In type 2 diabetes, the level of HbA1c decreased greater in patients with GKA treatment compared with placebo (WMD = -0.339%, 95% CI -0.524 to -0.154%, P < 0.001). The OR comparing GKA versus placebo was 1.448 for risk of hypoglycemia (95% CI 0.808 to 2.596, P = 0.214). The WMD comparing GKA versus placebo was 0.322 mmol/L for triglyceride (TG) levels (95% CI 0.136 to 0.508 mmol/L, P = 0.001). When stratified by drug type, selectivity, and study duration, a significant difference was found between groups. In type 1 diabetes, the result of HbA1c change and lipid indicators showed no significant difference between the TPP399 group and the placebo group.
CONCLUSIONS
In patients with type 2 diabetes, GKA treatment was associated with a better glycemic control but a significant elevation in TG concentration in general. The efficacy and safety varied with drug type and selectivity.
SYSTEMATIC REVIEW REGISTRATION
International Prospective Register of Systematic Reviews, identifier CRD42022378342.
Topics: Humans; Glucokinase; Glycated Hemoglobin; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 1; Hypoglycemia
PubMed: 37223016
DOI: 10.3389/fendo.2023.1175198 -
Frontiers in Immunology 2022Duvelisib is the first FDA-approved oral dual inhibitor of phosphatidylinositol-3-kinase PI3K-delta (PI3K-δ) and PI3K-gamma (PI3K-γ). Although many clinical studies... (Meta-Analysis)
Meta-Analysis
Safety and efficacy of dual PI3K-δ, γ inhibitor, duvelisib in patients with relapsed or refractory lymphoid neoplasms: A systematic review and meta-analysis of prospective clinical trials.
BACKGROUND
Duvelisib is the first FDA-approved oral dual inhibitor of phosphatidylinositol-3-kinase PI3K-delta (PI3K-δ) and PI3K-gamma (PI3K-γ). Although many clinical studies support the efficacy of duvelisib, the safety of duvelisib remains with great attention. This systematic review and meta-analysis aimed to evaluate the safety and efficacy of duvelisib in treating different relapsed or refractory (RR) lymphoid neoplasm types.
METHODS
We searched prospective clinical trials from PUBMED, EMBASE, Cochrane Library, and ClinicalTrials.gov. For efficacy analysis, Overall response rate (ORR), complete response rate (CR), partial response rate (PR), rate of stable disease (SDR), rate of progressive disease (PDR), median progression-free survival (mPFS), 12-/24-month PFS, and 12-month overall survival (OS) were assessed. For safety analysis, the incidences of any grade and grade ≥3 adverse events (AEs), serious AEs, and treatment-related discontinuation and death were evaluated. Subgroup analysis based on the disease type was performed.
RESULTS
We included 11 studies and 683 patients, including 305 chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), 187 B-cell indolent non-Hodgkin lymphoma (iNHL), 39 B-cell aggressive non-Hodgkin lymphoma (aNHL), and 152 T-cell non-Hodgkin lymphoma (T-NHL) patients. The pooled ORR in CLL/SLL, iNHL, aNHL and T-NHL was 70%, 70%, 28% and 47%, respectively. Additionally, the pooled ORR in CLL/SLL patients with or without TP53 mutation/17p-deletion (62% vs. 74%, p=0.45) and in follicular lymphoma (FL) or other iNHL (69% vs. 57%, p=0.38) had no significant differences. Mantle cell lymphoma (MCL) patients had higher pooled ORR than other aNHL (68% vs. 17%, p=0.04). Angioimmunoblastic TCL (AITL) patients had higher pooled ORR than other PTCL patients (67% vs. 42%, p=0.01). The pooled incidence of any grade, grade ≥3, serious AEs, treatment-related discontinuation and death was 99%, 79%, 63%, 33% and 3%, respectively. The most frequent any-grade AEs were diarrhea (47%), ALT/AST increase (39%), and neutropenia (38%). The most frequent grade ≥3 AEs were neutropenia (25%), ALT/AST increased (16%), diarrhea (12%), and anemia (12%).
CONCLUSION
Generally, duvelisib could offer favorable efficacy in patients with RR CLL/SLL, iNHL, MCL, and AITL. Risk and severity in duvelisib treatment may be mitigated through proper identification and management.
Topics: Humans; Adult; Phosphatidylinositol 3-Kinases; Leukemia, Lymphocytic, Chronic, B-Cell; Prospective Studies; Lymphoma, Non-Hodgkin; Lymphoma, Mantle-Cell; Lymphoma, B-Cell; Neutropenia; Diarrhea
PubMed: 36685572
DOI: 10.3389/fimmu.2022.1070660 -
Medicine Jul 2023EGFR-TKI (tyrosine kinase inhibitor) monotherapy has become the first-line treatment option for patients with EGFR-mutated non-small cell lung cancer (NSCLC). Prolonging... (Meta-Analysis)
Meta-Analysis
Comparation of EGFR-TKI (EGFR tyrosine kinase inhibitors) combination therapy and osimertinib for untreated EGFR-mutated advanced non-small cell lung cancers: A systematic review and network meta-analysis.
BACKGROUND
EGFR-TKI (tyrosine kinase inhibitor) monotherapy has become the first-line treatment option for patients with EGFR-mutated non-small cell lung cancer (NSCLC). Prolonging the survival time, improving the progression-free survival of front-line treatment, and delaying the occurrence of drug resistance. At present, combination therapy is being widely used. Evaluate the therapeutic effect of TKI joint and Osimertinib drug therapy for positive patients with gene positive.
MATERIAL AND METHODS
Articles that met the inclusion criteria were searched through electronic databases. treatment emergent adverse events were summarized, and progression-free survival (PFS) and overall survival (OS) were calculated. Appropriate networks for different outcomes were created to incorporate all the evidence. Bayesian network-based multitreatment was used to compare the efficacy and specific toxicity of all treatment regimens.
RESULTS
Fourteen eligible studies involving 2325 patients were included. Of these, 7 studies compared EGFR-TKI plus chemotherapy with EGFR-TKI alone, and 6 studies compared EGFR-TKI plus antiangiogenic therapy with EGFR-TKI alone. One study compared Osimertinib and GP, ER, EB, and GCP were more effective than SOC in PFS analysis; however, there was no significant difference between osimertinib and the other 4 combination regimens. The cumulative probabilities of being the most efficacious treatments were (PFS, OS, treatment emergent adverse events): O (73%, 16%, 0%, 0%), GCP (14%, 64%, 10%, 16%), GP (2%, 17%,8%), and EB (3%, 3%, 8%), ER (5%, NA, 4%);GA(1%, NA, 69%).
CONCLUSION
Osimertinib has the lowest side effects and provides better PFS first-line treatment in advanced EGFR-mutated NSCLC.GCP is the best regimen for OS, but its toxicity limits its application, and it may be the first choice for patients with higher survival requirements.
Topics: Humans; Bayes Theorem; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Lung Neoplasms; Mutation; Network Meta-Analysis; Tyrosine Kinase Inhibitors
PubMed: 37505120
DOI: 10.1097/MD.0000000000034483 -
Frontiers in Endocrinology 2023Noonan syndrome (NS) is a genetic multisystem disorder characterised by variable clinical manifestations including dysmorphic facial features, short stature, congenital...
BACKGROUND
Noonan syndrome (NS) is a genetic multisystem disorder characterised by variable clinical manifestations including dysmorphic facial features, short stature, congenital heart disease, renal anomalies, lymphatic malformations, chest deformities, cryptorchidism in males.
METHODS
In this narrative review, we summarized the available data on puberty and gonadal function in NS subjects and the role of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway in fertility. In addition, we have reported our personal experience on pubertal development and vertical transmission in NS.
CONCLUSIONS
According to the literature and to our experience, NS patients seem to have a delay in puberty onset compared to the physiological timing reported in healthy children. Males with NS seem to be at risk of gonadal dysfunction secondary not only to cryptorchidism but also to other underlying developmental factors including the MAP/MAPK pathway and genetics. Long-term data on a large cohort of males and females with NS are needed to better understand the impact of delayed puberty on adult height, metabolic profile and well-being. The role of genetic counselling and fertility related-issues is crucial.
Topics: Male; Child; Adult; Female; Humans; Noonan Syndrome; Cryptorchidism; Gonads; Puberty; Mitogen-Activated Protein Kinases
PubMed: 37576960
DOI: 10.3389/fendo.2023.1213098 -
Annals of Oncology : Official Journal... Sep 2012Triple-negative breast cancer (TNBC) is a distinct subset of breast cancer (BC) defined by the lack of immunohistochemical expression of the estrogen and progesterone... (Review)
Review
BACKGROUND
Triple-negative breast cancer (TNBC) is a distinct subset of breast cancer (BC) defined by the lack of immunohistochemical expression of the estrogen and progesterone receptors and human epidermal growth factor receptor 2. It is highly heterogeneous and displays overlapping characteristics with both basal-like and BC susceptibility gene 1 and 2 mutant BCs. This review evaluates the activity of emerging targeted agents in TNBC.
DESIGN
A systematic review of PubMed and conference databases was carried out to identify randomised clinical trials reporting outcomes in women with TNBC treated with targeted and platinum-based therapies.
RESULTS AND DISCUSSION
Our review identified TNBC studies of agents with different mechanisms of action, including induction of synthetic lethality and inhibition of angiogenesis, growth, and survival pathways. Combining targeted agents with chemotherapy in TNBC produced only modest gains in progression-free survival, and had little impact on survival. Six TNBC subgroups have been identified and found to differentially respond to specific targeted agents. The use of biological preselection to guide therapy will improve therapeutic indices in target-bearing populations.
CONCLUSION
Ongoing clinical trials of targeted agents in unselected TNBC populations have yet to produce substantial improvements in outcomes, and advancements will depend on their development in target-selected populations.
Topics: Antineoplastic Agents; Breast Neoplasms; ErbB Receptors; Female; Humans; Molecular Targeted Therapy; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; TOR Serine-Threonine Kinases; Treatment Outcome
PubMed: 22517820
DOI: 10.1093/annonc/mds067 -
Radiotherapy and Oncology : Journal of... Oct 2023The addition of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) to endocrine therapy in hormone receptor-positive (HR+) human epidermal growth factor 2-negative (HER2-)... (Meta-Analysis)
Meta-Analysis
Safety and feasibility of CDK4/6 inhibitors treatment combined with radiotherapy in patients with HR-positive/HER2-negative breast cancer. A systematic review and meta-analysis.
BACKGROUND AND PURPOSE
The addition of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) to endocrine therapy in hormone receptor-positive (HR+) human epidermal growth factor 2-negative (HER2-) breast cancer has led to practice-changing improvements in overall survival. However, there are conflicting data concerning the safety of CDK4/6i combination with radiotherapy, and no consensus guidelines exist to guide practice. We conducted a meta-analysis to assess the safety and feasibility of CDK4/6i treatment with radiotherapy.
MATERIALS AND METHODS
A comprehensive search was performed in PubMed/MEDLINE, Web of Science, and Scopus, for studies in advanced/metastatic breast cancer receiving CDK4/6i and radiotherapy with the provided safety data on the occurrence of toxicity. The main outcomes were safety (grade 3-5 adverse events), CDK 4/6i dose reduction, and the discontinuation rate due to toxicity.
RESULTS
Fifteen studies comprising 1133 patients with HR+/HER2- breast cancer patients were included. Among them, 617 pts received CDK4/6i and radiotherapy; the median follow-up was 17.0 months (IQR 9.2 - 18.0), and the median age was 58.8 years (IQR 55.5---62.5). The pooled prevalence of severe hematologic toxicity was 29.4% (95% CI 14.0% - 47.4%; I = 93%; τ = 0.084; p < 0.01 and severe non-hematologic toxicity was 2.8% (95% CI 1.1% - 4.8%; I = 0%; τ = 0.0; p = 0.67). The pooled prevalence of CDK4/6i dose reduction was 24.0% (95% CI 11.1% - 39.4%; I = 90%; τ = 0.052; p < 0.01) with no difference between CDK4/6i plus RT vs. CDK4/6i (odds ratio of 0.934; 95% CI 0.66 - 1.33; I = 0%; τ = 0.0; p = 0.56). The pooled prevalence of CDK4/6i discontinuation due to toxicity was 2.3% (95% CI 0.4% - 5.2%; I = 23%; τ = 0.002; p = 0.24).
CONCLUSION
The findings of this study suggest that radiotherapy in addition to CDK4/6i treatment in breast cancer patients is generally safe and well tolerated and remains a viable treatment option.
Topics: Female; Humans; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Consensus; Cyclin-Dependent Kinase 4; Epidermal Growth Factor; Feasibility Studies; Protein Kinase Inhibitors; Radiotherapy
PubMed: 37536378
DOI: 10.1016/j.radonc.2023.109839 -
Archives of Gerontology and Geriatrics Nov 2023Debates persist regarding the performance of existing glomerular filtration rate (GFR) estimating equations in older individuals. We performed this meta-analysis to... (Comparative Study)
Comparative Study Meta-Analysis Review
BACKGROUND
Debates persist regarding the performance of existing glomerular filtration rate (GFR) estimating equations in older individuals. We performed this meta-analysis to assess the accuracy and bias of six commonly used equations, including the Chronic Kidney Disease Epidemiology Collaboration creatinine equation (CKD-EPI) and its combination with cystatin C (CKD-EPI), with the corresponding pair of the Berlin Initiative Study equations (BIS1 and BIS2) and the Full Age Spectrum equations (FAS and FAS).
METHODS
PubMed and the Cochrane Library were searched for studies comparing estimated GFR (eGFR) with measured GFR (mGFR). We analyzed the difference in P30 and bias among the six equations and investigated subgroups based on the area (Asian and non-Asian), mean age (60-74 years and ≥75 years), and levels of mean mGFR (<45 mL/min/1.73m and ≥45 mL/min/1.73m).
RESULTS
27 studies with 18,112 participants were included, all reporting P30 and bias. BIS1 and FAS exhibited significantly higher P30 than CKD-EPI. While no significant differences were observed between FAS and BIS1, or among the three combined equations in terms of either P30 or bias. Subgroup analyses revealed FAS and FAS achieved better results in most situations. However, in the subgroup of mGFR<45 mL/min/1.73m, CKD-EPI had relatively higher P30 and significantly smaller bias.
CONCLUSIONS
Overall, BIS and FAS provided relatively more accurate estimates of GFR than CKD-EPI in older adults. FAS and FAS may be better suited for various conditions, while CKD-EPI would be a better option for older individuals with impaired renal function.
Topics: Aged; Humans; Asian; Creatinine; ErbB Receptors; Glomerular Filtration Rate; Renal Insufficiency, Chronic; Middle Aged; Reproducibility of Results; Models, Biological
PubMed: 37379796
DOI: 10.1016/j.archger.2023.105107 -
Journal of Infection and Public Health Sep 2021To systematically investigate the relationship between cardiac biomarkers and COVID-19 severity and mortality. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To systematically investigate the relationship between cardiac biomarkers and COVID-19 severity and mortality.
METHODS
We performed a literature search using PubMed, Web of Science, and Google Scholar. The standardized mean difference (SMD) and 95% confidence interval (CI) were applied to estimate the combined results of 67 studies. A meta-analysis of cardiac biomarkers was used to evaluate disease mortality and severity in COVID-19 patients.
RESULTS
A meta-analysis of 7812 patients revealed that patients with high levels of cardiac troponin I (SMD = 0.81 U/L, 95% CI = 0.14-1.48, P = 0.017), cardiac troponin T (SMD = 0.78 U/L, 95% CI = 0.07-1.49, P = 0.032), high-sensitive cardiac troponin I (SMD = 0.66 pg/mL, 95% CI = 0.51-0.81, P < 0.001), high-sensitive cardiac troponin T (SMD = 0.93 U/L, 95% CI = 0.21-1.65, P = 0.012), creatine kinase-MB (SMD = 0.54 U/L, 95% CI = 0.39-0.69, P < 0.001), and myoglobin (SMD = 0.80 U/L, 95% CI = 0.57-1.03, P < 0.001) were associated with prominent disease severity in COVID-19 infection. Moreover, 9532 patients with a higher serum level of cardiac troponin I (SMD = 0.51 U/L, 95% CI = 0.37-0.64, P < 0.001), high-sensitive cardiac troponin (SMD = 0.51 ng/L, 95% CI = 0.29-0.73, P < 0.001), high-sensitive cardiac troponin I (SMD = 0.51 pg/mL, 95% CI = 0.38-0.63, P < 0.001), high-sensitive cardiac troponin T (SMD = 0.85 U/L, 95% CI = 0.63-1.07, P < 0.001), creatine kinase-MB (SMD = 0.48 U/L, 95% CI = 0.32-0.65, P < 0.001), and myoglobin (SMD = 0.55 U/L, 95% CI = 0.45-0.65, P < 0.001) exhibited a prominent level of mortality from COVID-19 infection.
CONCLUSION
Cardiac biomarkers (cardiac troponin I, cardiac troponin T, high-sensitive cardiac troponin, high-sensitive cardiac troponin I, high-sensitive cardiac troponin T, creatine kinase-MB, and myoglobin) should be more frequently applied in identifying high-risk COVID-19 patients so that timely treatment can be implemented to reduce severity and mortality in COVID-19 patients.
Topics: Biomarkers; COVID-19; Creatine Kinase, MB Form; Humans; Myoglobin; Severity of Illness Index; Troponin I; Troponin T
PubMed: 34416596
DOI: 10.1016/j.jiph.2021.07.016 -
Biomolecules Sep 2023Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) have transformed the treatment of hormone receptor-positive (HR+) and human epidermal growth factor receptor... (Review)
Review
Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) have transformed the treatment of hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer over the last decade. These inhibitors are currently established as first- and second-line systemic treatment choices for both endocrine-sensitive and -resistant breast cancer populations alongside endocrine therapy (ET) or monotherapy. Data on targeted therapy continue to mature, and the number of publications has been constantly rising. Although these drugs have been demonstrated to prolong overall survival (as well as progression-free survival (PFS) in breast cancer patients), changing the paradigm of all current knowledge, they also cause important adverse events (AEs). This review provides the latest summary and update on the safety profile of the three CDK4/6 inhibitors, as it appears from all major phase II and III randomized clinical trials regarding palbociclib, ribociclib, and abemaciclib, including the most relevant 15 clinical trials.
Topics: Humans; Female; Breast Neoplasms; Progression-Free Survival; Cyclin-Dependent Kinase 4; Clinical Trials, Phase II as Topic
PubMed: 37759823
DOI: 10.3390/biom13091422