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Journal of Cachexia, Sarcopenia and... Feb 2022Sarcopenic obesity is a distinct condition of sarcopenia in the context of obesity, with the cumulative health risks of both phenotypes. Differential expression of... (Review)
Review
Sarcopenic obesity is a distinct condition of sarcopenia in the context of obesity, with the cumulative health risks of both phenotypes. Differential expression of microRNAs (miRNAs) has been reported separately in people with obesity and sarcopenia and may play a role in the pathogenesis of sarcopenic obesity. However, this has not been explored to date. This study aimed to identify differentially expressed miRNAs reported in serum, plasma, and skeletal muscle of people with obesity and sarcopenia and whether there are any commonalities between these conditions. We performed a systematic review on Embase and MEDLINE (PROSPERO, CRD42020224486) for differentially expressed miRNAs (fold change >1.5 or P-value <0.05) in (i) sarcopenia or frailty and (ii) obesity or metabolic syndrome. The functions and targets of miRNAs commonly changed in both conditions, in the same direction, were searched using PubMed. Following deduplication, 247 obesity and 42 sarcopenia studies were identified for full-text screening. Screening identified 36 obesity and 6 sarcopenia studies for final inclusion. A total of 351 miRNAs were identified in obesity and 157 in sarcopenia. Fifty-five miRNAs were identified in both obesity and sarcopenia-by sample type, 48 were found in plasma and one each in serum and skeletal muscle. Twenty-four miRNAs were identified from 10 of the included studies as commonly changed in the same direction (22 in plasma and one each in serum and skeletal muscle) in obesity and sarcopenia. The majority of miRNA-validated targets identified in the literature search were members of the phosphoinositide 3-kinase/protein kinase B and transforming growth factor-β signalling pathways. The most common targets identified were insulin-like growth factor 1 (miR-424-5p, miR-483-3p, and miR-18b-5p) and members of the SMAD family (miR-483-3p, miR-92a-3p, and miR-424-5p). The majority of commonly changed miRNAs were involved in protein homeostasis, mitochondrial dynamics, determination of muscle fibre type, insulin resistance, and adipogenesis. Twenty-four miRNAs were identified as commonly dysregulated in obesity and sarcopenia with functions and targets implicated in the pathogenesis of sarcopenic obesity. Given the adverse health outcomes associated with sarcopenic obesity, understanding the pathogenesis underlying this phenotype has the potential to lead to effective screening, monitoring, or treatment strategies. Further research is now required to confirm whether these miRNAs are differentially expressed in older adults with sarcopenic obesity.
Topics: Adipogenesis; Aged; Humans; MicroRNAs; Obesity; Phosphatidylinositol 3-Kinases; Sarcopenia
PubMed: 34984856
DOI: 10.1002/jcsm.12878 -
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 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 -
Breast Cancer Research and Treatment Sep 2023In light of the clinically meaningful results of the PI3K inhibitors in PIK3CA-mutated metastatic breast cancer (BC) patients, the reliable identification of PIK3CA... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
In light of the clinically meaningful results of the PI3K inhibitors in PIK3CA-mutated metastatic breast cancer (BC) patients, the reliable identification of PIK3CA mutations is of outmost importance. However, lack of evidence on the optimal site and timing of assessment, presence of temporal heterogeneity and analytical factors pose several challenges in clinical routine. We aimed to study the discordance rates of PIK3CA mutational status between primary and matched metastatic tumors.
METHODS
A systematic literature search was performed in three different databases (Embase, Pubmed, Web of Science) and-upon screening-a total of 25 studies reporting PIK3CA mutational status both on primary breast tumors and their matched metastases were included in this meta-analysis. The random-effects model was used for pooled analyses of discordance of PIK3CA mutational status.
RESULTS
The overall discordance rate of PIK3CA mutational status was 9.8% (95% CI, 7.0-13.0; n = 1425) and did not significantly differ within BC subtypes or metastatic sites. The change was bi-directional, more commonly observed from PIK3CA mutated to wild-type status (14.9%, 95% CI 11.8-18.2; n tumor pairs = 453) rather than the opposite direction (8.9%, 95% CI 6.1-12.1; n tumor pairs = 943).
CONCLUSIONS
Our results indicate the need of obtaining metastatic biopsies for PIK3CA-mutation analysis and the possibility of testing of the primary tumor, in case a re-biopsy deemed non-feasible.
Topics: Humans; Female; Breast Neoplasms; Phosphatidylinositol 3-Kinases; Class I Phosphatidylinositol 3-Kinases; Mutation
PubMed: 37392328
DOI: 10.1007/s10549-023-07010-1 -
Asian Pacific Journal of Cancer... Mar 2023Cholangiocarcinoma (CCA) is the second most frequent hepatobiliary cancer after hepatocellular carcinoma with a poor prognosis and limited treatment options. This study...
BACKGROUND
Cholangiocarcinoma (CCA) is the second most frequent hepatobiliary cancer after hepatocellular carcinoma with a poor prognosis and limited treatment options. This study aimed to review existing knowledge on the genetic basis of CCA, molecular targets/signaling pathways involved in the pathogenesis, disease progression and prognosis, including potential targets for targeted therapies of CCA.
METHODS
The systematic review was performed in compliance with PRISMA guidelines. A systematic search in PubMed and Science Direct databases was performed using the following keywords: "cholangiocarcinoma", AND "molecular target" AND/OR "signaling pathway", AND/OR "targeted therapy", AND/OR "cancer chemotherapy." The eligibility criteria included: i) full-text articles published in English, ii) articles with in vitro and/or in vivo and/or clinical studies of molecular targets/signaling pathwanys related to CCA pathogenesis/disease progression/prognosis and/or targeted therapy. Seventy-three studies that fulfilled the eligibility criteria were finally included in the final data synthesis.
RESULTS
A total of 833 relevant articles published up to April 2022 were identified and 73 sttudies that fulfilled the eligibility criteria were finally included in the analysis. The molecular biomarkers and drugs targeting signalling pathways were reported. Recent research has been focused on targeting the apoptotic and cell proliferation pathways, and in addition, the angiogenesis and metastasis pathway. More effort focused on testing the efficacy of combination therapies against the cancer cell and specifically CCA. The PI3K (Phosphoinositide 3-kinases)/ERK/Akt (AKT serine/threonine kinase 1)/mTOR (mammalian target of rapamycin) signaling pathway and HER2 (Human epidermal growth factor receptor 2) and EGFR (Epidermal Growth Factor Receptor) pathways are the most potential targets for CCA therapy.
CONCLUSION
The information obtained could be exploited for further development of diagnostic tools for early diagnosis of CCA, as well as effective CCA-targeted therapies.
Topics: Humans; Proto-Oncogene Proteins c-akt; Signal Transduction; Cholangiocarcinoma; Cell Proliferation; Phosphatidylinositol 3-Kinases; Bile Ducts, Intrahepatic; Bile Duct Neoplasms; Disease Progression; Cell Line, Tumor
PubMed: 36974526
DOI: 10.31557/APJCP.2023.24.3.741 -
Oncotarget Oct 2020Alpelisib is a first-in-class α-specific phosphatidylinositol 3-kinase inhibitor approved for the treatment of patients with estrogen receptor-positive metastatic... (Review)
Review
PURPOSE
Alpelisib is a first-in-class α-specific phosphatidylinositol 3-kinase inhibitor approved for the treatment of patients with estrogen receptor-positive metastatic breast cancer. High absolute risk (AR) of relevant toxicities has been observed with this treatment. This meta-analysis aimed to improve the precision of the estimated AR of selected adverse events (AEs) associated with this new agent.
MATERIALS AND METHODS
A literature search was conducted in August 2019 to identify trials analyzing the anti-tumor efficacy and toxicity profile of alpelisib. Heterogeneity was assessed by using statistics. Data were analyzed using random effect meta-analyses for AR. Eleven trials and 511 patients were included.
RESULTS
There was no evidence of heterogeneity between studies regarding the AR of most AEs except for all-grade weight loss and grade 3-4 stomatitis. The number of serious AEs was clearly reported in only one study, of which the most common was hyperglycemia; the most common all-grade AEs were hyperglycemia (59%), diarrhea (56%), nausea (44%), and rash (38%). Grade 3/4 hyperglycemia and rash occurred in 28% and 10% of patients, respectively. No treatment-associated deaths were observed, and 18% of patients had to stop treatment due to toxicities.
CONCLUSIONS
Alpelisib is associated with clinically relevant AEs that can lead to treatment discontinuation. The most common AE was hyperglycemia. No treatment-related deaths were observed.
PubMed: 33144920
DOI: 10.18632/oncotarget.27770 -
Cancer Medicine Feb 2023Cutaneous adverse effects (AEs) are common following the phosphoinositide-3-kinase (PI3K) inhibitors treatment. We aim to estimate the incidence and risk of PI3K... (Meta-Analysis)
Meta-Analysis Review
Risk of cutaneous adverse events in cancer patients treated with phosphatidylinositol-3-kinase inhibitors: A systematic review and meta-analysis of randomized controlled trials.
BACKGROUND
Cutaneous adverse effects (AEs) are common following the phosphoinositide-3-kinase (PI3K) inhibitors treatment. We aim to estimate the incidence and risk of PI3K inhibitor-related cutaneous AEs.
METHODS
The protocol was submitted to the PROSPERO registry. We searched ClinicalTrials.gov and international databases up to July 29, 2022. Meta-analysis was conducted by using risk ratios (RRs) with 95% confidence intervals (CIs).
RESULTS
Fourteen randomized controlled trials (RCTs) comprising 3877 patients were analyzed in this study. Compared with control arms, PI3K inhibitors showed a significant increase in the risk of all-grade rash, high-grade rash, and serious rash events (RR 2.29, 95% CI 1.58-3.31, p < 0.00001; RR 9.34, 95% CI 4.21-20.69, p < 0.00001; RR 5.11, 95% CI 2.11-12.36, p = 0.0003). The overall incidences of all-grade rash and high-grade rash were 26.2% (592/2257) and 4.4% (66/1487). Subgroup analyses of all-grade rash according to cancer types and PI3K inhibitor assignations identified the significant associations. PI3K inhibitors also significantly increased the risk of pruritus and dry skin (RR 1.63, 95% CI 1.14-2.33, p = 0.007; RR 3.34, 95% CI 2.30-4.85, p < 0.00001), with incidences of 13.4% (284/2115) and 9.8% (141/1436) in the treatment group.
CONCLUSION
There is a significantly increased risk of some cutaneous AEs in patients using PI3K inhibitors. Advance intervention is recommended in case of severe and life-threatening events. Further research is required to investigate the risk factors and pathogenesis.
Topics: Humans; Randomized Controlled Trials as Topic; Neoplasms; Phosphoinositide-3 Kinase Inhibitors; Exanthema; Phosphatidylinositol 3-Kinases; Phosphatidylinositols
PubMed: 35986570
DOI: 10.1002/cam4.5153 -
Annals of Oncology : Official Journal... Oct 2016Somatic mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase/AKT pathway play a vital role in carcinogenesis. Approximately 15%-20% of colorectal cancers... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Somatic mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase/AKT pathway play a vital role in carcinogenesis. Approximately 15%-20% of colorectal cancers (CRCs) harbor activating mutations in PIK3CA, making it one of the most frequently mutated genes in CRC. We thus carried out a systematic review and meta-analysis investigating the prognostic significance of PIK3CA mutations in CRC.
MATERIALS AND METHODS
Electronic databases were searched from inception through May 2015. We extracted the study characteristics and prognostic data of each eligible study. The hazard ratio (HR) and 95% confidence interval (CI) were derived and pooled using the random-effects Mantel-Haenszel model.
RESULTS
Twenty-eight studies enrolling 12 747 patients were eligible for inclusion. Data on overall survival (OS) and progression-free survival (PFS) were available from 19 and 10 studies, respectively. Comparing PIK3CA-mutated CRC patients with PIK3CA-wild-type CRC patients, the summary HRs for OS and PFS were 0.96 (95% CI 0.83-1.12) and 1.20 (95% CI 0.98-1.46), respectively. The trim-and-fill, Copas model and subgroup analyses stratified by the study characteristics confirmed the robustness of the results. Five studies reported the CRC prognosis for PIK3CA mutations in exons 9 and 20 separately; neither exon 9 mutation nor exon 20 mutation in PIK3CA was significantly associated with patient survival.
CONCLUSIONS
Our findings suggest that PIK3CA mutation has the neutral prognostic effects on CRC OS and PFS. Evidence was accumulating for the establishment of CRC survival between PIK3CA mutations and patient-specific clinical or molecular profiles.
Topics: Biomarkers, Tumor; Class I Phosphatidylinositol 3-Kinases; Colorectal Neoplasms; Disease-Free Survival; Drug Resistance, Neoplasm; Humans; Mutation; Prognosis; Proportional Hazards Models
PubMed: 27436848
DOI: 10.1093/annonc/mdw264 -
Journal of Vascular Surgery. Venous and... Mar 2022PIK3CA (activating mutations of the p110α subunit of phosphatidylinositol 3-kinases)-related overgrowth spectrums (PROS) include a variety of clinical presentations...
BACKGROUND
PIK3CA (activating mutations of the p110α subunit of phosphatidylinositol 3-kinases)-related overgrowth spectrums (PROS) include a variety of clinical presentations that are associated with hypertrophy of different parts of the body. We performed a systematic literature review to assess the current treatment options and their efficacy and safety for PROS.
METHODS
A literature search was performed in Embase, MEDLINE (Ovid), Web of Science Core Collection, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and Google Scholar to retrieve studies on the treatment of hypertrophy in PROS. Randomized controlled trials, cohort studies, and case series with ≥10 patients were included in the present review. The titles, abstracts, and full text were assessed by two reviewers independently. The risk of bias was assessed using the Newcastle-Ottawa scale.
RESULTS
We included 16 studies of the treatment of hypertrophy in PROS patients, 13 (81.3%) from clinical retrospective studies and 3 (13.7%) from prospective cohort studies. The risk of bias grade was low for 2, medium for 12, and high for 2 studies. Of the 16 studies, 13 reported on surgical treatment and 3 reported pharmacologic treatment using phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway inhibitors in PROS patients. In 3 studies, PROS was defined by a mutation in the PIK3CA gene, and 13 studies relied on a clinical definition of PROS. Surgical therapy was beneficial for a specific subgroup of PROS (macrodactyly). However, little has been reported concerning surgery and the potential benefits for other PROS entities. The reported side effects after surgical therapy were mostly prolonged wound healing or scarring. PI3K/mTOR pathway inhibition was beneficial in patients with PROS by reducing hypertrophy and systemic symptoms. The adverse effects reported included infection, changes in blood count, liver enzymes, and metabolic measures.
CONCLUSIONS
Surgery is a locally limited treatment option for specific types of PROS. A promising treatment option for PROS is pharmacologic PIK3CA inhibition. However, the level of evidence on the treatment of overgrowth in PROS patients is limited.
Topics: Class I Phosphatidylinositol 3-Kinases; Genetic Predisposition to Disease; Humans; Hypertrophy; MTOR Inhibitors; Molecular Targeted Therapy; Mutation; Phenotype; Phosphoinositide-3 Kinase Inhibitors; Signal Transduction; Surgical Procedures, Operative; Syndrome; Treatment Outcome
PubMed: 34358672
DOI: 10.1016/j.jvsv.2021.07.008 -
Biomedicine & Pharmacotherapy =... Sep 2022Development and identification of molecular compounds capable of killing or inhibiting transformed cells promoting carcinogenesis without inducing toxic effects to the... (Review)
Review
Development and identification of molecular compounds capable of killing or inhibiting transformed cells promoting carcinogenesis without inducing toxic effects to the normal cells are of utmost significance. A systematic review was conducted in screening for important literature was extensively performed by searching the Web of Science, Ovid, BMC Springer, Elsevier, Embase, and MEDLINE databases for optimum selectivity. Google Scholar was also used to supplement information. Pharmacotherapeutic biomolecules active against colon cancer carcinogenesis in Musa acuminata and Musa balbisiana (bananas), Punica granatum L (pomegranate), Glycine max (Soybean), Brassica oleracea L var. italica Plenck (Broccoli), and Hibiscus rosa-sinesis and Hibiscus sabdariffa (hibiscus) were evaluated. Signaling pathways like phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), protein kinase B (AKT), and nuclear factor-kappa B (NFκB) correlate the mediation of COX-2 expression. Increased levels of COX-2 are correlated with the occurrence and progression of colon cancer. Natural antioxidants in herbal plants including polyphenols and carotenoids inhibit the oxidation of lipids, proteins, and nucleic acids and thereby preventing the initiation of oxidizing chain reactions. These bioactive compounds should be considered an important dietary supplement.
Topics: Carcinogenesis; Colonic Neoplasms; Cyclooxygenase 2; Hibiscus; Humans; Phosphatidylinositol 3-Kinases; Plants, Medicinal
PubMed: 35820316
DOI: 10.1016/j.biopha.2022.113383