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Signal Transduction and Targeted Therapy Mar 2023The TP53 tumor suppressor is the most frequently altered gene in human cancers, and has been a major focus of oncology research. The p53 protein is a transcription... (Review)
Review
The TP53 tumor suppressor is the most frequently altered gene in human cancers, and has been a major focus of oncology research. The p53 protein is a transcription factor that can activate the expression of multiple target genes and plays critical roles in regulating cell cycle, apoptosis, and genomic stability, and is widely regarded as the "guardian of the genome". Accumulating evidence has shown that p53 also regulates cell metabolism, ferroptosis, tumor microenvironment, autophagy and so on, all of which contribute to tumor suppression. Mutations in TP53 not only impair its tumor suppressor function, but also confer oncogenic properties to p53 mutants. Since p53 is mutated and inactivated in most malignant tumors, it has been a very attractive target for developing new anti-cancer drugs. However, until recently, p53 was considered an "undruggable" target and little progress has been made with p53-targeted therapies. Here, we provide a systematic review of the diverse molecular mechanisms of the p53 signaling pathway and how TP53 mutations impact tumor progression. We also discuss key structural features of the p53 protein and its inactivation by oncogenic mutations. In addition, we review the efforts that have been made in p53-targeted therapies, and discuss the challenges that have been encountered in clinical development.
Topics: Humans; Tumor Suppressor Protein p53; Apoptosis; Autophagy; Cell Cycle; Ferroptosis
PubMed: 36859359
DOI: 10.1038/s41392-023-01347-1 -
Food and Chemical Toxicology : An... Feb 2023Aspartame has been studied extensively and evaluated for its safety in foods and beverages yet concerns for its potential carcinogenicity have persisted, driven... (Review)
Review
Aspartame has been studied extensively and evaluated for its safety in foods and beverages yet concerns for its potential carcinogenicity have persisted, driven primarily by animal studies conducted at the Ramazzini Institute (RI). To address this controversy, an updated systematic review of available human, animal, and mechanistic data was conducted leveraging critical assessment tools to consider the quality and reliability of data. The evidence base includes 12 animal studies and >40 epidemiological studies reviewed by the World Health Organization which collectively demonstrate a lack of carcinogenic effect. Assessment of >1360 mechanistic endpoints, including many guideline-based genotoxicity studies, demonstrate a lack of activity associated with endpoints grouped to key characteristics of carcinogens. Other non-specific mechanistic data (e.g., mixed findings of oxidative stress across study models, tissues, and species) do not provide evidence of a biologically plausible carcinogenic pathway associated with aspartame. Taken together, available evidence supports that aspartame consumption is not carcinogenic in humans and that the inconsistent findings of the RI studies may be explained by flaws in study design and conduct (despite additional analyses to address study limitations), as acknowledged by authoritative bodies.
Topics: Animals; Humans; Aspartame; Carcinogenesis; Carcinogenicity Tests; Carcinogens; Reproducibility of Results; Sweetening Agents
PubMed: 36493943
DOI: 10.1016/j.fct.2022.113549 -
Journal of the National Cancer Institute Apr 2022KRAS and BRAF mutations are well-established predictive and prognostic factors in metastatic colorectal cancer; however, their impact in the adjuvant setting has not yet... (Meta-Analysis)
Meta-Analysis
BACKGROUND
KRAS and BRAF mutations are well-established predictive and prognostic factors in metastatic colorectal cancer; however, their impact in the adjuvant setting has not yet been established.
METHODS
We performed a meta-analysis of adjuvant phase III trials in patients with stage II and III colon cancer with available data on the impact of KRAS or BRAF mutations on both disease-free survival (DFS) and overall survival (OS). Trials were subgrouped based on whether adjustment for microsatellite instability (MSI) was performed and the subgroup effect was analyzed through a meta-regression. To increase the precision of the estimates, a joint DFS-OS (so-called "multivariate") meta-analysis was performed. All statistical tests were 2-sided.
RESULTS
Nine trials were selected (QUASAR 2, PETACC-8, N0147, CALGB-89803, NSABP-C07, NSABP-C08, PETACC-3, QUASAR, MOSAIC) including a total of 10 893 patients. In the primary meta-analysis, KRAS mutation was associated with poor DFS (pooled hazard ratio [HR] = 1.36, 95% confidence interval [CI] = 1.15 to 1.61, P < .001) and OS (pooled HR = 1.27, 95% CI = 1.03 to 1.55, P = .03) and BRAF mutation was also associated with poor DFS (pooled HR = 1.33, 95% CI = 1.00 to 1.78, P = .05) and OS (pooled HR = 1.49, 95% CI = 1.31 to 1.70, P < .001). The effect of the mutations on outcome was enhanced in the MSI-adjusted subgroup for both the KRAS mutation (pooled HR for DFS = 1.43, 95% CI = 1.15 to 1.79, P = .001; and pooled HR for OS = 1.33, 95% CI = 1.03 to 1.71, P = .03) and the BRAF mutation (pooled HR for DFS = 1.59, 95% CI = 1.22 to 2.07, P = .001; and pooled HR for OS = 1.67, 95% CI = 1.37 to 2.04, P < .001). The interaction between BRAF and MSI adjustment was statistically significant for DFS (Pinteraction = .02). This interaction was even more pronounced in the DFS-OS multivariate meta-analysis.
CONCLUSIONS
Both KRAS and BRAF mutations were statistically significantly associated with both DFS and OS, with the mutation effect being enhanced by MSI adjustment. Effective adjuvant treatment for microsatellite-stable BRAF or KRAS-mutated colon cancer represents an unmet clinical need, and exploring the use of recently available BRAF and KRAS inhibitors in this setting would be highly desirable.
Topics: Colonic Neoplasms; Colorectal Neoplasms; Humans; Male; Microsatellite Instability; Mutation; Neoplasm Staging; Prognosis; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Testicular Neoplasms
PubMed: 34542636
DOI: 10.1093/jnci/djab190 -
Epidemiology of Bladder Cancer: A Systematic Review and Contemporary Update of Risk Factors in 2018.European Urology Dec 2018Bladder cancer (BC) is a significant health problem, and understanding the risk factors for this disease could improve prevention and early detection.
CONTEXT
Bladder cancer (BC) is a significant health problem, and understanding the risk factors for this disease could improve prevention and early detection.
OBJECTIVE
To provide a systematic review and summary of novel developments in epidemiology and risk factors for BC.
EVIDENCE ACQUISITION
A systematic review of original articles was performed by two pairs of reviewers (M.G.C., I.J., F.E., and K.P.) using PubMed/Medline in December 2017, updated in April 2018. To address our primary objective of reporting contemporary studies, we restricted our search to include studies from the last 5yr. We subdivided our review according to specific risk factors (PICO [Population Intervention Comparator Outcome]).
EVIDENCE SYNTHESIS
Our search found 2191 articles, of which 279 full-text manuscripts were included. We separated our manuscripts by the specific risk factor they addressed (PICO). According to GLOBOCAN estimates, there were 430000 new BC cases and 165000 deaths worldwide in 2012. Tobacco smoking and occupational exposure to carcinogens remain the factors with the highest attributable risk. The literature was limited by heterogeneity of data.
CONCLUSIONS
Evidence is emerging regarding gene-environment interactions, particularly for tobacco and occupational exposures. In some populations, incidence rates are declining, which may reflect a decrease in smoking. Standardisation of reporting may help improve epidemiologic evaluation of risk.
PATIENT SUMMARY
Bladder cancer is common worldwide, and the main risk factors are tobacco smoking and exposure to certain chemicals in the working and general environments. There is ongoing research to identify and reduce risk factors, as well as to understand the impact of genetics on bladder cancer risk.
Topics: Carcinogens, Environmental; Gene-Environment Interaction; Humans; Incidence; Occupational Exposure; Prevalence; Risk Assessment; Risk Factors; Smoking; Time Factors; Urinary Bladder Neoplasms
PubMed: 30268659
DOI: 10.1016/j.eururo.2018.09.001 -
Toxicology and Industrial Health Jul 2022Today, tattooing has become very popular among people all over the world. Tattooists, with the help of tiny needles, place tattoo ink inside the skin surface and...
Tattoo inks are toxicological risks to human health: A systematic review of their ingredients, fate inside skin, toxicity due to polycyclic aromatic hydrocarbons, primary aromatic amines, metals, and overview of regulatory frameworks.
Today, tattooing has become very popular among people all over the world. Tattooists, with the help of tiny needles, place tattoo ink inside the skin surface and unintentionally introduce a large number of unknown ingredients. These ingredients include polycyclic aromatic hydrocarbons (PAHs), heavy metals, and primary aromatic amines (PAAs), which are either unintentionally introduced along with the ink or produced inside the skin by different types of processes for example cleavage, metabolism and photodecomposition. These could pose toxicological risks to human health, if present beyond permissible limits. PAH such as Benzo(a)pyrene is present in carbon black ink. PAAs could be formed inside the skin as a result of reductive cleavage of organic azo dyes. They are reported to be highly carcinogenic by environmental protection agencies. Heavy metals, namely, cadmium, lead, mercury, antimony, beryllium, and arsenic are responsible for cancer, neurodegenerative diseases, cardiovascular, gastrointestinal, lungs, kidneys, liver, endocrine, and bone diseases. Mercury, cobalt sulphate, other soluble cobalt salts, and carbon black are in Group 2B, which means they may cause cancer in humans. Cadmium and compounds of cadmium, on the other hand, are in Group 1 (carcinogenic to humans). The present article addresses the various ingredients of tattoo inks, their metabolic fate inside human skin and unintentionally added impurities that could pose toxicological risk to human health. Public awareness and regulations that are warranted to be implemented globally for improving the safety of tattooing.
Topics: Amines; Cadmium; Carcinogens; Humans; Ink; Mercury; Metals; Polycyclic Aromatic Hydrocarbons; Soot; Tattooing
PubMed: 35592919
DOI: 10.1177/07482337221100870 -
Clinical Lung Cancer Sep 2023MET exon 14 (METex14) skipping is a rare oncogenic driver in non-small-cell lung cancer (NSCLC) for which targeted therapy with MET tyrosine kinase inhibitors (TKIs) was... (Review)
Review
INTRODUCTION
MET exon 14 (METex14) skipping is a rare oncogenic driver in non-small-cell lung cancer (NSCLC) for which targeted therapy with MET tyrosine kinase inhibitors (TKIs) was recently approved. Given the heterogeneity in published data of METex14 skipping NSCLC, we conducted a systematic literature review to evaluate its frequency, patient characteristics, and outcomes.
METHODS
On June 13, 2022 we conducted a systematic literature review of publications and conference abstracts reporting frequency, patient characteristics, or outcomes of patients with METex14 skipping NSCLC.
RESULTS
We included 139 studies reporting frequency or patient characteristics (350,997 patients), and 39 studies reporting clinical outcomes (3989 patients). Median METex14 skipping frequency was 2.0% in unselected patients with NSCLC, with minimal geographic variation. Median frequency was 2.4% in adenocarcinoma or nonsquamous subgroups, 12.0% in sarcomatoid, and 1.3% in squamous histology. Patients with METex14 skipping NSCLC were more likely to be elderly, have adenocarcinoma histology; there was no marked sex or smoking status distribution. In first line of treatment, median objective response rate ranged from 50.7% to 68.8% with targeted therapies (both values correspond to MET TKIs), was 33.3% with immunotherapy, and ranged from 23.1% to 27.0% with chemotherapy.
CONCLUSIONS
Patients with METex14 skipping are more likely to have certain characteristics, but no patient subgroup can be ruled out; thus, it is crucial to test all patients with NSCLC to identify suitable candidates for MET inhibitor therapy. MET TKIs appeared to result in higher efficacy outcomes, although no direct comparison with chemotherapy or immunotherapy regimens was found.
Topics: Aged; Humans; Adenocarcinoma; Carcinoma, Non-Small-Cell Lung; Exons; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met
PubMed: 37451931
DOI: 10.1016/j.cllc.2023.06.008 -
Journal of Occupational and... Oct 2023Asbestos is a mineral that is carcinogenic to humans. Its use has been banned in many occidental countries yet it is still produced in the United States, and materials... (Meta-Analysis)
Meta-Analysis Review
Asbestos is a mineral that is carcinogenic to humans. Its use has been banned in many occidental countries yet it is still produced in the United States, and materials that contain asbestos remain in many occupational settings and indoor environments. Even though asbestos carcinogenicity is well known, there is scant literature on its specific effects regarding small cell lung cancer (SCLC). We therefore conducted a systematic review and meta-analysis to determine SCLC risk among workers exposed to asbestos. A systematic search of the literature was conducted to identify studies which reported occupational exposure to asbestos and SCLC-related deaths and/or incidence. We identified seven case-control studies that included 3,231 SCLC cases; four studies reported smoking-adjusted risks. A significantly increased risk of SCLC (pooled OR 1.89; 95% CI, 1.25-2.86) was observed on pooling studies on men (six studies) that displayed moderate heterogeneity (I = 46.0%). Overall, our synthesis suggests that occupational exposure to asbestos significantly increases the risk of SCLC on men.
Topics: Male; Humans; United States; Small Cell Lung Carcinoma; Lung Neoplasms; Asbestos; Occupational Exposure; Carcinogens; Occupational Diseases
PubMed: 37405865
DOI: 10.1080/15459624.2023.2232421 -
American Journal of Cancer Research 2020The initiation and progression of cancer is dependent on the acquisition of mutations in oncogenes or tumor suppressor genes that ultimately leads to the dysregulation... (Review)
Review
The initiation and progression of cancer is dependent on the acquisition of mutations in oncogenes or tumor suppressor genes that ultimately leads to the dysregulation of key regulatory pathways. Though these mutations often occur in direct regulators of such pathways, some may confer tumorigenic potential by indirectly targeting several pathways congruently thereby exerting pleiotropic effects. In recent years, the tumor suppressor gene Speckle Type POZ Protein (SPOP) has gained a lot of attention as it has been found to be altered in a variety of different cancers. SPOP appears to exert pleiotropic tumorigenic effects as multiple different regulatory pathways become dysregulated upon SPOP alterations. SPOP has been identified as an E3 ubiquitin ligase substrate binding subunit of the proteasome complex. Since protein degradation is critical in regulating proper cellular function it is not surprising that the proteasome pathway is often found to be disrupted in cancer. Many studies have now indicated that mutations or changes in the expression of SPOP are one of several underlying reasons of proteasome pathway disruption in different cancers. Ultimately, either SPOP downregulation or mutation promotes stabilization of direct SPOP targets which subsequently promotes cancer through the dysregulation of key regulatory pathways. In this review, we will discuss the current literature on cancer-specific SPOP alterations as well the SPOP targets that are stabilized, and the pathways that are dysregulated, as a result.
PubMed: 32266086
DOI: No ID Found -
European Respiratory Review : An... Mar 2021Globally, radon is the leading risk factor for lung cancer in never-smokers (LCINS). In this study, we systematically reviewed and meta-analysed the evidence of the risk... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Globally, radon is the leading risk factor for lung cancer in never-smokers (LCINS). In this study, we systematically reviewed and meta-analysed the evidence of the risk of LCINS associated with residential radon exposure.
METHODS
Medline and Embase databases were searched using predefined inclusion and exclusion criteria to identify relevant studies published from 1 January 1990 to 5 March 2020 focused on never-smokers. We identified four pooled collaborative studies (incorporating data from 24 case-control studies), one case-control study and one cohort study for systematic review. Meta-analysis was performed on the results of the four pooled studies due to different measures of effect and outcome reported in the cohort study and insufficient information reported for the case-control study. In a analysis, the corresponding risk for ever-smokers was also examined.
RESULTS
Risk estimates of lung cancer from residential radon exposure were pooled in the meta-analysis for 2341 never-smoker cases, 8967 never-smoker controls, 9937 ever-smoker cases and 12 463 ever-smoker controls. Adjusted excess relative risks (aERRs) per 100 Bq·m of radon level were 0.15 (95% CI 0.06-0.25) for never-smokers and 0.09 (95% CI 0.03-0.16) for ever-smokers, and the difference between them was statistically insignificant (p=0.32). The aERR per 100 Bq·mwas higher for men (0.46; 95% CI 0.15-0.76) than for women (0.09; 95% CI -0.02-0.20) among never-smokers (p=0.027).
CONCLUSION
This study provided quantified risk estimates for lung cancer from residential radon exposure among both never-smokers and ever-smokers. Among never-smokers in radon-prone areas, men were at higher risk of lung cancer than women.
Topics: Case-Control Studies; Cohort Studies; Environmental Exposure; Female; Humans; Lung Neoplasms; Male; Radon; Risk Factors; Smokers
PubMed: 33536262
DOI: 10.1183/16000617.0230-2020 -
Cancer Investigation Sep 2023RET proto-oncogene encodes receptor tyrosine kinase. Selpercatinib and pralsetinib are the only RET-specific tyrosine kinase inhibitors approved by FDA in RET-altered... (Review)
Review
RET proto-oncogene encodes receptor tyrosine kinase. Selpercatinib and pralsetinib are the only RET-specific tyrosine kinase inhibitors approved by FDA in RET-altered tumors. We searched PubMed, Embase, Cochrane, WOS, and Clinicaltrials.gov. Objective-response, complete-response, and partial-response were 60-89%, 0-11%, and 55-89%, respectively, with the use of RET-specific drugs. ≥Grade 3 adverse events were seen in 28-53% of the patients, with hypertension, change in ALT, QT prolongation, neutropenia, and pneumonitis among the common side effects. Hence, selpercatinib and pralsetinib were effective and well tolerated by most of the patients with RET-altered tumors.
Topics: Humans; Neoplasms; Drug-Related Side Effects and Adverse Reactions; Hypertension; Neutropenia; Protein Kinase Inhibitors; Lung Neoplasms; Proto-Oncogene Proteins c-ret
PubMed: 37782113
DOI: 10.1080/07357907.2023.2255655