Summary Background Information from patient surveys can help to identify patient groups and cancers with the greatest potential for improvement in the experience and timeliness of cancer diagnosis. ...We aimed to examine variation in the number of pre-referral consultations with a general practitioner between patients with different cancers and sociodemographic characteristics. Methods We analysed data from 41 299 patients with 24 different cancers who took part in the 2010 National Cancer Patient Experience Survey in England. We examined variation in the number of general practitioner consultations with cancer symptoms before hospital referral to diagnose cancer. Logistic regression was used to identify independent predictors of three or more pre-referral consultations, adjusting for cancer type, age, sex, deprivation quintile, and ethnic group. Findings We identified wide variation between cancer types in the proportion of patients who had visited their general practitioner three or more times before hospital referral (7·4% 625 of 8408 for breast cancer and 10·1% 113 of 1124 for melanoma; 41·3% 193 of 467 for pancreatic cancer and 50·6% 939 of 1854 for multiple myeloma). In multivariable analysis, with patients with rectal cancer as the reference group, those with subsequent diagnosis of multiple myeloma (odds ratio OR 3·42, 95% CI 3·01–3·90), pancreatic cancer (2·35, 1·91–2·88), stomach cancer (1·96, 1·65–2·34), and lung cancer (1·68, 1·48–1·90) were more likely to have had three or more pre-referral consultations; conversely patients with subsequent diagnosis of breast cancer (0·19; 0·17–0·22), melanoma (0·34, 0·27–0·43), testicular cancer (0·47, 0·33–0·67), and endometrial cancer (0·59, 0·49–0·71) were more likely to have been referred to hospital after only one or two consultations. The probability of three or more pre-referral consultations was greater in young patients (OR for patients aged 16–24 years vs 65–74 years 2·12, 95% CI 1·63–2·75; p<0·0001), those from ethnic minorities (OR for Asian vs white 1·73, 1·45–2·08; p<0·0001; OR for black vs white 1·83, 1·51–2·23; p<0·0001), and women (OR for women vs men 1·28, 1·21–1·36; p<0·0001). We identified strong evidence of interactions between cancer type and age group and sex (p<0·0001 for both), and between age and ethnicity (p=0·0013). The model including these interactions showed a particularly strong sex effect for bladder cancer (OR for women vs men 2·31, 95% CI 1·98–2·69) and no apparent ethnic group differences in young patients aged 16–24 years, whilst the only cancers without an apparent age gradient were testicular cancer and mesothelioma. Interpretation Our findings could help to prioritise and stratify early diagnosis initiatives and research, focusing on patients with cancers and sociodemographic characteristics with the largest potential for improvement. Funding None.
Activating mutations in KIT/PDGFRA receptor tyrosine kinases drive gastrointestinal stromal tumors (GIST). KIT/PDGFRA inhibitors, such as imatinib do not evoke an effective cytocidal response, ...leaving room for quiescence and development of multiple secondary resistance mutations. As the majority of the secondary resistance clones activate PI3K and MAPK pathways, we investigated whether combined targeting of KIT/PI3K/MAPK (KPM) pathways overcomes drug resistance and quiescence in GIST cells. We monitored the proliferation of imatinib–sensitive and–resistant GIST cell lines after treating them with various combinations of drugs to inhibit KPM pathways. Cytocidal response was evaluated through proliferation, apoptosis and colony outgrowth assays. Combined inhibition of KPM signaling pathways using a KPM inhibitor cocktail decreased the survival of drug-resistant GIST cells and dramatically reduced their proliferation. Downstream pathway analysis showed that the residual PI3K/MAPK signaling observed after KIT inhibitor treatment plays a role in mediating quiescence and drug resistance. The KPM inhibitor cocktail with sunitinib or regorafenib effectively induced apoptosis and prevented colony outgrowth after long-term drug removal, suggesting that it can be used as an effective strategy against quiescence and drug resistance in metastatic GIST.
More than 90% of chondroblastomas contain a heterozygous mutation replacing lysine-36 with methionine-36 (K36M) in the histone H3 variant H3.3. Here we show that H3K36 methylation is reduced globally ...in human chondroblastomas and in chondrocytes harboring the same genetic mutation, due to inhibition of at least two H3K36 methyltransferases, MMSET and SETD2, by the H3.3K36M mutant proteins. Genes with altered expression as well as H3K36 di- and trimethylation in H3.3K36M cells are enriched in cancer pathways. In addition, H3.3K36M chondrocytes exhibit several hallmarks of cancer cells, including increased ability to form colonies, resistance to apoptosis, and defects in differentiation. Thus, H3.3K36M proteins reprogram the H3K36 methylation landscape and contribute to tumorigenesis, in part through altering the expression of cancer-associated genes.
Recently, there has been intense interest in the study of gastrointestinal stromal tumour (GIST); one might call it a virtual GIST revolution. This is due largely to the realization that most GISTs ...express KIT and harbour activating c‐KIT (KIT) or platelet‐derived growth factor receptor‐alpha (PDGFRA) receptor tyrosine kinase mutations that can be targeted by small molecule pharmacological inhibitors. Pathologists have benefited greatly from this revolution, mainly in the form of an improved ability to classify GISTs and, even more recently, in understanding the molecular underpinnings that underlie many fascinating clinical and pathological correlations. It is the purpose of this review to summarize recent developments in GIST classification and the molecular pathogenesis of GIST.
Integrating transcriptomic sequencing with conventional cytogenetics, we identified WWTR1 (WW domain-containing transcription regulator 1) (3q25) and CAMTA1 (calmodulin-binding transcription ...activator 1) (1p36) as the two genes involved in the t(1;3)(p36;q25) chromosomal translocation that is characteristic of epithelioid hemangioendothelioma (EHE), a vascular sarcoma. This WWTR1/CAMTA1 gene fusion is under the transcriptional control of the WWTR1 promoter and encodes a putative chimeric transcription factor that joins the amino terminus of WWTR1, a protein that is highly expressed in endothelial cells, in-frame to the carboxyl terminus of CAMTA1, a protein that is normally expressed only in brain. Thus, CAMTA1 expression is activated inappropriately through a promoter-switch mechanism. The gene fusion is present in virtually all EHEs tested but is absent from all other vascular neoplasms, demonstrating it to be a disease-defining genetic alteration. A sensitive and specific break-apart fluorescence in situ hybridization assay was also developed to detect the translocation and will assist in the evaluation of this diagnostically challenging neoplasm. The chimeric WWTR1/CAMTA1 transcription factor may represent a therapeutic target for EHE and offers the opportunity to shed light on the functions of two poorly characterized proteins.
Summary
Little is known about the epidemiological characteristics of sleep and awake bruxism (SB and AB) in adolescents. The aims of the study were: to assess the prevalence rates of self‐reported SB ...and AB in Israeli adolescents; to determine the associations between SB/AB and several demographical, exogenous and psychosocial factors in Israeli adolescents; and to investigate the possible concordance between SB and AB. The study made use of a questionnaire. The study population included 1000 students from different high schools in the centre of Israel. Prevalence of self‐reported SB and AB in the Israeli adolescents studied was 9·2% and 19·2%, respectively. No gender difference was found regarding the prevalence of SB and AB. Multiple variable regression analysis revealed that the following predicting variables were related to SB: temporomandibular joint sounds (P = 0·002) and feeling stressed (P = 0·001). The following predicting variables were related to AB: age (P = 0·018), temporomandibular joint sounds (P = 0·002), oro‐facial pain (P = 0·006), and feeling stressed (P = 0·002) or sad (P = 0·006). A significant association was found between SB and AB; that is, an individual reporting SB had a higher probability of reporting AB compared with an individual who did not report SB (odds ratio = 5·099). Chewing gum was the most common parafunction reported by adolescents. The results of this study demonstrate that self‐reports of AB and SB are common in the Israeli adolescents population studied and are not related to gender. The significant correlation found between SB and AB may be a confounding bias that affects proper diagnosis of bruxism through self‐reported questionnaires only.
Here we report the discovery of oncogenic mutations in the Hedgehog and mitogen-activated protein kinase (MAPK) pathways in over 80% of ameloblastomas, locally destructive odontogenic tumors of the ...jaw, by genomic analysis of archival material. Mutations in SMO (encoding Smoothened, SMO) are common in ameloblastomas of the maxilla, whereas BRAF mutations are predominant in tumors of the mandible. We show that a frequently occurring SMO alteration encoding p.Leu412Phe is an activating mutation and that its effect on Hedgehog-pathway activity can be inhibited by arsenic trioxide (ATO), an anti-leukemia drug approved by the US Food and Drug Administration (FDA) that is currently in clinical trials for its Hedgehog-inhibitory activity. In a similar manner, ameloblastoma cells harboring an activating BRAF mutation encoding p.Val600Glu are sensitive to the BRAF inhibitor vemurafenib. Our findings establish a new paradigm for the diagnostic classification and treatment of ameloblastomas.
The Hippo signaling pathway is a highly conserved pathway that plays important roles in the regulation of cell proliferation and apoptosis. Transcription factors TEAD1-4 and transcriptional ...coregulators YAP/TAZ are the downstream effectors of the Hippo pathway and can modulate Hippo biology. Dysregulation of this pathway is implicated in tumorigenesis and acquired resistance to therapies. The emerging importance of YAP/TAZ-TEAD interaction in cancer development makes it a potential therapeutic target. In the past decade, disrupting YAP/TAZ-TEAD interaction as an effective approach for cancer treatment has achieved great progress. This approach followed a trajectory wherein peptidomimetic YAP-TEAD protein-protein interaction disruptors (PPIDs) were first designed, followed by the discovery of allosteric small molecule PPIDs, and currently, the development of direct small molecule PPIDs. YAP and TEAD form three interaction interfaces. Interfaces 2 and 3 are amenable for direct PPID design. One direct YAP-TEAD PPID (IAG933) that targets interface 3 has entered a clinical trial in 2021. However, in general, strategically designing effective small molecules PPIDs targeting TEAD interfaces 2 and 3 has been challenging compared with allosteric inhibitor development. This review focuses on the development of direct surface disruptors and discusses the challenges and opportunities for developing potent YAP/TAZ-TEAD inhibitors for the treatment of cancer.
Gastrointestinal stromal tumour Rubin, Brian P, MD; Heinrich, Michael C, Prof; Corless, Christopher L, Prof
The Lancet (British edition),
05/2007, Letnik:
369, Številka:
9574
Journal Article
Recenzirano
Summary Gastrointestinal stromal tumours are the most common mesenchymal neoplasm of the gastrointestinal tract and are highly resistant to conventional chemotherapy and radiotherapy. Such tumours ...usually have activating mutations in either KIT (75–80%) or PDGFRA (5–10%), two closely related receptor tyrosine kinases. These mutations lead to ligand-independent activation and signal transduction mediated by constitutively activated KIT or PDGFRA. Targeting these activated proteins with imatinib mesylate, a small-molecule kinase inhibitor, has proven useful in the treatment of recurrent or metastatic gastrointestinal stromal tumours and is now being tested as an adjuvant or neoadjuvant. However, resistance to imatinib is a growing problem and other targeted therapeutics such as sunitinib are available. The important interplay between the molecular genetics of gastrontestinal stromal tumour and responses to targeted therapeutics serves as a model for the study of targeted therapies in other solid tumours.
β-carotene 15,15'-oxygenase (BCO1) catalyzes the first step in the conversion of dietary provitamin A carotenoids to vitamin A. This enzyme is expressed in a variety of developing and adult tissues, ...suggesting that its activity may regulate local retinoid synthesis. Vitamin A and related compounds (retinoids) are critical regulators of lung epithelial development, integrity, and injury repair. A balance between the actions of retinoids and glucocorticoids (GCs) promotes normal lung development and, in particular, alveolarization. Alterations in this balance, including vitamin A deficiency and GC excess, contribute to the development of chronic lung disorders. Consequently, we investigated if GCs counteract retinoid effects in alveolar epithelial cells by mechanisms involving BCO1-dependent local vitamin A metabolism. We demonstrate that BCO1 is expressed in human fetal lung tissue and human alveolar epithelial-like A549 cells. Our results indicate A549 cells metabolize β-carotene to retinal and retinoic acid (RA). GCs exposure using dexamethasone (DEX) decreases BCO1 mRNA and protein levels in A549 cells and reduces BCO1 promoter activity via inhibiting peroxisome proliferator-activated receptor γ (PPARγ) DNA binding. DEX also induces expression of PPARα, which in turn most likely causes a decrease in PPARγ/RXRα heterodimer binding to the bco1 gene promoter and consequent inhibition of bco1 gene expression. PPARα knockdown with siRNA abolishes DEX-induced suppression of BCO1 expression, confirming the requirement for PPARα in this DEX-mediated BCO1 mechanism. Taken together, these findings provide the first evidence that GCs regulate vitamin A (retinoid) signaling via inhibition of bco1 gene expression in a PPARα-dependent manner. These results explicate novel aspects of local GC:retinoid interactions that may contribute to alveolar tissue remodeling in chronic lung diseases that affect children and, possibly, adults.
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