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BACKGROUND: The nuclear factor kappa B (NF-κB) is a critical pathway that regulates various cellular functions, including immune response, proliferation, growth, and apoptosis. Furthermore, this pathway is tightly regulated to ensure stability in the presence of immunogenic triggers or genotoxic stimuli. The lack of control of the NF-κB pathway can lead to the initiation of different diseases, mainly autoimmune diseases and cancer, including Renal cell carcinoma (RCC). RCC is the most common type of kidney cancer and is characterized by complex genetic composition and elusive molecular mechanisms. AIM OF REVIEW: The current review summarizes the mechanism of NF-κB dysregulation in different subtypes of RCC and its impact on pathogenesis. KEY SCIENTIFIC CONCEPT OF REVIEW: This review highlights the prominent role of NF-κB in RCC development and progression by driving the expression of multiple genes and interplaying with different pathways, including the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway. In silico analysis of RCC cohorts and molecular studies have revealed that multiple NF-κB members and target genes are dysregulated. The dysregulation includes receptors such as TLR2, signal-transmitting members including RelA, and target genes, for instance, HIF-1α. The lack of effective regulatory mechanisms results in a constitutively active NF-κB pathway, which promotes cancer growth, migration, and survival. In this review, we comprehensively summarize the role of dysregulated NF-κB-related genes in the most common subtypes of RCC, including clear cell RCC (ccRCC), chromophobe RCC (chRCC), and papillary RCC (PRCC).
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Prostate cancer is the second most commonly diagnosed cancer in men. The mammalian insulin-like growth factor (IGF) family is made up of three ligands (IGF-I, IGF-II, and insulin), three receptors (IGF-I receptor (IGF-1R), insulin receptor (IR), and IGF-II receptor (IGF-2R)), and six IGF-binding proteins (IGFBPs). IGF-I and IGF-II were identified as potent mitogens and were previously associated with an increased risk of cancer development including prostate cancer. Several reports showed controversy about the expression of the IGF family and their connection to prostate cancer risk due to the high degree of heterogeneity among prostate tumors, sampling bias, and evaluation techniques. Despite that, it is clear that several IGF family members play a role in prostate cancer development, metastasis, and androgen-independent progression. In this review, we aim to expand our understanding of prostate tumorigenesis and regulation through the IGF system. Further understanding of the role of IGF signaling in PCa shows promise and needs to be considered in the context of a comprehensive treatment strategy.
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Neoplasias da Próstata , Somatomedinas , Humanos , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Masculino , Somatomedinas/metabolismo , Animais , Transdução de Sinais , Fator de Crescimento Insulin-Like I/metabolismo , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Peptídeos Semelhantes à InsulinaRESUMO
Prostate cancer (PCa) is considered one of the most common cancers worldwide. Despite advances in patient diagnosis, management, and risk stratification, 10%-20% of patients progress to castration-resistant disease. Our previous report highlighted a protective role of Dickkopf-3 (DKK3) in PCa stroma. This role was proposed to be mediated through opposing extracellular matrix protein 1 (ECM-1) and TGF-ß signalling activity. However, a detailed analysis of the prognostic value of DKK3, ECM-1 and members of the TGF-ß signalling pathway in PCa was not thoroughly investigated. In this study, we explored the prognostic value of DKK3, ECM-1 and TGFB1 using a bioinformatical approach through analysis of large publicly available datasets from The Cancer Genome Atlas Program (TGCA) and Pan-Cancer Atlas databases. Our results showed a significant gradual loss of DKK3 expression with PCa progression (p < 0.0001) associated with increased DNA methylation in its promoter region (p < 1.63E-12). In contrast, patients with metastatic lesions showed significantly higher levels of TGFB1 expression compared to primary tumours (p < 0.00001). Our results also showed a marginal association between more advanced tumour stage presented as positive lymph node involvement and low DKK3 mRNA expression (p = 0.082). However, while ECM1 showed no association with tumour stage (p = 0.773), high TGFB1 expression showed a significant association with more advanced stage presented as advanced T3 stage compared to patients with low TGFB1 mRNA expression (p < 0.001). Interestingly, while ECM1 showed no significant association with patient outcome, patients with high DKK3 mRNA expression showed a significant association with favourable outcomes presented as prolonged disease-specific (p = 0.0266), progression-free survival (p = 0.047) and disease-free (p = 0.05). In contrast, high TGFB1 mRNA expression showed a significant association with poor patient outcomes presented as shortened progression-free (p = 0.00032) and disease-free survival (p = 0.0433). Moreover, DKK3, TGFB1 and ECM1 have acted as immune-associated genes in the PCa tumour microenvironment. In conclusion, our findings showed a distinct prognostic value for this three-gene signature in PCa. While both DKK3 and TGFB1 showed a potential role as a clinical marker for PCa stratification, ECM1 showed no significant association with the majority of clinicopathological parameters, which reduce its clinical significance as a reliable prognostic marker.
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Hepatocellular carcinoma (HCC) is an aggressive tumor and one of the most challenging cancers to treat. Here, we evaluated the in vitro and in vivo ameliorating impacts of seedless black Vitis vinifera (VV) polyphenols on HCC. Following the preparation of the VV crude extract (VVCE) from seedless VV (pulp and skin), three fractions (VVF1, VVF2, and VVF3) were prepared. The anticancer potencies of the prepared fractions, compared to 5-FU, were assessed against HepG2 and Huh7 cells. In addition, the effects of these fractions on p-dimethylaminoazobenzene-induced HCC in mice were evaluated. The predicted impacts of selected phenolic constituents of VV fractions on the activity of essential HCC-associated enzymes (NADPH oxidase "NADPH-NOX2", histone deacetylase 1 "HDAC1", and sepiapterin reductase "SepR") were analyzed using molecular docking. The results showed that VVCE and its fractions induced apoptosis and collapsed CD133+ stem cells in the studied cancer cell lines with an efficiency greater than 5-FU. VVF1 and VVF2 exhibited the most effective anticancer fractions in vitro; therefore, we evaluated their influences in mice. VVF1 and VVF2 improved liver morphology and function, induced apoptosis, and lowered the fold expression of various crucial genes that regulate cancer stem cells and other vital pathways for HCC progression. For most of the examined parameters, VVF1 and VVF2 had higher potency than 5-FU, and VVF1 showed more efficiency than VVF2. The selected phenolic compounds displayed competitive inhibitory action on NADPH-NOX2, HDAC1, and SepR. In conclusion, these findings declare that VV polyphenolic fractions, particularly VVF1, could be promising safe anti-HCC agents.
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Apoptose , Carcinoma Hepatocelular , Proliferação de Células , Neoplasias Hepáticas , Células-Tronco Neoplásicas , Extratos Vegetais , Polifenóis , Vitis , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Polifenóis/farmacologia , Polifenóis/isolamento & purificação , Apoptose/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Vitis/química , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Proliferação de Células/efeitos dos fármacos , Camundongos , Extratos Vegetais/farmacologia , Extratos Vegetais/isolamento & purificação , Células Hep G2 , Linhagem Celular Tumoral , Masculino , Simulação de Acoplamento Molecular , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificaçãoRESUMO
The Dickkopf family proteins (DKKs) are strong Wnt signaling antagonists that play a significant role in colorectal cancer (CRC) development and progression. Recent work has shown that DKKs, mainly DKK1, are associated with the induction of chemoresistance in CRC and that DKK1 expression in cancer cells correlates with that of protein arginine N-methyltransferase 5 (PRMT5). This points to the presence of a regulatory loop between DKK1 and PRMT5. Herein, we addressed the question of whether PRMT5 contributes to DKK1 expression in CRC and hence CRC chemoresistance. Both in silico and in vitro approaches were used to explore the relationship between PRMT5 and different DKK members. Our data demonstrated that DKK1 expression is significantly upregulated in CRC clinical samples, KRAS-mutated CRC in particular and that the levels of DKK1 positively correlate with PRMT5 activation. Chromatin immunoprecipitation (ChIP) data indicated a possible epigenetic role of PRMT5 in regulating DKK1, possibly through the symmetric dimethylation of H3R8. Knockdown of DKK1 or treatment with the PRMT5 inhibitor CMP5 in combination with doxorubicin yielded a synergistic anti-tumor effect in KRAS mutant, but not KRAS wild-type, CRC cells. These findings suggest that PRMT5 regulates DKK1 expression in CRC and that inhibition of PRMT5 modulates DKK1 expression in such a way that reduces CRC cell growth.
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Neoplasias Colorretais , Peptídeos e Proteínas de Sinalização Intercelular , Proteína-Arginina N-Metiltransferases , Humanos , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Doxorrubicina/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacosRESUMO
Gene expression is one of the most critical cellular processes. It is controlled by complex mechanisms at the genomic, epigenomic, transcriptomic, and proteomic levels. Any aberration in these mechanisms can lead to dysregulated gene expression. One recently discovered process that controls gene expression includes chemical modifications of RNA molecules by RNA-modifying proteins, a field known as epitranscriptomics. Epitranscriptomics can regulate mRNA splicing, nuclear export, stabilization, translation, or induce degradation of target RNA molecules. Dysregulation in RNA-modifying proteins has been found to contribute to many pathological conditions, such as cancer, diabetes, obesity, cardiovascular diseases, and neurological diseases, among others. This article reviews the role of epitranscriptomics in the pathogenesis and progression of renal cell carcinoma. It summarizes the molecular function of RNA-modifying proteins in the pathogenesis of renal cell carcinoma.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , RNA , Carcinoma de Células Renais/genética , Proteômica , Proteínas , Neoplasias Renais/genéticaRESUMO
BACKGROUND: Embryonic pluripotency markers are recognized for their role in ER- BC aggressiveness, but their significance in ER+ BC remains unclear. This study aims to investigate the prevalence of expression of pluripotency markers in ER+ BC and their effect on survival and prognostic indicators. METHODS: We analyzed data of ER+ BC patients from three large cancer datasets to assess the expression of three pluripotency markers (NANOG, SOX-2, and OCT4), and the stem cell marker ALDH1A1. Additionally, we investigated associations between gene expression, through mRNA-Seq analysis, and overall survival (OS). The prevalence of mutational variants within these genes was explored. Using immunohistochemistry (IHC), we examined the expression and associations with clinicopathologic prognostic indicators of the four markers in 81 ER+ BC patients. RESULTS: Through computational analysis, NANOG and ALDH1A1 genes were significantly upregulated in ER+ BC compared to ER- BC patients (p < 0.001), while POU5F1 (OCT4) was downregulated (p < 0.001). NANOG showed an adverse impact on OS whereas ALDH1A1 was associated with a highly significant improved survival in ER+ BC (p = 4.7e-6), except for the PR- and HER2+ subgroups. Copy number alterations (CNAs) ranged from 0.4% to 1.6% in these genes, with the highest rate detected in SOX2. In the IHC study, approximately one-third of tumors showed moderate to strong expression of each of the four markers, with 2-4 markers strongly co-expressed in 56.8% of cases. OCT-4 and ALDH1A1 showed a significant association with a high KI-67 index (p = 0.009 and 0.008, respectively), while SOX2 showed a significant association with perinodal fat invasion (p = 0.017). CONCLUSION: Pluripotency markers and ALDH1A1 are substantially expressed in ER+ BC tumors with different, yet significant, associations with prognostic and survival outcomes. This study suggests these markers as targets for prospective clinical validation studies of their prognostic value and their possible therapeutic roles.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Estudos Prospectivos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Prognóstico , Estrogênios , Células-Tronco Embrionárias/metabolismo , Família Aldeído Desidrogenase 1 , Retinal Desidrogenase/genéticaRESUMO
Titanium dental implants are one of the modalities to replace missing teeth. The release of titanium particles from the implant's surface may modulate the immune cells, resulting in implant failure. However, little is known about the immune microenvironment that plays a role in peri-implant inflammation as a consequence of titanium particles. In this study, the peri-implant gingival tissues were collected from patients with failed implants, successful implants and no implants, and then a whole transcriptome analysis was performed. The gene set enrichment analysis confirmed that macrophage M1/M2 polarization and lymphocyte proliferation were differentially expressed between the study groups. The functional clustering and pathway analysis of the differentially expressed genes between the failed implants and successful implants versus no implants revealed that the immune response pathways were the most common in both comparisons, implying the critical role of infiltrating immune cells in the peri-implant tissues. The H&E and IHC staining confirmed the presence of titanium particles and immune cells in the tissue samples, with an increase in the infiltration of lymphocytes and macrophages in the failed implant samples. The in vitro validation showed a significant increase in the level of IL-1ß, IL-8 and IL-18 expression by macrophages. Our findings showed evidence that titanium particles modulate lymphocyte and macrophage polarization in peri-implant gingival tissues, which can help in the understanding of the imbalance in osteoblast-osteoclast activity and failure of dental implant osseointegration.
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Implantes Dentários , Titânio , Humanos , Titânio/efeitos adversos , Titânio/análise , Gengiva , Linfócitos/química , Macrófagos/química , Inflamação , Implantes Dentários/efeitos adversosRESUMO
Breast cancer is the second leading cause of cancer death among women. The present study is an effort to reveal the antiproliferative and antioxidant actions of mango seed kernel extract (KE), peel extract (PE), and their combination (KEPE) on mammary tumors induced by 7,12 dimethylbenz[a]anthracene (DMBA). Seven groups of adult female Sprague-Dawley rats were prepared, including C: (control), DMBA: (rats were administered with DMBA), (DMBA-KE), (DMBA-PE), and (DMBA-KEPE): rats were administered with DMBA and then treated with KE, PE, and (both KE and PE), respectively, (KE) and (PE): rats were administered with KE and PE, separately. The study focused on the assessment of markers of endocrine derangement [serum 17-ß estradiol (E2)], apoptosis [caspase-3 and deoxyribonucleic acid fragmentation (DNAF)], and oxidative stress [lipid peroxidation and antioxidants (glutathione, glutathione-S-transferase, glutathione reductase, glutathione peroxidase, and superoxide dismutase)]. Histopathological examination and immunohistochemical expression of caspase-3 and estrogen receptor-α (ER-α) in mammary gland tissues (MGTs) were determined, as well as the characterization of mango extracts. The results showed that DMBA administration induced mammary tumors by increasing cell proliferation and evading apoptosis. In addition, DMBA administration caused oxidative stress by the production of reactive oxygen species, which increased lipid peroxidation and decreased cellular antioxidants, allowing cancer to progress. In contrast, treatment with DMBA-KE, DMBA-PE, or DMBA-KEPE diminished mammary tumors induced by DMBA, where they reduced oxidative stress via increased antioxidant parameters including reduced glutathione, superoxide dismutase, total glutathione peroxidase, glutathione reductase, and glutathione S-transferase. Also, different treatments decreased proliferation through the reduction of E2, and ER-α expression levels. However, these treatments increased the apoptosis of unwanted cells as they increased caspase-3 activity and DNAF. All these changes led to the prevention of breast injuries and the reduction of mammary tumors. This demonstrates that the contents of mango extracts, especially phenolics and flavonoids, have an important role in mammary tumor treatment through their potential antioxidant, antiproliferative, proapoptotic, and anti-estrogenic effects. KE and PE administration for 4 weeks had no adverse effects. Conclusion: Each of KE, PE, and KEPE has a therapeutic effect against DMBA-induced mammary tumors via induction of apoptosis and reduction of each of the OS, proliferation, and estrogenic effects. So, they can play an important role in the pharmacological tole.
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Neoplasias Mamárias Experimentais , Mangifera , Ratos , Feminino , Animais , Antioxidantes/metabolismo , Ratos Sprague-Dawley , Mangifera/metabolismo , Caspase 3 , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/prevenção & controle , Glutationa , Superóxido Dismutase , Carcinogênese , OxirredutasesRESUMO
Background: Vitamin D receptor (VDR) and insulin-like growth factor 1 receptor (IGF1R) are known to be involved in breast cancer (BC) progression. Our previous work reported a correlation of differential localization of IGF1R with hormone receptor status in BC. A recent report described VDR and IGF1R as potential indicators of BC prognosis, but their interplay was not discussed. The present study focused on understanding the association of VDR expression with IGF1R activation, different molecular markers, and subtypes of BC. Methods: A retrospective study was designed to evaluate the VDR expression among 48 BC patients pathologically diagnosed as invasive BC and were surgically treated at Sharjah Breast Care Center, University Hospital Sharjah (UHS), United Arab Emirates (UAE). Formalin-fixed paraffin-embedded (FFPE) tumor blocks with appropriate clinicopathological data were subjected to immunohistochemistry (IHC), and VDR protein expression was interpreted based on the staining intensity (SI) and the percentage of the positively stained cells (PP). Results: Nearly 44% of cases in the study were vitamin D deficient. A positive VDR expression with strong intensity (score > 4) was seen in 27 cases (56.3%). The expression pattern for VDR was equally distributed in cytoplasm and nucleus. For the IGF1R intensity, 24 cases (50%) of total cohort showed strong expression. A significant association was detected between IGF1R and VDR expression (P = 0.031). Conclusions: The present study identified positive association between IGF1R and VDR expression where most of the cases with strong VDR expression displayed strong IGF1R expression. These findings may contribute to current understanding on the role of VDR in BC and its interaction with IGF1R.
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While it is considered one of the most common cancers and the leading cause of death in men worldwide, prognostic stratification and treatment modalities are still limited for patients with prostate cancer (PCa). Recently, the introduction of genomic profiling and the use of new techniques like next-generation sequencing (NGS) in many cancers provide novel tools for the discovery of new molecular targets that might improve our understanding of the genomic aberrations in PCa and the discovery of novel prognostic and therapeutic targets. In this study, we investigated the possible mechanisms through which Dickkopf-3 (DKK3) produces its possible protective role in PCa using NGS in both the DKK3 overexpression PCa cell line (PC3) model and our patient cohort consisting of nine PCa and five benign prostatic hyperplasia. Interestingly, our results have shown that DKK3 transfection-modulated genes are involved in the regulation of cell motility, senescence-associated secretory phenotype (SASP), and cytokine signaling in the immune system, as well as in the regulation of adaptive immune response. Further analysis of our NGS using our in vitro model revealed the presence of 36 differentially expressed genes (DEGs) between DKK3 transfected cells and PC3 empty vector. In addition, both CP and ACE2 genes were differentially expressed not only between the transfected and empty groups but also between the transfected and Mock cells. The top common DEGs between the DKK3 overexpression cell line and our patient cohort are the following: IL32, IRAK1, RIOK1, HIST1H2BB, SNORA31, AKR1B1, ACE2, and CP. The upregulated genes including IL32, HIST1H2BB, and SNORA31 showed tumor suppressor functions in various cancers including PCa. On the other hand, both IRAK1 and RIOK1 were downregulated and involved in tumor initiation, tumor progression, poor outcome, and radiotherapy resistance. Together, our results highlighted the possible role of the DKK3-related genes in protecting against PCa initiation and progression.
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Hiperplasia Prostática , Neoplasias da Próstata , Humanos , Masculino , Enzima de Conversão de Angiotensina 2/metabolismo , Neoplasias da Próstata/patologia , Linhagem Celular , Aldeído Redutase/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismoRESUMO
Colorectal cancer is a notorious disease, with almost half of the patients succumbing to the disease. The prevalence and incidence rates of colorectal cancer are increasing in many parts of the world, highlighting the need to discover new biomarkers for diagnosis and therapy. Caldesmon (CaD), an actin-binding protein that plays a significant role in controlling cell motility, has emerged as a promising biomarker. The CALD1 gene encodes CaD as multiple transcripts that mainly encode two protein isoforms: High-molecular-weight (h-CaD), expressed in smooth muscle, and low-molecular-weight (l-CaD), expressed in nonsmooth muscle cells. Most studies have suggested an oncogenic role of CaD in colorectal cancer, but the exact subcellular localization of the two CaD isoforms in tumor cells and stroma have not been clarified yet. Here, we analyzed tissue samples from 262 colorectal cancer patients by immunohistochemistry analysis using specific antibodies for l-CaD and h-CaD. The results showed elevated cytoplasmic expression levels of l-Cad in 187/262 (71.4%) cases. l-Cad was expressed at low levels in the normal colon mucosa and was also consistently expressed in the cancer-associated stroma of all cases, suggesting that it could play a role in modulating the tumor microenvironment. l-CaD expression in cancer cells was associated with preinvasive stages of cancer. Survival analysis indicated that patients with high l-CaD expression in tumor cells could respond poorly to selective chemotherapeutic 5FU, but not combination chemotherapy. h-CaD was expressed in colonic and vascular smooth muscle cells as expected and to a lesser extent in the tumor-associated stroma, but it was not expressed in the cancer cells or normal colon mucosal epithelial cells. Collectively, these data clarify how the expression patterns of CaD isoforms in colorectal cancer can have applications in the management of colorectal cancer patients.
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Proteínas de Ligação a Calmodulina , Neoplasias Colorretais , Humanos , Proteínas de Ligação a Calmodulina/genética , Proteínas de Ligação a Calmodulina/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Movimento Celular/fisiologia , Células Epiteliais/metabolismo , Neoplasias Colorretais/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Microambiente TumoralRESUMO
BACKGROUND: Melanocytic neoplasms range from banal nevi to malignant melanomas. The genetic background has been extensively studied in the Caucasian population. BRAF mutations were reported among the early driver mutations in nevogenesis. Nevertheless, the pathogenesis in the Egyptian population has not been elucidated. AIM AND METHODS: The present study was carried out to assess the sensitivity and specificity of immunohistochemistry (IHC) using the RM-08 clone in reference to allele-specific real-time PCR (CAST-PCR) for the detection of the BRAF V600E mutation in 50 formalin-fixed paraffin-embedded blocks of melanocytic neoplasms with prior bleaching using hydrogen peroxide in Tris-HCL and Bovine Serum Albumin respectively. RESULTS: IHC staining was interpreted using staining reaction (positive versus negative) and staining pattern (negative and heterogeneous versus homogenous). Using the staining pattern, the specificity increased from 73.3 to 88.2%, the negative predictive value increased from 73.3 to 100%, the diagnostic accuracy increased from 71.4 to 90.48% and the overall accuracy increased from 69.9 to 77.3%. The sensitivity and positive predictive value remained unchanged. The K-agreement coefficient increased from 0.364 (fair agreement) to 0.741 (good agreement) and was statistically significant (p = 0.00). Next-generation sequencing was performed in 11 cases, 8 cases with IHC-positive and BRAF wild type in addition to 3 cases that failed PCR analysis and revealed no BRAF V600E. No statistically significant difference was found in the clinicopathological parameters between BRAF V600E and BRAF wild-type melanomas. CONCLUSIONS: These findings suggest that IHC staining homogeneity may be more accurate in predicting BRAF V600E mutational status. However, IHC cannot replace molecular methods.
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Colorectal cancer (CRC) is one of the most common malignancies worldwide; it is the fourth leading cause of cancer-related deaths. CRC arises due to mutations that can affect oncogenes, tumour suppressor genes and DNA repair genes. The lack of novel diagnostic and therapeutic targets and the development of chemoresistance are some of the major issues when dealing with CRC. The overexpression of ATP-binding cassette (ABC) transporters is considered one facilitating mechanism for chemoresistance. Furthermore, ABC transporters have additional roles in cancer development beyond multidrug resistance. In CRC, lipid dysregulation has a key role in tumour development and progression, as cancer cells rely on lipids for energy and rapid cell proliferation. ABC subfamily A (ABCA) contains the largest members of ABC proteins, mainly known for their role in lipid transport, mostly membrane lipids such as cholesterol and phospholipids. Although the exact mechanism of action of these members is not confirmed, their expression is usually correlated with tumour progression and therapy resistance, probably due to their role in lipid homeostasis. CRC shows alteration in the expression of ABCA transporters, which is usually linked to poor prognosis and overall survival. Therefore, as lipid transporters, their role in CRC is investigated, and their diagnostic and prognostic potential is evaluated. This minireview presents evidence from various studies suggesting that ABCA transporters might have an active role in CRC and can be utilized as potential diagnostic and therapeutic targets.
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Transportadores de Cassetes de Ligação de ATP , Neoplasias Colorretais , Humanos , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Subfamília A de Transportador de Cassetes de Ligação de ATP , Fosfolipídeos , Neoplasias Colorretais/patologia , Trifosfato de AdenosinaRESUMO
The transcriptomic regulation induced by isotretinoin (13-cis retinoic acid) is still a matter of debate as short-term exposures of immortalized sebocytes with isotretinoin produced conflicting results. Based on translational evidence, it has been hypothesized that oral isotretinoin treatment upregulates the expression of the transcription factor p53. Twenty-five patients suffering from acne vulgaris were treated with isotretinoin (0.6 mg/kg body weight) for 6 weeks. Biopsies from back skin were taken before and after isotretinoin treatment for the determination of p53 expression by immunohistochemical staining, quantification of p53 protein concentration by enzyme-linked immunosorbent assay and TP53 gene expression by quantitative reverse transcription real time PCR. Fifteen socio-demographically cross-matched healthy volunteers served as controls. Isotretinoin treatment significantly increased the nuclear expression of p53 in sebaceous glands of treated patients compared to pre-treatment levels and p53 levels of untreated controls. Furthermore, the p53 protein and gene expression significantly increased in the skin after treatment. The magnitude of p53 expression showed an inverse correlation to acne severity score and body mass index. Under clinical conditions, isotretinoin induced the expression of p53, which controls multiple transcription factors involved in the pathogenesis of acne vulgaris including FoxO1, androgen receptor and critical genes involved in the induction of autophagy and apoptosis. Increased p53-FoxO1 signalling enhanced by systemic isotretinoin treatment explains the underlying transcriptomic changes causing sebum suppression but also the adverse effects associated with systemic isotretinoin therapy.
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Acne Vulgar , Isotretinoína , Glândulas Sebáceas , Pele , Humanos , Acne Vulgar/tratamento farmacológico , Acne Vulgar/genética , Acne Vulgar/patologia , Isotretinoína/farmacologia , Isotretinoína/uso terapêutico , Glândulas Sebáceas/efeitos dos fármacos , Glândulas Sebáceas/metabolismo , Pele/efeitos dos fármacos , Pele/patologia , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
Kidney cancer has several types, with renal cell carcinoma (RCC) being the most prevalent and severe type, accounting for more than 85% of adult patients. The manual analysis of whole slide images (WSI) of renal tissues is the primary tool for RCC diagnosis and prognosis. However, the manual identification of RCC is time-consuming and prone to inter-subject variability. In this paper, we aim to distinguish between benign tissue and malignant RCC tumors and identify the tumor subtypes to support medical therapy management. We propose a novel multiscale weakly-supervised deep learning approach for RCC subtyping. Our system starts by applying the RGB-histogram specification stain normalization on the whole slide images to eliminate the effect of the color variations on the system performance. Then, we follow the multiple instance learning approach by dividing the input data into multiple overlapping patches to maintain the tissue connectivity. Finally, we train three multiscale convolutional neural networks (CNNs) and apply decision fusion to their predicted results to obtain the final classification decision. Our dataset comprises four classes of renal tissues: non-RCC renal parenchyma, non-RCC fat tissues, clear cell RCC (ccRCC), and clear cell papillary RCC (ccpRCC). The developed system demonstrates a high classification accuracy and sensitivity on the RCC biopsy samples at the slide level. Following a leave-one-subject-out cross-validation approach, the developed RCC subtype classification system achieves an overall classification accuracy of 93.0% ± 4.9%, a sensitivity of 91.3% ± 10.7%, and a high classification specificity of 95.6% ± 5.2%, in distinguishing ccRCC from ccpRCC or non-RCC tissues. Furthermore, our method outperformed the state-of-the-art Resnet-50 model.
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A tumor is a result of stepwise accumulation of genetic and epigenetic alterations. This notion has deepened the understanding of cancer biology and has introduced the era of targeted therapies. On the other hand, there have been a series of attempts of using the immune system to treat tumors, dating back to ancient history, to sporadic reports of inflamed tumors undergoing spontaneous regression. This was succeeded by modern immunotherapies and immune checkpoint inhibitors. The recent breakthrough has broadened the sight to other players within tumor tissue. Tumor microenvironment is a niche or a system orchestrating reciprocal and dynamic interaction of various types of cells including tumor cells and non-cellular components. The output of this complex communication dictates the functions of the constituent elements present within it. More complicated factors are biochemical and biophysical settings unique to TME. This mini review provides a brief guide on a range of factors to consider in the TME research.
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Colorectal cancer (CRC) is one of the most prevalent cancer types worldwide, with a high mortality rate due to metastasis. The tumor microenvironment (TME) contains multiple interactions between the tumor and the host, thus determining CRC initiation and progression. Various immune cells exist within the TME, such as tumor-infiltrating lymphocytes (TILs), tumor-associated macrophages (TAMs), and tumor-associated neutrophils (TANs). The immunotherapy approach provides novel opportunities to treat solid tumors, especially toward immune checkpoints. Despite the advances in the immunotherapy of CRC, there are still obstacles to successful treatment. In this review, we highlighted the role of these immune cells in CRC, with a particular emphasis on immune checkpoint molecules involved in CRC pathogenesis.