This study analyzed 264 gastric cancers for mutations in exons 9 and 20 of the PIK3CA gene. PIK3CA mutations were found in 42 cases (16%), all heterozygous missense mutations. The most common mutation was H1047R in exon 20 (62% of mutations) and the second most common was Q546K in exon 9 (9.5% of mutations). A meta-analysis of 27 publications found that the ratio of exon 20 to exon 9 mutations varied by cancer type, being highest in gastric cancer. The exon mutation selectivity is a signature of the cancer type.
This document summarizes a study that performed comprehensive molecular characterization of 161 cases of papillary renal cell carcinoma (PRCC). The key findings were:
1) Type 1 and type 2 PRCC were found to be distinct types of renal cancer characterized by different genetic alterations, with type 2 further classified into three subgroups based on molecular differences associated with patient survival.
2) Type 1 tumors were associated with MET alterations, while type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-antioxidant response pathway.
3) A distinct subtype of type 2 PRCC was identified that had a CpG island methyl
This document describes a study investigating the role of the protein Morgana in breast cancer metastasis. The study found that knocking down Morgana impaired migration, invasion, and metastasis of breast cancer cells in vitro and in vivo. Mechanistically, Morgana was found to increase the transcriptional activity of NF-κB, leading to increased expression of metastasis-promoting genes like MMP-9. Overexpressing Morgana had the opposite effect of increasing NF-κB target gene expression. Therefore, Morgana appears to promote breast cancer metastasis by activating the NF-κB pathway and increasing expression of pro-metastatic genes.
1) Prodigiosin, a bacterial metabolite, induces apoptosis in human breast cancer cells. Gene expression profiling found that prodigiosin strongly increased expression of the NAG-1 gene.
2) Experiments showed that prodigiosin triggers accumulation of the tumor suppressor protein p53, but induction of NAG-1 was independent of p53.
3) Prodigiosin causes inhibition of AKT and activation of glycogen synthase kinase-3B (GSK-3B). Induction of NAG-1 and apoptosis correlated with GSK-3B activation. Inhibiting GSK-3B reduced apoptosis, suggesting GSK-3B plays a key role in the proap
1. Aberrations in sphingolipid metabolism are implicated in promoting glioblastoma multiforme (GBM) aggressiveness. GBM exhibits lower levels of ceramide and higher levels of sphingosine-1-phosphate (S1P) compared to normal brain tissue.
2. GBM manipulates sphingolipid pathways to shift the balance towards higher S1P and lower ceramide. Mechanisms include upregulating S1P-producing enzymes and downregulating ceramide-producing enzymes and phosphatases.
3. Receptors for the bioactive sphingolipid S1P are also upregulated in GBM, suggesting S1P signaling contributes to GBM
Acute myeloid leukemia (AML) is a hematopoietic malignancy with a dismal outcome in the majority of cases. A detailed understanding of the genetic alterations and gene expression changes that contribute to its pathogenesis is important to improve prognostication, disease monitoring, and therapy. In this context, leukemia-associated misexpression of microRNAs (miRNAs) has been studied, but no coherent picture has emerged yet, thus warranting further investigations.
This document summarizes a study investigating the role of microRNA-122 (miR-122) in regulating intrahepatic metastasis of hepatocellular carcinoma (HCC). The study found that miR-122 expression is significantly downregulated in HCC tumors with intrahepatic metastasis. Restoring miR-122 expression in metastatic HCC cell lines reduced in vitro migration, invasion, and tumor growth in vivo. Computational analysis identified multiple target genes of miR-122, including ADAM17, which was shown to be involved in metastasis. Silencing ADAM17 had similar effects as restoring miR-122, reducing in vitro and in vivo measures of metastasis. The study suggests that miR-122 acts as a tumor suppressor
Hepatocellular carcinoma (HCC) arises from mutations in genes that regulate cell growth. While over 40% of HCCs originate from cancer stem cells, the mechanisms of cancer stem cell formation are not fully understood. The transforming growth factor beta (TGF-β) signaling pathway plays an important role in suppressing tumor formation in the liver and intestinal stem cell niches. Loss of TGF-β signaling results in a phenotype similar to Beckwith-Wiedemann syndrome, which is associated with increased cancer risk. Understanding the TGF-β pathway and other key pathways involved in HCC formation could lead to new therapeutic strategies for preventing and treating this lethal cancer.
Clinical and experimental studies regarding the expression and diagnostic val...Enrique Moreno Gonzalez
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a multifunctional Ig-like cell adhesion molecule that has a wide range of biological functions. According to previous reports, serum CEACAM1 is dysregulated in different malignant tumours and associated with tumour progression. However, the serum CEACAM1 expression in nonsmall-cell lung carcinomas (NSCLC) is unclear. The different expression ratio of CEACAM1-S and CEACAM1-L isoform has seldom been investigated in NSCLC. This research is intended to study the serum CEACAM1 and the ratio of CEACAM1-S/L isoforms in NSCLC.
This document summarizes a study that performed comprehensive molecular characterization of 161 cases of papillary renal cell carcinoma (PRCC). The key findings were:
1) Type 1 and type 2 PRCC were found to be distinct types of renal cancer characterized by different genetic alterations, with type 2 further classified into three subgroups based on molecular differences associated with patient survival.
2) Type 1 tumors were associated with MET alterations, while type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-antioxidant response pathway.
3) A distinct subtype of type 2 PRCC was identified that had a CpG island methyl
This document describes a study investigating the role of the protein Morgana in breast cancer metastasis. The study found that knocking down Morgana impaired migration, invasion, and metastasis of breast cancer cells in vitro and in vivo. Mechanistically, Morgana was found to increase the transcriptional activity of NF-κB, leading to increased expression of metastasis-promoting genes like MMP-9. Overexpressing Morgana had the opposite effect of increasing NF-κB target gene expression. Therefore, Morgana appears to promote breast cancer metastasis by activating the NF-κB pathway and increasing expression of pro-metastatic genes.
1) Prodigiosin, a bacterial metabolite, induces apoptosis in human breast cancer cells. Gene expression profiling found that prodigiosin strongly increased expression of the NAG-1 gene.
2) Experiments showed that prodigiosin triggers accumulation of the tumor suppressor protein p53, but induction of NAG-1 was independent of p53.
3) Prodigiosin causes inhibition of AKT and activation of glycogen synthase kinase-3B (GSK-3B). Induction of NAG-1 and apoptosis correlated with GSK-3B activation. Inhibiting GSK-3B reduced apoptosis, suggesting GSK-3B plays a key role in the proap
1. Aberrations in sphingolipid metabolism are implicated in promoting glioblastoma multiforme (GBM) aggressiveness. GBM exhibits lower levels of ceramide and higher levels of sphingosine-1-phosphate (S1P) compared to normal brain tissue.
2. GBM manipulates sphingolipid pathways to shift the balance towards higher S1P and lower ceramide. Mechanisms include upregulating S1P-producing enzymes and downregulating ceramide-producing enzymes and phosphatases.
3. Receptors for the bioactive sphingolipid S1P are also upregulated in GBM, suggesting S1P signaling contributes to GBM
Acute myeloid leukemia (AML) is a hematopoietic malignancy with a dismal outcome in the majority of cases. A detailed understanding of the genetic alterations and gene expression changes that contribute to its pathogenesis is important to improve prognostication, disease monitoring, and therapy. In this context, leukemia-associated misexpression of microRNAs (miRNAs) has been studied, but no coherent picture has emerged yet, thus warranting further investigations.
This document summarizes a study investigating the role of microRNA-122 (miR-122) in regulating intrahepatic metastasis of hepatocellular carcinoma (HCC). The study found that miR-122 expression is significantly downregulated in HCC tumors with intrahepatic metastasis. Restoring miR-122 expression in metastatic HCC cell lines reduced in vitro migration, invasion, and tumor growth in vivo. Computational analysis identified multiple target genes of miR-122, including ADAM17, which was shown to be involved in metastasis. Silencing ADAM17 had similar effects as restoring miR-122, reducing in vitro and in vivo measures of metastasis. The study suggests that miR-122 acts as a tumor suppressor
Hepatocellular carcinoma (HCC) arises from mutations in genes that regulate cell growth. While over 40% of HCCs originate from cancer stem cells, the mechanisms of cancer stem cell formation are not fully understood. The transforming growth factor beta (TGF-β) signaling pathway plays an important role in suppressing tumor formation in the liver and intestinal stem cell niches. Loss of TGF-β signaling results in a phenotype similar to Beckwith-Wiedemann syndrome, which is associated with increased cancer risk. Understanding the TGF-β pathway and other key pathways involved in HCC formation could lead to new therapeutic strategies for preventing and treating this lethal cancer.
Clinical and experimental studies regarding the expression and diagnostic val...Enrique Moreno Gonzalez
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a multifunctional Ig-like cell adhesion molecule that has a wide range of biological functions. According to previous reports, serum CEACAM1 is dysregulated in different malignant tumours and associated with tumour progression. However, the serum CEACAM1 expression in nonsmall-cell lung carcinomas (NSCLC) is unclear. The different expression ratio of CEACAM1-S and CEACAM1-L isoform has seldom been investigated in NSCLC. This research is intended to study the serum CEACAM1 and the ratio of CEACAM1-S/L isoforms in NSCLC.
Knocking down pyruvate kinase M2 (PKM2) in colorectal cancer cells increases butyrate oxidation and decreases cell proliferation. Specifically:
- PKM2 knockdown cells exhibited no difference in glucose oxidation but showed increased butyrate oxidation compared to control cells.
- Increased butyrate oxidation may lead to decreased histone deacetylase activity and increased histone acetylation, allowing genes like p21 that regulate the cell cycle to be more actively transcribed and increasing apoptosis.
- The findings confirm the importance of PKM2 in cancer cell metabolism and suggest that PKM2 knockdown impacts butyrate oxidation and shifts metabolism away from a glycolytic phenotype toward one
Continuous Exposure to Chrysotile Asbestos Can CauseGhazal Khan
This document summarizes a study that found continuous exposure to chrysotile asbestos can induce transformation of human mesothelial cells through signaling of HMGB1 and TNF-α, similar to effects of crocidolite asbestos exposure. Both asbestos types induced epithelial-to-mesenchymal transition in cells, characterized by downregulation of E-cadherin and phosphorylation/nuclear translocation of β-catenin. While crocidolite exposure induced sustained gene expression changes and HMGB1 release, chrysotile effects returned to baseline within 5-8 weeks. Continuous chrysotile exposure was required to maintain elevated HMGB1 levels, supporting the role of fiber persistence in biological activity.
Differences in microRNA expression during tumor development in the transition...Enrique Moreno Gonzalez
The prostate is divided into three glandular zones, the peripheral zone (PZ), the transition zone (TZ), and the central zone. Most prostate tumors arise in the peripheral zone (70-75%) and in the transition zone (20-25%) while only 10% arise in the central zone. The aim of this study was to investigate if differences in miRNA expression could be a possible explanation for the difference in propensity of tumors in the zones of the prostate.
Inhibition of KPNA4 Attenuates Prostate Cancer MetastasisXin Li
This document summarizes a study examining the role of karyopherin α4 (KPNA4) in prostate cancer progression and metastasis. The study found that KPNA4 expression is positively correlated with prostate cancer stage and grade. Knockdown of KPNA4 reduced prostate cancer cell migration, invasion and distant metastasis in mouse models. Mechanistically, KPNA4 was found to be regulated by the tumor suppressive microRNA miR-708 and to modulate tumor necrosis factor (TNF)-α and -β expression through the nuclear factor kappa B (NF-κB) pathway to alter the tumor microenvironment and macrophage polarization.
Scientists screened 18 novel compounds for their ability to kill cancer cells. Several compounds showed potent cytotoxic effects, with IC50 values less than 1 μM on multiple cell lines. Three compounds - TMCOS-3, TMCOS-6, and TMCOS-11 - were found to induce apoptotic cell death through DNA fragmentation and caspase activation. TMCOS-11 was found to specifically inhibit tubulin polymerization and cause cell cycle arrest in the G2/M phase. These findings suggest that some of the compounds may be promising new anti-cancer drugs that work by targeting the microtubule protein tubulin.
ST-001 NanoFenretinide - SciTech Development Lead Drug CompoundSciTech Development
SciTech’s lead compound, ST-001, is a small-molecule immune oncology (IO) nanoFenretinide cancer drug employed as an aqueous nanoparticle suspension for IV administration. The ST-001 nanoFenretinide drug is comprised of the active pharmaceutical ingredient (API) fenretinide in a patented combination with carefully selected phospholipids (inactive ingredients). ST-001 is designed to deliver a 15-fold higher drug to lipid ratio and a >6x concentration of the API than conventional IV formulations achieving therapeutically effective doses without the toxic side effects observed with other delivery systems – a benefit previously unattainable. Recent discovery of the API’s immunotherapeutic effect, in which a reactivated natural immune response compliments the previously understood safe, direct, chemotherapeutic effect (functioning as dual mechanisms of action), has added materially to its value as a versatile therapeutic.
Vorinostat combined with DNMTi epigenetically controls the proliferation of l...MustafaFathy6
This study evaluated the effects of combining the histone deacetylase inhibitor (HDACi) vorinostat with other chemotherapeutic drugs on lung cancer cells. Vorinostat alone and in combination with carboplatin was most effective at reducing cell viability of A549 lung cancer cells. Global DNA methylation patterns varied depending on the drug combinations, with vorinostat and carboplatin causing hypomethylation and vorinostat and cyclophosphamide resulting in hypermethylation. The results suggest that combining epigenetic and chemotherapeutic drugs may be more effective at controlling lung cancer proliferation than single agents alone. However, more experiments are needed to confirm these findings.
This document discusses screening methods for anticancer drugs. It begins with an introduction to cancer and the importance of screening methods to find agents that can target solid tumors. It then covers the history of anticancer drug screening, including early small-scale studies on tumor growth. Various definitions of cancer and types of cancer are provided. The document focuses on in vitro and in vivo screening methods, such as dye exclusion assays, enzyme assays, and methods using animal models like inducing tumors in mice. It concludes that understanding these screening methods can help in developing novel anticancer drugs with improved selectivity and specificity.
Frizzled-8 receptor is activated by the Wnt-2 ligand in non-small cell lung c...Enrique Moreno Gonzalez
This document summarizes a research study that investigated the activation of Wnt-2 signaling through the Frizzled-8 receptor in non-small cell lung cancer (NSCLC). The study found a correlation between increased expression of Wnt-2 and Frizzled-8 in lung cancer tissue samples. A novel dominant-negative Wnt-2 construct (dnhWnt-2) inhibited Wnt-2 signaling activation and reduced colony formation of NSCLC cells in vitro and tumor growth in a mouse xenograft model. The dnhWnt-2 construct may provide a new therapeutic approach for targeting the Wnt pathway in lung cancer.
Assessing the clinical utility of cancer genomic and proteomic data across tu...Gul Muneer
This document summarizes a study that used machine learning to predict cancer patient survival based on integrating multiple types of molecular and clinical data from The Cancer Genome Atlas. The study found that combining molecular data like gene expression, methylation, and mutations with clinical data significantly improved survival prediction for kidney, ovarian, and lung cancers compared to using single data types alone. Analyzing the models provided biological insights into molecular subtypes and markers correlated with survival outcomes. The results suggest that more comprehensive molecular profiling of tumors could help stratify patients and identify targets for personalized cancer treatment.
As an uncommon malignant tumor, hypopharyngeal cancer accounts for 3–5% of head and neck tumors [1]. Most pathological types of hypopharyngeal cancer are squamous cell carcinoma. Due to the occult anatomical location of hypopharyngeal cancer and poor surgical effect, local recurrence or distant metastasis often occurs in patients with hypopharyngeal cancer following surgery.
This study examined the expression of HER-2 and LRP in tumor tissue samples from 65 gastric cancer patients and 32 non-gastric cancer patients. Immunohistochemical staining and Western blot analysis were used to test for HER-2 and LRP expression and phosphorylation levels. The results showed that HER-2 and LRP expression in gastric cancer tissues were positively correlated and higher than in non-gastric cancer tissues. HER-2 phosphorylation was highest in gastric cancer patients with lymphatic metastasis. This suggests that LRP may cause primary resistance in gastric cancer and that HER-2 activation may mediate gastric cancer resistance by influencing LRP expression.
The use of genetic engineering technology in animals has been associated with ethical issues, some of which relate to animal welfare. Discuss examples of genetically engineering animals and evaluate the ethical concerns of genetic engineering.
Overexpression of peptide deformylase in breast, colon, and lung cancersEnrique Moreno Gonzalez
Human mitochondrial peptide deformylase (PDF) has been proposed as a novel cancer therapeutic target. However, very little is known about its expression and regulation in human tissues. The purpose of this study was to characterize the expression pattern of PDF in cancerous tissues and to identify mechanisms that regulate its expression.
This study performed a genome-wide analysis of DNA methylation in colorectal carcinoma (CRC) tissue samples from 24 Bangladeshi patients. The researchers found a total of 627 differentially methylated loci covering 513 genes when comparing CRC tissue to normal adjacent tissue, with 535 loci covering 465 genes being newly identified. Gene set enrichment analysis showed hypermethylation in CRC of gene sets related to inhibition of adenylate cyclase activity, Rac guanyl-nucleotide exchange factor activity, regulation of retinoic acid receptor signaling, and estrogen receptor activity. Predictive models based on differentially methylated loci showed potential for CRC diagnosis with around 89% sensitivity and specificity.
The document summarizes a study investigating the expression and role of apoptosis-related molecules like TRAIL, FasL, and their receptors in pancreatic adenocarcinoma cell lines. The key findings were:
1) The pancreatic cancer cell lines expressed high levels of apoptosis-inducing ligands and receptors but showed variable susceptibility to TRAIL-induced cell death.
2) Treatment with chemotherapy drugs did not increase their susceptibility to apoptosis, likely due to their differential expression of decoy receptors and inhibitor molecules.
3) This suggests pancreatic cancers develop resistance to immune-mediated apoptosis, allowing immune evasion and tumor progression.
Proteogenomic analysis of human colon cancer reveals new therapeutic opportun...Gul Muneer
We performed the first proteogenomic study on a prospectively collected colon cancer cohort. Comparative proteomic and phosphoproteomic analysis of paired tumor and normal adjacent tissues produced a catalog of colon cancer-associated proteins and phosphosites, including known and putative new biomarkers, drug targets, and cancer/testis antigens. Proteogenomic integration not only prioritized genomically inferred targets, such as copy-number drivers and mutation-derived neoantigens, but also yielded novel findings. Phosphoproteomics data associated Rb phosphorylation with increased proliferation and decreased apoptosis in colon cancer, which explains why this classical tumor suppressor is amplified in colon tumors and suggests a rationale for targeting Rb phosphorylation in colon cancer. Proteomics identified an association between decreased CD8 T cell infiltration and increased glycolysis in microsatellite instability-high (MSI-H) tumors, suggesting glycolysis as a potential target to overcome the resistance of MSI-H tumors to immune checkpoint blockade. Proteogenomics presents new avenues for biological discoveries and therapeutic development.
This document provides an overview of oncogenes and tumor suppressor genes and their role in cancer initiation and progression. It discusses how mutations in proto-oncogenes can activate them into oncogenes, causing increased or altered protein production and stimulating cell proliferation. Tumor suppressor genes normally inhibit cell growth but mutations can repress them, deregulating the cell cycle. The interactions between oncogene activation and tumor suppressor gene inactivation are required for full malignant transformation. Understanding these genetic factors involved in carcinogenesis can provide insights into cancer prevention, diagnosis, and treatment.
SciTech Development pitch deck including company overview, proprietary technology, lead drug ST-001 nanoFenretinide, patents, addressable market sizes, competiton, key personnel, advisory board, drug product characteristics, fenretinide history, cancer indications and drug mechanism of action (MOA).
Objective: Tongue squamous cell carcinoma (TSCC) is a prominent type of oral cancer. Despite the numerous research studies on SCC and microRNAs (miRs), the relation between TSCC and miR-135b-5p is poorly discussed. This experiment aims to find out the possible effect of miR-135b-5p on TSCC with the network of its downstream genes.
Study Design: TSCC tissues and adjacent normal tissues were harvested. Then, expression of miR-135b-5p and AT-rich interactive domain‑containing protein 1A gene (ARID1A) and the phosphatidyl inositol 3-kinase/protein kinase B (PI3K/AKT) pathway was analyzed. After the transfection of miR-135b-5p inhibitor and its negative control into TSCC cells, functional assays were employed to measure cell proliferation, apoptosis, and cycle. Next, the target relation between miR-135b-5p and ARID1A was confirmed. In addition, the fact that miR-135b-5p promoted TSCC development via mediating ARID1A was demonstrated by functional rescue experiment.
Results: miR-135b-5p was upregulated in TSCC tissues and cells, while ARID1A was suppressed (p< 0.05). Silenced miR-135b-5p discouraged TSCC cell proliferation, improved apoptosis, induced cell cycle arrest, and increased ARID1A expression while inactivating the PI3K/AKT axis (p<0.05). Furthermore, knockdown of ARID1A reversed the impacts on TSCC cell proliferation and apoptosis exerted by silencing miR-135b-5p.
Conclusion: This research supported that silenced miR-135b-5p impeded TSCC proliferation and apoptosis by promoting ARID1A and inactivating the PI3K/AKT axis, which may provide some indications for TSCC alleviation.
Keywords: apoptosis; ARID1A; ARID1A protein, human; carcinoma, squamous cell; cell line, tumor; cell proliferation; drug resistance, neoplasm; microRNA-135b-5p; microRNAs; PI3K/AKT pathway; neoplasm metastasis; neoplastic stem cells; proliferation; protein binding; tongue; tongue squamous cell carcinoma
Este documento discute la prevención del cáncer gástrico. Explica que el cáncer gástrico es el quinto cáncer más común y la segunda causa de muerte por cáncer en Panamá. Luego describe los factores de riesgo como la infección por H. pylori, el tabaquismo y la dieta, y propone estrategias de prevención primaria como evitar el tabaco, adoptar una dieta rica en frutas y vegetales, y erradicar H. pylori. También recomienda la dete
This case report describes a 70-year-old female diagnosed with gastric adenocarcinoma with osteoclast-like giant cells (OGCs). Histopathological examination revealed a moderately differentiated adenocarcinoma with prominent lympho-histocytic infiltration and OGCs in the stroma. Immunohistochemistry showed the tumor cells were positive for pancytokeratin and the OGCs were positive for CD68. Additionally, the tumor and lymph nodes were positive for Epstein-Barr virus. The authors conclude that gastric carcinomas with OGCs are rare tumors that must be distinguished from more aggressive anaplastic carcinomas.
Knocking down pyruvate kinase M2 (PKM2) in colorectal cancer cells increases butyrate oxidation and decreases cell proliferation. Specifically:
- PKM2 knockdown cells exhibited no difference in glucose oxidation but showed increased butyrate oxidation compared to control cells.
- Increased butyrate oxidation may lead to decreased histone deacetylase activity and increased histone acetylation, allowing genes like p21 that regulate the cell cycle to be more actively transcribed and increasing apoptosis.
- The findings confirm the importance of PKM2 in cancer cell metabolism and suggest that PKM2 knockdown impacts butyrate oxidation and shifts metabolism away from a glycolytic phenotype toward one
Continuous Exposure to Chrysotile Asbestos Can CauseGhazal Khan
This document summarizes a study that found continuous exposure to chrysotile asbestos can induce transformation of human mesothelial cells through signaling of HMGB1 and TNF-α, similar to effects of crocidolite asbestos exposure. Both asbestos types induced epithelial-to-mesenchymal transition in cells, characterized by downregulation of E-cadherin and phosphorylation/nuclear translocation of β-catenin. While crocidolite exposure induced sustained gene expression changes and HMGB1 release, chrysotile effects returned to baseline within 5-8 weeks. Continuous chrysotile exposure was required to maintain elevated HMGB1 levels, supporting the role of fiber persistence in biological activity.
Differences in microRNA expression during tumor development in the transition...Enrique Moreno Gonzalez
The prostate is divided into three glandular zones, the peripheral zone (PZ), the transition zone (TZ), and the central zone. Most prostate tumors arise in the peripheral zone (70-75%) and in the transition zone (20-25%) while only 10% arise in the central zone. The aim of this study was to investigate if differences in miRNA expression could be a possible explanation for the difference in propensity of tumors in the zones of the prostate.
Inhibition of KPNA4 Attenuates Prostate Cancer MetastasisXin Li
This document summarizes a study examining the role of karyopherin α4 (KPNA4) in prostate cancer progression and metastasis. The study found that KPNA4 expression is positively correlated with prostate cancer stage and grade. Knockdown of KPNA4 reduced prostate cancer cell migration, invasion and distant metastasis in mouse models. Mechanistically, KPNA4 was found to be regulated by the tumor suppressive microRNA miR-708 and to modulate tumor necrosis factor (TNF)-α and -β expression through the nuclear factor kappa B (NF-κB) pathway to alter the tumor microenvironment and macrophage polarization.
Scientists screened 18 novel compounds for their ability to kill cancer cells. Several compounds showed potent cytotoxic effects, with IC50 values less than 1 μM on multiple cell lines. Three compounds - TMCOS-3, TMCOS-6, and TMCOS-11 - were found to induce apoptotic cell death through DNA fragmentation and caspase activation. TMCOS-11 was found to specifically inhibit tubulin polymerization and cause cell cycle arrest in the G2/M phase. These findings suggest that some of the compounds may be promising new anti-cancer drugs that work by targeting the microtubule protein tubulin.
ST-001 NanoFenretinide - SciTech Development Lead Drug CompoundSciTech Development
SciTech’s lead compound, ST-001, is a small-molecule immune oncology (IO) nanoFenretinide cancer drug employed as an aqueous nanoparticle suspension for IV administration. The ST-001 nanoFenretinide drug is comprised of the active pharmaceutical ingredient (API) fenretinide in a patented combination with carefully selected phospholipids (inactive ingredients). ST-001 is designed to deliver a 15-fold higher drug to lipid ratio and a >6x concentration of the API than conventional IV formulations achieving therapeutically effective doses without the toxic side effects observed with other delivery systems – a benefit previously unattainable. Recent discovery of the API’s immunotherapeutic effect, in which a reactivated natural immune response compliments the previously understood safe, direct, chemotherapeutic effect (functioning as dual mechanisms of action), has added materially to its value as a versatile therapeutic.
Vorinostat combined with DNMTi epigenetically controls the proliferation of l...MustafaFathy6
This study evaluated the effects of combining the histone deacetylase inhibitor (HDACi) vorinostat with other chemotherapeutic drugs on lung cancer cells. Vorinostat alone and in combination with carboplatin was most effective at reducing cell viability of A549 lung cancer cells. Global DNA methylation patterns varied depending on the drug combinations, with vorinostat and carboplatin causing hypomethylation and vorinostat and cyclophosphamide resulting in hypermethylation. The results suggest that combining epigenetic and chemotherapeutic drugs may be more effective at controlling lung cancer proliferation than single agents alone. However, more experiments are needed to confirm these findings.
This document discusses screening methods for anticancer drugs. It begins with an introduction to cancer and the importance of screening methods to find agents that can target solid tumors. It then covers the history of anticancer drug screening, including early small-scale studies on tumor growth. Various definitions of cancer and types of cancer are provided. The document focuses on in vitro and in vivo screening methods, such as dye exclusion assays, enzyme assays, and methods using animal models like inducing tumors in mice. It concludes that understanding these screening methods can help in developing novel anticancer drugs with improved selectivity and specificity.
Frizzled-8 receptor is activated by the Wnt-2 ligand in non-small cell lung c...Enrique Moreno Gonzalez
This document summarizes a research study that investigated the activation of Wnt-2 signaling through the Frizzled-8 receptor in non-small cell lung cancer (NSCLC). The study found a correlation between increased expression of Wnt-2 and Frizzled-8 in lung cancer tissue samples. A novel dominant-negative Wnt-2 construct (dnhWnt-2) inhibited Wnt-2 signaling activation and reduced colony formation of NSCLC cells in vitro and tumor growth in a mouse xenograft model. The dnhWnt-2 construct may provide a new therapeutic approach for targeting the Wnt pathway in lung cancer.
Assessing the clinical utility of cancer genomic and proteomic data across tu...Gul Muneer
This document summarizes a study that used machine learning to predict cancer patient survival based on integrating multiple types of molecular and clinical data from The Cancer Genome Atlas. The study found that combining molecular data like gene expression, methylation, and mutations with clinical data significantly improved survival prediction for kidney, ovarian, and lung cancers compared to using single data types alone. Analyzing the models provided biological insights into molecular subtypes and markers correlated with survival outcomes. The results suggest that more comprehensive molecular profiling of tumors could help stratify patients and identify targets for personalized cancer treatment.
As an uncommon malignant tumor, hypopharyngeal cancer accounts for 3–5% of head and neck tumors [1]. Most pathological types of hypopharyngeal cancer are squamous cell carcinoma. Due to the occult anatomical location of hypopharyngeal cancer and poor surgical effect, local recurrence or distant metastasis often occurs in patients with hypopharyngeal cancer following surgery.
This study examined the expression of HER-2 and LRP in tumor tissue samples from 65 gastric cancer patients and 32 non-gastric cancer patients. Immunohistochemical staining and Western blot analysis were used to test for HER-2 and LRP expression and phosphorylation levels. The results showed that HER-2 and LRP expression in gastric cancer tissues were positively correlated and higher than in non-gastric cancer tissues. HER-2 phosphorylation was highest in gastric cancer patients with lymphatic metastasis. This suggests that LRP may cause primary resistance in gastric cancer and that HER-2 activation may mediate gastric cancer resistance by influencing LRP expression.
The use of genetic engineering technology in animals has been associated with ethical issues, some of which relate to animal welfare. Discuss examples of genetically engineering animals and evaluate the ethical concerns of genetic engineering.
Overexpression of peptide deformylase in breast, colon, and lung cancersEnrique Moreno Gonzalez
Human mitochondrial peptide deformylase (PDF) has been proposed as a novel cancer therapeutic target. However, very little is known about its expression and regulation in human tissues. The purpose of this study was to characterize the expression pattern of PDF in cancerous tissues and to identify mechanisms that regulate its expression.
This study performed a genome-wide analysis of DNA methylation in colorectal carcinoma (CRC) tissue samples from 24 Bangladeshi patients. The researchers found a total of 627 differentially methylated loci covering 513 genes when comparing CRC tissue to normal adjacent tissue, with 535 loci covering 465 genes being newly identified. Gene set enrichment analysis showed hypermethylation in CRC of gene sets related to inhibition of adenylate cyclase activity, Rac guanyl-nucleotide exchange factor activity, regulation of retinoic acid receptor signaling, and estrogen receptor activity. Predictive models based on differentially methylated loci showed potential for CRC diagnosis with around 89% sensitivity and specificity.
The document summarizes a study investigating the expression and role of apoptosis-related molecules like TRAIL, FasL, and their receptors in pancreatic adenocarcinoma cell lines. The key findings were:
1) The pancreatic cancer cell lines expressed high levels of apoptosis-inducing ligands and receptors but showed variable susceptibility to TRAIL-induced cell death.
2) Treatment with chemotherapy drugs did not increase their susceptibility to apoptosis, likely due to their differential expression of decoy receptors and inhibitor molecules.
3) This suggests pancreatic cancers develop resistance to immune-mediated apoptosis, allowing immune evasion and tumor progression.
Proteogenomic analysis of human colon cancer reveals new therapeutic opportun...Gul Muneer
We performed the first proteogenomic study on a prospectively collected colon cancer cohort. Comparative proteomic and phosphoproteomic analysis of paired tumor and normal adjacent tissues produced a catalog of colon cancer-associated proteins and phosphosites, including known and putative new biomarkers, drug targets, and cancer/testis antigens. Proteogenomic integration not only prioritized genomically inferred targets, such as copy-number drivers and mutation-derived neoantigens, but also yielded novel findings. Phosphoproteomics data associated Rb phosphorylation with increased proliferation and decreased apoptosis in colon cancer, which explains why this classical tumor suppressor is amplified in colon tumors and suggests a rationale for targeting Rb phosphorylation in colon cancer. Proteomics identified an association between decreased CD8 T cell infiltration and increased glycolysis in microsatellite instability-high (MSI-H) tumors, suggesting glycolysis as a potential target to overcome the resistance of MSI-H tumors to immune checkpoint blockade. Proteogenomics presents new avenues for biological discoveries and therapeutic development.
This document provides an overview of oncogenes and tumor suppressor genes and their role in cancer initiation and progression. It discusses how mutations in proto-oncogenes can activate them into oncogenes, causing increased or altered protein production and stimulating cell proliferation. Tumor suppressor genes normally inhibit cell growth but mutations can repress them, deregulating the cell cycle. The interactions between oncogene activation and tumor suppressor gene inactivation are required for full malignant transformation. Understanding these genetic factors involved in carcinogenesis can provide insights into cancer prevention, diagnosis, and treatment.
SciTech Development pitch deck including company overview, proprietary technology, lead drug ST-001 nanoFenretinide, patents, addressable market sizes, competiton, key personnel, advisory board, drug product characteristics, fenretinide history, cancer indications and drug mechanism of action (MOA).
Objective: Tongue squamous cell carcinoma (TSCC) is a prominent type of oral cancer. Despite the numerous research studies on SCC and microRNAs (miRs), the relation between TSCC and miR-135b-5p is poorly discussed. This experiment aims to find out the possible effect of miR-135b-5p on TSCC with the network of its downstream genes.
Study Design: TSCC tissues and adjacent normal tissues were harvested. Then, expression of miR-135b-5p and AT-rich interactive domain‑containing protein 1A gene (ARID1A) and the phosphatidyl inositol 3-kinase/protein kinase B (PI3K/AKT) pathway was analyzed. After the transfection of miR-135b-5p inhibitor and its negative control into TSCC cells, functional assays were employed to measure cell proliferation, apoptosis, and cycle. Next, the target relation between miR-135b-5p and ARID1A was confirmed. In addition, the fact that miR-135b-5p promoted TSCC development via mediating ARID1A was demonstrated by functional rescue experiment.
Results: miR-135b-5p was upregulated in TSCC tissues and cells, while ARID1A was suppressed (p< 0.05). Silenced miR-135b-5p discouraged TSCC cell proliferation, improved apoptosis, induced cell cycle arrest, and increased ARID1A expression while inactivating the PI3K/AKT axis (p<0.05). Furthermore, knockdown of ARID1A reversed the impacts on TSCC cell proliferation and apoptosis exerted by silencing miR-135b-5p.
Conclusion: This research supported that silenced miR-135b-5p impeded TSCC proliferation and apoptosis by promoting ARID1A and inactivating the PI3K/AKT axis, which may provide some indications for TSCC alleviation.
Keywords: apoptosis; ARID1A; ARID1A protein, human; carcinoma, squamous cell; cell line, tumor; cell proliferation; drug resistance, neoplasm; microRNA-135b-5p; microRNAs; PI3K/AKT pathway; neoplasm metastasis; neoplastic stem cells; proliferation; protein binding; tongue; tongue squamous cell carcinoma
Este documento discute la prevención del cáncer gástrico. Explica que el cáncer gástrico es el quinto cáncer más común y la segunda causa de muerte por cáncer en Panamá. Luego describe los factores de riesgo como la infección por H. pylori, el tabaquismo y la dieta, y propone estrategias de prevención primaria como evitar el tabaco, adoptar una dieta rica en frutas y vegetales, y erradicar H. pylori. También recomienda la dete
This case report describes a 70-year-old female diagnosed with gastric adenocarcinoma with osteoclast-like giant cells (OGCs). Histopathological examination revealed a moderately differentiated adenocarcinoma with prominent lympho-histocytic infiltration and OGCs in the stroma. Immunohistochemistry showed the tumor cells were positive for pancytokeratin and the OGCs were positive for CD68. Additionally, the tumor and lymph nodes were positive for Epstein-Barr virus. The authors conclude that gastric carcinomas with OGCs are rare tumors that must be distinguished from more aggressive anaplastic carcinomas.
This study aimed to determine the most accurate method for defining in vitro chemosensitivity using an ATP-based chemotherapy response assay (ATP-CRA). 48 patients with advanced gastric cancer were treated with paclitaxel and cisplatin chemotherapy after obtaining tumor samples for ATP-CRA testing. The chemosensitivity index method showed the highest accuracy of 77.8% for predicting clinical response. In vitro chemosensitive tumors had a higher response rate to chemotherapy compared to chemoresistant tumors. The ATP-CRA could predict clinical response to paclitaxel and cisplatin chemotherapy in advanced gastric cancer patients with high accuracy.
This study performed a cost-effectiveness analysis of adjuvant chemoradiotherapy for resected gastric cancer based on results from the Intergroup 0116 trial. The analysis found that the incremental cost of adding chemoradiotherapy was $20,100 and provided an additional 0.53 quality-adjusted life years, resulting in an incremental cost-effectiveness ratio of $38,400 per quality-adjusted life year gained. A probabilistic sensitivity analysis predicted a 67% likelihood that the ratio would be less than $50,000 per quality-adjusted life year, which compares favorably to other widely used cancer treatments.
This document summarizes trends in gastrointestinal diseases at a single institution in Korea over the past two decades from 1990 to 2006. Some key findings include:
1) Admission rates for GI diseases increased between 1990 and 2006, with gastric cancer, colon cancer, and colon adenomas/polyps becoming the most prevalent.
2) While gastric cancer rates decreased, colon cancer rates doubled over the two decades.
3) Detection and treatment of early gastric cancer and colon adenomas increased noticeably.
4) New emerging diseases included inflammatory bowel disease and gastroesophageal reflux.
This study performed a cost-effectiveness analysis of adjuvant chemoradiotherapy for resected gastric cancer based on results from the Intergroup 0116 trial. An economic model was constructed to examine costs and quality-adjusted survival benefits. Results found that adjuvant chemoradiotherapy cost $20,100 more but provided 0.53 more quality-adjusted life years, resulting in an incremental cost-effectiveness ratio of $38,400 per quality-adjusted life year gained. Sensitivity analyses suggested a 67% likelihood the ratio would be less than $50,000 per quality-adjusted life year, which compares favorably to other cancer treatments.
This clinical practice guideline summarizes key points on Helicobacter pylori infections and gastroduodenal ulcer disease. It was developed by an interdisciplinary group in accordance with German guidelines. H. pylori infection can be accurately diagnosed non-invasively or invasively. Eradication therapy is recommended for H. pylori-associated ulcers or gastric MALT lymphoma. First-line eradication therapy consists of a proton pump inhibitor combined with clarithromycin and either metronidazole or amoxicillin.
This study performed a cost-effectiveness analysis of adjuvant chemoradiotherapy for resected gastric cancer based on results from the Intergroup 0116 trial. The analysis found that the incremental cost of adding chemoradiotherapy was $20,100 and provided an additional 0.53 quality-adjusted life years, resulting in an incremental cost-effectiveness ratio of $38,400 per quality-adjusted life year gained. This ratio compares favorably to other widely used cancer treatments, suggesting adjuvant chemoradiotherapy is a cost-effective option for resected gastric cancer patients.
1) The earliest reports of possible gastric cancer cases date back to ancient Egyptian and Greek civilizations in 1600 BC and the 2nd century AD, though understanding of cancer was limited.
2) The first modern medical description of gastric cancer was not until the 18th century, explaining the mystery of Napoleon Bonaparte's death from stomach cancer in 1821.
3) An autopsy of Napoleon revealed a cancerous ulcer occupying most of his stomach wall, representing one of the earliest confirmed cases of gastric cancer.
This document summarizes key signaling pathways in muscle-invasive bladder carcinoma. It discusses molecular markers that indicate basal or luminal subtypes of bladder cancer, which differ in response to treatment. Basal cancers often overexpress EGFR and respond to chemotherapy, while luminal cancers involve alterations in genes like FGFR3, ERBB2/3 and are generally less aggressive. The document also reviews markers for cancer stem cells, receptor tyrosine kinase signaling pathways, cytoskeleton proteins, the PI3K-Akt-mTOR pathway, and VEGF/VEGFR pathways that are clinically significant for modeling and optimizing treatment of muscle-invasive bladder cancer.
This document discusses molecular parameters that have prognostic or predictive value in colorectal cancer. It summarizes that microsatellite instability (MSI) confers a favorable prognosis while chromosome instability (CIN) indicates an unfavorable prognosis. Certain gene mutations like KRAS and BRAF also have prognostic or predictive significance. Molecular testing for markers like methylated DNA in stool samples shows potential as a noninvasive screening method for early detection of colorectal cancer.
This document is a literature review presented to Anglia Ruskin University by Omar Naveed examining proton beam therapy (PBT) and intensity-modulated radiation therapy (IMRT) for treating prostate cancer. It provides background on prostate cancer and discusses the mechanisms and pathways involved in the disease. It also describes PBT and IMRT, explaining that PBT uses energized proton particles to target tumor cells, while sparing surrounding healthy tissue. The literature review aims to conduct a meta-analysis to determine if PBT or IMRT is more effective for prostate cancer treatment based on toxicity and cost. It will analyze data sources and use statistical tests to evaluate the therapies.
This document discusses new strategies for combating cancer through molecular biology approaches. It describes prevention strategies that focus on pre-invasive lesions by inhibiting carcinogen initiation events, cell proliferation associated with promotion, or the development of the invasive phenotype in precancerous lesions. Targets for prevention strategies include biochemical species produced by carcinogens and aberrantly expressed proteins from genetic/environmental risk factors. Gene expression profiling using cDNA microarrays can help understand carcinogenesis at the molecular level and identify new therapeutic targets. The document also discusses inhibiting metastasis through strategies like modifying cell adhesion with MMP inhibitors or anticoagulants, and inhibiting angiogenesis. Gene therapy approaches for cancer treatment aim to correct genetic mutations or deliver therapeutic genes to stimulate anti-tumor immune
Quantitative expression analysis and prognostic significance of the BCL2-asso...Enrique Moreno Gonzalez
Nasopharyngeal carcinoma (NPC) is a highly metastatic epithelial malignancy showing high prevalence in Southeast Asia and North Africa. The BCL2-associated X (BAX) gene encodes the most important pro-apoptotic member of the BCL2 family. We have recently shown that BCL2 and BCL2L12, two other members of the same apoptosis-related family, possess significant prognostic value in NPC. The objective of the current study was to analyze BAX mRNA expression in nasopharyngeal biopsies of NPC patients, and to assess its prognostic potential in this disease.
The expression of ITPK in normal colon and colorectal cancer cells - Papermaldjuan
This document summarizes research into the expression of inositol 1,4,5-trisphosphate kinase (ITPK) isoforms in normal colon cells and colorectal cancer cells. The researchers hypothesize that ITPK isoform C (ITPKC) is downregulated in colorectal carcinoma cells compared to normal colon cells. They extracted RNA from normal colon and colorectal cancer cell lines and found the RNA to be intact. Quantitative PCR will be used to analyze expression levels of the three ITPK isoforms in the cell lines. Western blot analysis validated antibodies for detecting ITPK isoforms A and B. Preliminary results showed ITPK isoform A expression varied across colorectal cancer
This document discusses the role of the cell polarity regulator PARD3 in lung squamous cell carcinomas (LSCC). The key points are:
1. PARD3 was found to be somatically and biallelically inactivated through mutations, deletions, and promoter hypermethylation in 8% of examined LSCC tumors and cell lines. Most alterations resulted in truncated or non-functional PARD3 proteins.
2. Reconstitution of normal PAR3 activity in vivo reduced the invasive and metastatic properties of tumors, suggesting PARD3 acts as a tumor suppressor in LSCC.
3. PARD3 alterations prevented the formation of tight junctions between cells and the downstream signaling of STAT
Deadenylase Expression in Small Cell Lung Cancer Related To Clinical Characte...JohnJulie1
Lung cancer is the second common malignancy and the most aggressive cancer worldwide with late diagnosis and poor prognosis. The search for biomarkers that promote early diagnosis and improve therapeutic strategies focuses to the understanding of the mechanisms underlying cancer development and progression. The deregulation of gene expression is one of the cancer hallmarks reflected to the stability...
Deadenylase Expression in Small Cell Lung Cancer Related To Clinical Characte...AnonIshanvi
Lung cancer is the second common malignancy and the most aggressive cancer worldwide with late diagnosis and poor prognosis. The search for biomarkers that promote early diagnosis and improve therapeutic strategies focuses to the understanding of the mechanisms underlying cancer development and progression
Deadenylase Expression in Small Cell Lung Cancer Related To Clinical Characte...daranisaha
Lung cancer is the second common malignancy and the most aggressive cancer worldwide with late diagnosis and poor prognosis. The search for biomarkers that promote early diagnosis and improve therapeutic strategies focuses to the understanding of the mechanisms underlying cancer development and progression. The deregulation of gene expression is one of the cancer hallmarks reflected to the stability...
Deadenylase Expression in Small Cell Lung Cancer Related To Clinical Characte...EditorSara
Lung cancer is the second common malignancy and the most aggressive cancer worldwide with late diagnosis and poor prognosis. The search for biomarkers that promote early diagnosis and improve therapeutic strategies focuses to the understanding of the mechanisms underlying cancer development and progression. The deregulation of gene expression is one of the cancer hallmarks reflected to the stability..
Deadenylase Expression in Small Cell Lung Cancer Related To Clinical Characte...semualkaira
Lung cancer is the second common malignancy and the most aggressive cancer worldwide with late diagnosis and poor prognosis. The search for biomarkers that promote early diagnosis and improve therapeutic strategies focuses to the understanding of the mechanisms underlying cancer development and progression. The deregulation of gene expression is one of the cancer hallmarks reflected to the stability..
Deadenylase Expression in Small Cell Lung Cancer Related To Clinical Characte...semualkaira
Lung cancer is the second common malignancy and the most aggressive cancer worldwide with late diagnosis and poor prognosis. The search for biomarkers that promote early diagnosis and improve therapeutic strategies focuses to the understanding of the mechanisms underlying cancer development and progression. The deregulation of gene expression is one of the cancer hallmarks reflected to the stability...
Deadenylase Expression in Small Cell Lung Cancer Related To Clinical Characte...NainaAnon
This study examined the expression levels of deadenylases in small cell lung cancer (SCLC) clinical samples and their correlation to patient clinical characteristics and survival. Real-time PCR analysis found that the deadenylases PARN, CNOT6, CNOT7, and NOC were differentially expressed between malignant and normal lung tissue samples. Higher expression levels of PARN, CNOT6, and CNOT7 correlated with older patient age and decreased overall survival of 180 days or less. The results suggest these deadenylases may serve as prognostic biomarkers for SCLC patient outcomes.
This review discusses the relationship between the protein arginine methyltransferase (PRMT) family and tumor metastasis. PRMT expression is often elevated in cancers and associated with poorer prognosis. PRMTs regulate metastasis through various mechanisms, including modifying the tumor microenvironment, promoting epithelial-mesenchymal transition, and altering cellular metabolism. Several PRMTs, such as PRMT1 and PRMT5, enhance lung metastasis of breast cancer and other cancers by methylating proteins involved in these pathways. Inhibiting arginine methylation through PRMT inhibitors shows promise in reducing tumor metastasis across cancer types based on preclinical studies.
This document describes a study that used weighted gene co-expression network analysis (WGCNA) to identify spleen tyrosine kinase (SYK) as a potential oncogenic driver and therapeutic target in a subset of small-cell lung cancer (SCLC). The analysis identified a SCLC-specific gene co-expression module and hub network (SSHN) that robustly classified SCLC samples across multiple datasets. Within the SSHN, SYK exhibited one of the highest statistical associations with SCLC. Validation experiments found SYK protein expression in a subset of SCLC patient samples and cell lines. Knockdown of SYK reduced proliferation and increased cell death in SYK-positive SCLC cell lines, suggesting a role for
This document summarizes a study exploring the effects of baicalein (BAI) on bladder cancer cells. The study found that BAI inhibits proliferation and promotes apoptosis in bladder cancer cells. It also inhibits bladder cancer cell migration by down-regulating microRNA (miR)-106 expression. Specifically, BAI affects bladder cancer cells by inhibiting the JNK and MEK/ERK pathways through reducing miR-106 levels. P21 was also identified as a target of miR-106. The study utilized techniques like transfection, PCR, western blot analysis, and cell migration assays to analyze these regulatory mechanisms and effects of BAI on bladder cancer cells.
This document summarizes recent research on the role of epigenetic regulation in human cancers. It discusses how epigenetic mechanisms like DNA methylation and histone modifications can disrupt gene expression and lead to tumorigenesis. Specifically, it describes how hypermethylation of CpG islands can silence tumor suppressor genes, and how certain histone modifications are associated with transcriptional activation or repression. The document also reviews emerging epigenetic therapies and challenges in the field, such as a lack of predictive biomarkers and unclear mechanisms of response/resistance.
Dr. Alexandre Arcaro obtained his PhD studying phosphoinositide 3-kinase (PI3K) and completed postdoctoral research on PI3K and lung cancer, going on to focus his work at Bern University Hospital on using PI3K/mTOR pathway inhibitors as promising new targeted therapies for cancers like acute myeloid leukemia, glioblastoma, medulloblastoma, and neuroblastoma. He discusses the urgent need for novel glioblastoma treatments due to its poor prognosis, the limitations of current mTOR inhibitors, and his hopes that more PI3K/mTOR pathway inhibitors will be approved to benefit more
Pushing the limits of ePRTC: 100ns holdover for 100 daysAdtran
At WSTS 2024, Alon Stern explored the topic of parametric holdover and explained how recent research findings can be implemented in real-world PNT networks to achieve 100 nanoseconds of accuracy for up to 100 days.
GraphRAG for Life Science to increase LLM accuracyTomaz Bratanic
GraphRAG for life science domain, where you retriever information from biomedical knowledge graphs using LLMs to increase the accuracy and performance of generated answers
GraphSummit Singapore | The Art of the Possible with Graph - Q2 2024Neo4j
Neha Bajwa, Vice President of Product Marketing, Neo4j
Join us as we explore breakthrough innovations enabled by interconnected data and AI. Discover firsthand how organizations use relationships in data to uncover contextual insights and solve our most pressing challenges – from optimizing supply chains, detecting fraud, and improving customer experiences to accelerating drug discoveries.
“An Outlook of the Ongoing and Future Relationship between Blockchain Technologies and Process-aware Information Systems.” Invited talk at the joint workshop on Blockchain for Information Systems (BC4IS) and Blockchain for Trusted Data Sharing (B4TDS), co-located with with the 36th International Conference on Advanced Information Systems Engineering (CAiSE), 3 June 2024, Limassol, Cyprus.
For the full video of this presentation, please visit: https://www.edge-ai-vision.com/2024/06/building-and-scaling-ai-applications-with-the-nx-ai-manager-a-presentation-from-network-optix/
Robin van Emden, Senior Director of Data Science at Network Optix, presents the “Building and Scaling AI Applications with the Nx AI Manager,” tutorial at the May 2024 Embedded Vision Summit.
In this presentation, van Emden covers the basics of scaling edge AI solutions using the Nx tool kit. He emphasizes the process of developing AI models and deploying them globally. He also showcases the conversion of AI models and the creation of effective edge AI pipelines, with a focus on pre-processing, model conversion, selecting the appropriate inference engine for the target hardware and post-processing.
van Emden shows how Nx can simplify the developer’s life and facilitate a rapid transition from concept to production-ready applications.He provides valuable insights into developing scalable and efficient edge AI solutions, with a strong focus on practical implementation.
HCL Notes and Domino License Cost Reduction in the World of DLAUpanagenda
Webinar Recording: https://www.panagenda.com/webinars/hcl-notes-and-domino-license-cost-reduction-in-the-world-of-dlau/
The introduction of DLAU and the CCB & CCX licensing model caused quite a stir in the HCL community. As a Notes and Domino customer, you may have faced challenges with unexpected user counts and license costs. You probably have questions on how this new licensing approach works and how to benefit from it. Most importantly, you likely have budget constraints and want to save money where possible. Don’t worry, we can help with all of this!
We’ll show you how to fix common misconfigurations that cause higher-than-expected user counts, and how to identify accounts which you can deactivate to save money. There are also frequent patterns that can cause unnecessary cost, like using a person document instead of a mail-in for shared mailboxes. We’ll provide examples and solutions for those as well. And naturally we’ll explain the new licensing model.
Join HCL Ambassador Marc Thomas in this webinar with a special guest appearance from Franz Walder. It will give you the tools and know-how to stay on top of what is going on with Domino licensing. You will be able lower your cost through an optimized configuration and keep it low going forward.
These topics will be covered
- Reducing license cost by finding and fixing misconfigurations and superfluous accounts
- How do CCB and CCX licenses really work?
- Understanding the DLAU tool and how to best utilize it
- Tips for common problem areas, like team mailboxes, functional/test users, etc
- Practical examples and best practices to implement right away
Dr. Sean Tan, Head of Data Science, Changi Airport Group
Discover how Changi Airport Group (CAG) leverages graph technologies and generative AI to revolutionize their search capabilities. This session delves into the unique search needs of CAG’s diverse passengers and customers, showcasing how graph data structures enhance the accuracy and relevance of AI-generated search results, mitigating the risk of “hallucinations” and improving the overall customer journey.
Goodbye Windows 11: Make Way for Nitrux Linux 3.5.0!SOFTTECHHUB
As the digital landscape continually evolves, operating systems play a critical role in shaping user experiences and productivity. The launch of Nitrux Linux 3.5.0 marks a significant milestone, offering a robust alternative to traditional systems such as Windows 11. This article delves into the essence of Nitrux Linux 3.5.0, exploring its unique features, advantages, and how it stands as a compelling choice for both casual users and tech enthusiasts.
Threats to mobile devices are more prevalent and increasing in scope and complexity. Users of mobile devices desire to take full advantage of the features
available on those devices, but many of the features provide convenience and capability but sacrifice security. This best practices guide outlines steps the users can take to better protect personal devices and information.
Driving Business Innovation: Latest Generative AI Advancements & Success StorySafe Software
Are you ready to revolutionize how you handle data? Join us for a webinar where we’ll bring you up to speed with the latest advancements in Generative AI technology and discover how leveraging FME with tools from giants like Google Gemini, Amazon, and Microsoft OpenAI can supercharge your workflow efficiency.
During the hour, we’ll take you through:
Guest Speaker Segment with Hannah Barrington: Dive into the world of dynamic real estate marketing with Hannah, the Marketing Manager at Workspace Group. Hear firsthand how their team generates engaging descriptions for thousands of office units by integrating diverse data sources—from PDF floorplans to web pages—using FME transformers, like OpenAIVisionConnector and AnthropicVisionConnector. This use case will show you how GenAI can streamline content creation for marketing across the board.
Ollama Use Case: Learn how Scenario Specialist Dmitri Bagh has utilized Ollama within FME to input data, create custom models, and enhance security protocols. This segment will include demos to illustrate the full capabilities of FME in AI-driven processes.
Custom AI Models: Discover how to leverage FME to build personalized AI models using your data. Whether it’s populating a model with local data for added security or integrating public AI tools, find out how FME facilitates a versatile and secure approach to AI.
We’ll wrap up with a live Q&A session where you can engage with our experts on your specific use cases, and learn more about optimizing your data workflows with AI.
This webinar is ideal for professionals seeking to harness the power of AI within their data management systems while ensuring high levels of customization and security. Whether you're a novice or an expert, gain actionable insights and strategies to elevate your data processes. Join us to see how FME and AI can revolutionize how you work with data!
Climate Impact of Software Testing at Nordic Testing DaysKari Kakkonen
My slides at Nordic Testing Days 6.6.2024
Climate impact / sustainability of software testing discussed on the talk. ICT and testing must carry their part of global responsibility to help with the climat warming. We can minimize the carbon footprint but we can also have a carbon handprint, a positive impact on the climate. Quality characteristics can be added with sustainability, and then measured continuously. Test environments can be used less, and in smaller scale and on demand. Test techniques can be used in optimizing or minimizing number of tests. Test automation can be used to speed up testing.
AI 101: An Introduction to the Basics and Impact of Artificial IntelligenceIndexBug
Imagine a world where machines not only perform tasks but also learn, adapt, and make decisions. This is the promise of Artificial Intelligence (AI), a technology that's not just enhancing our lives but revolutionizing entire industries.
HCL Notes und Domino Lizenzkostenreduzierung in der Welt von DLAUpanagenda
Webinar Recording: https://www.panagenda.com/webinars/hcl-notes-und-domino-lizenzkostenreduzierung-in-der-welt-von-dlau/
DLAU und die Lizenzen nach dem CCB- und CCX-Modell sind für viele in der HCL-Community seit letztem Jahr ein heißes Thema. Als Notes- oder Domino-Kunde haben Sie vielleicht mit unerwartet hohen Benutzerzahlen und Lizenzgebühren zu kämpfen. Sie fragen sich vielleicht, wie diese neue Art der Lizenzierung funktioniert und welchen Nutzen sie Ihnen bringt. Vor allem wollen Sie sicherlich Ihr Budget einhalten und Kosten sparen, wo immer möglich. Das verstehen wir und wir möchten Ihnen dabei helfen!
Wir erklären Ihnen, wie Sie häufige Konfigurationsprobleme lösen können, die dazu führen können, dass mehr Benutzer gezählt werden als nötig, und wie Sie überflüssige oder ungenutzte Konten identifizieren und entfernen können, um Geld zu sparen. Es gibt auch einige Ansätze, die zu unnötigen Ausgaben führen können, z. B. wenn ein Personendokument anstelle eines Mail-Ins für geteilte Mailboxen verwendet wird. Wir zeigen Ihnen solche Fälle und deren Lösungen. Und natürlich erklären wir Ihnen das neue Lizenzmodell.
Nehmen Sie an diesem Webinar teil, bei dem HCL-Ambassador Marc Thomas und Gastredner Franz Walder Ihnen diese neue Welt näherbringen. Es vermittelt Ihnen die Tools und das Know-how, um den Überblick zu bewahren. Sie werden in der Lage sein, Ihre Kosten durch eine optimierte Domino-Konfiguration zu reduzieren und auch in Zukunft gering zu halten.
Diese Themen werden behandelt
- Reduzierung der Lizenzkosten durch Auffinden und Beheben von Fehlkonfigurationen und überflüssigen Konten
- Wie funktionieren CCB- und CCX-Lizenzen wirklich?
- Verstehen des DLAU-Tools und wie man es am besten nutzt
- Tipps für häufige Problembereiche, wie z. B. Team-Postfächer, Funktions-/Testbenutzer usw.
- Praxisbeispiele und Best Practices zum sofortigen Umsetzen
Communications Mining Series - Zero to Hero - Session 1DianaGray10
This session provides introduction to UiPath Communication Mining, importance and platform overview. You will acquire a good understand of the phases in Communication Mining as we go over the platform with you. Topics covered:
• Communication Mining Overview
• Why is it important?
• How can it help today’s business and the benefits
• Phases in Communication Mining
• Demo on Platform overview
• Q/A
2. Barbi et al. Journal of Experimental & Clinical Cancer Research 2010, 29:32 Page 2 of 8
http://www.jeccr.com/content/29/1/32
PIK3CA is a gene that encodes for the p110-alpha sub- were obtained with informed consent from the insititu-
unit of phosphoinositide-3-kinase (PI3K). Recently, a key tions that provided the materials.
role as oncogene is emerging for PIK3CA, as it is one of
the genes most frequently hit by somatic mutations in Mutation analysis
several types of human cancer [8,9]. PI3K is part of a fam- Normal and tumor DNA was extracted from manually
ily of ser-thr-kinases that interacts with phosphati- microdissected paraffin-embedded tissues as described
dylinositol bisphosphate (4,5-PIP2) to produce the [17]. Mononucleotide microsatellites BAT25 and BAT26
phosphatidylinositol trisphosphate (3,4,5-PIP3), a second (located in introns of the MSH2 and KIT genes, respec-
messenger with several functions. PIP3 mainly binds the tively) were examined by PCR amplification using fluo-
plekstrine homology (PH) domain of a number of target rescent dye-labeled primers as described [18]. PCR
molecules and leads to their activation through cell mem- amplification and sequencing of PIK3CA exons 9 and 20
brane targeting or modulation of their activity. One of the have been performed as described [19], using the follow-
best characterized targets of PI3K lipid products is the ing primers Exon9_Forward: GGGAAAAATATGACAA
protein kinase Akt. PI3K/Akt activation was demon- AGAAAGC; Exon9_Reverse: CTGAGATCAGC CAAAT
strated to be involved in the regulation of several cellular TCAGTT; Exon9_Sequencing: TAGCTAGAGACAAT-
functions like cell survival, cell growth and angiogenesis GAATTAAGGGAAA-3; Exon20_Forward: CTCAATGA
stimulation, inhibition of apoptosis, translation of several TGCTTGGCTCTG; Exon20_Reverse: TGGAATC CAG
proteins and hence, in the development of cancer [10,11]. AGTGAGCTTTC; Exon20_Sequencing: TTGATGACAT
Of the twenty exons that compose the PIK3CA gene, TGCATACATTCG.
more than 75% of the mutations are found in two hot- Sequence differences from the NCBI reference
spots located in exons 9 and 20, which encode for the sequence were identified via manual inspection of aligned
helical and kinase domains, respectively [8]. Expression electropherograms assisted by the Mutation Surveyor
of the most common variants (E542K, E545K and software package (SoftGenetics, State College, PA).
H1047R) is associated with an increased lipid kinase
Meta-analysis
activity and is oncogenic both in cell coltures and in vivo
To investigate the pattern of PIK3CA mutations in other
[12,13]. Mutations affecting the two hot-spots have
studies involving gastric as well as other cancer types, we
recently been demonstrated to be functionally different
analysed the prevalence of PIK3CA mutations in data
[14] and their respective rates of mutation have been
already present in literature and/or the COSMIC data-
often reported as associated to specific cancer types or
base [20]. The steps performed to search, select papers
particular patient features [15,16].
and collect data are detailed in Additional File 1. The full
In this study, we analysed 264 gastric cancers for the
list of references of included studies is provided in Addi-
presence of mutations in the exons 9 and 20, by means of
tional File 2.
direct sequencing, and correlated the presence of muta-
tions with clinical-pathological features, including MSI Statistical analysis
phenotype. In addition, we compared the prevalence of For meta-analysis, pooled prevalence estimates, preva-
mutations occurring in the two exons with other studies lence ratios and confidence intervals were calculated
investigating primary specimens of human cancer. using fixed-effects Poisson regression, adjusted for the
number of cases analyzed per study. Prevalences and con-
Methods fidence intervals of single studies were evaluated using
Patients and samples Clopper and Pearson method [21]. Correlation of the
Our study included 264 consecutive cases of advanced presence of the H1047R mutation with clinical-pathologi-
gastric cancer obtained from patients undergoing surgi- cal features, p-values and confidence intervals were eval-
cal intervention between 1989 and 2003 at the University uated by means of logistic regression analysis.
of Verona. All patients were treated by radical surgical Correlation with survival was evaluated by means of log-
removal with resection margins free of microscopic dis- rank test. For Cox multivariate regression, we selected the
ease and did not receive pre- or postoperative chemo- or most informative variables among the models that
radiotherapy. Histological classification was according to included mutational status, using a 'forward' stepwise
Laurén and the unified 1997 TNM system for gastric car- method. A p-value less than 0.05 was considered signifi-
cinoma was used for pathological staging. The clinical cant. For all the calculations and illustrations the R statis-
pathological features of the series are detailed in Table 1. tical software package was used [22].
This study was presented, reviewed and approved by the
Local Ethics Committee of the Verona Hospitals Concern Results
to include samples used for this analysis. Tumor samples We analysed the sequences of exons 9 and 20 of the
PIK3CA gene in 264 advanced gastric cancers. The list
3. Barbi et al. Journal of Experimental & Clinical Cancer Research 2010, 29:32 Page 3 of 8
http://www.jeccr.com/content/29/1/32
tional File 1). Both mutations involve an aminoacidic
Table 1: Clinical features of 264 cases of gastric cancers
analyzed for mutations in PI3KCA. change from threonin to isoleucin that implies a change
in the hydrophobic properties of the residues and may
Parameter Categories Frequency potentially affect the protein function. One case har-
boured two mutations namely E545K and L1067F, in
Gender F 89 (33.7%) exons 9 and 20, respectively.
M 175 (66.3%)
In our series, MSI cases only harbored the H1047R
mutation. H1047R was, in fact, observed in 8 of 39 MSI
cases and was significantly associated with MSI status
Age mean (sd) 67.4 (11.2) (OR 3.0; 95% CI 1.0 - 7.9; Fisher's test P = 0.035). The
presence of mutation H1047R did not correlate with
Lauren Intestinal 170 (65.4%) either survival or other clinical pathological features gen-
Mixed 27 (10.4%) erally associated with MSI, possibly due to the small
Diffuse 63 (24.2%)
number of cases harboring the mutation. Furthermore,
we did not observe any significant association between
the presence of mutation and survival when considering
pT 2 99 (37.4%) MSI cases only. In addition, we did not find any correla-
3 129 (48.7%) tion with clinical pathological features when considering
4 36 (13.6%) the presence of mutations in both exons (Table 3) or in
exon 9 and 20 separately. A multivariate survival analysis
pN 0 53 (20.2%)
was performed in order to evaluate the effect of the pres-
ence of mutation together with other clinical-pathologic
1 100 (38.0%)
variables (Table 4). After selection of the best model,
2 80 (30.4%) TNM stage, age and tumor location were significantly
3 30 (11.4%) associated with survival, whereas only a marginal effect
was observed for MSI status.
pM 0 215 (87.4%) In order to systematically compare our results with the
1 31 (12.6%)
available literature for stomach and other cancer types,
we selected 38 series described in 27 papers analyzing
mutations in the PIK3CA locus in primary cancer sam-
Tumor Location Antrum 107 (40.5%) ples (the full list of references is provided in Additional
Body 72 (27.3%) File 2). We limited the analysis to the mutations occur-
Fundus 69 (26.1%) ring at the aminoacids 542-549 and 1043-1048, of exons 9
Linitis 12 (4.5%) and 20, respectively, that were analyzed in common
Gastric stump 4 (1.5%)
between the series. These regions contain the large
majority of mutations observed in PIK3CA [8].
The prevalence of mutations in exons 9 and 20 for each
MSI MSI 39 (14.8%) series is represented in Figure 1. Although the overall
MSS 225 (85.2%) rates of mutation was variable among the series, even of
the same cancer type, the rates of mutation in exon 9 and
20 significantly correlated to each other (Spearman's ρ =
and frequency of mutations found are detailed in Table 2.
0.75, P-value < 0.001), suggesting that the ratio between
A total of 42 cases (15.9%; 95% CI 11.7% - 20.9%) har-
exon 9 and exon 20 mutations is dependent on the cancer
bored at least one mutation in the regions analyzed. All
type. Therefore, we evaluated the pooled ratio of preva-
the mutations found were heterozygous missense single
lence between exon 20 and 9 in different studies grouped
base substitutions. The most common mutation was
by cancer type, by means of Poisson regression analysis.
H1047R occurring at the active site of the kinasic domain
Results are shown in Table 5. For breast cancer, given the
in exon 20 and representing 62% of all the mutations. The
large number of studies reported, we divided the series
second most common mutation was Q546K that involves
according to the histotype (ductal and lobular), where the
an aminoacid change in the helicase domain in exon 9
information was available, and categorized the remainder
and represents 9.5% of all the mutations found.
series as breast cancer with histotype unspecified.
We found two missense mutations namely T1052I and
Among series of ductal histotype, prevalence of muta-
T1053I that were never reported before. The mutations
tions was significantly biased towards exon 20, whereas a
were confirmed using a second pair of primers (see Addi-
marginally significant preference for exon 9 was observed
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Table 2: Frequency of PI3KCA mutations found in 264 gastric cancers, by mutation type.
Mutation Overall frequency Percent/total cases Percent/mutated
(MSI only) cases
Exon 9 E542K 2 0.76% 4.76%
E545K 2 0.76% 4.76%
Q546K 4 1.52% 9.52%
Total Mutations (ex. 9) 8 3.03%
Exon 20 M1043V 1 0.38% 2.38%
H1047R 26 (8) 9.85% 61.90%
H1048T 1 0.38% 2.38%
G1050D 2 0.76% 4.76%
T1052I 1 0.38% 2.38%
T1053I 1 0.38% 2.38%
D1056N 2 0.76% 4.76%
L1067F 1 0.38% 2.38%
Total Mutations (ex.20) 35 13.26%
Total Mutations 42 15.91%
for lobular histotype series (see Table 5 and Figure 1). The region. As the mutations imply a change in the hydropho-
studies on colon cancer showed a significantly increased bicity of the aminoacidic residue, a functional role cannot
prevalence of mutations in exon 9 with all the series hav- be excluded. The mutations were found in MSS cases that
ing a similar mutational pattern. Tumors of the endome- did not show any particular feature.
trium were significantly more hit by mutations affecting We also found that the most common PIK3CA muta-
exon 20. For gastric cancer, the present series as well as tion (H1047R) was significantly associated with MSI phe-
the series reported by Samuels showed a greater preva- notype. The association is moderate and would benefit
lence of exon 20, whereas the remainder series showed from confirmation on an indipendent series. An associa-
little or no difference between exons. tion between PIK3CA mutations and MSI has been
reported or at least suggested in both colon and stomach
Discussion cancer [8,23,24,26]. At variance with our findings, in the
The aim of this study was to characterize the mutational two studies regarding gastric cancer and reporting muta-
status of PIK3CA in a large series of gastric cancers in tions by MSI status, exon 9 and exon 20 mutations were
order to determine its prevalence with an adequate preci- evenly distributed between the subtypes [23,24]. How-
sion and to correlate it with clinical-pathological features. ever, the small number of mutated MSI cases prevents
The overall prevalence of mutations was 15.9%, a value statistical comparison. The fact that only one type of
that is within the range of the currently available litera- mutation was found in our series of MSI tumors is not
ture [8,23-25], nonetheless the prevalences observed in surprising as the narrow spectrum of alterations of MSI
different series are heterogeneous, ranging from 4.5% to gastric tumors may, in turn, restrict the type of PIK3CA
25%. Reasons for such a heterogeneity may be due to spe- mutations that are oncogenic in that context.
cific interactions of the mutations with environmental Despite the large series analyzed, we did not find any
and genetic backgrounds, although experimental factors correlation of PIK3CA mutations with clinical pathologi-
can not be excluded. cal features of gastric cancers apart from the association
To our knowledge, the mutations involving aminoacids between MSI and H1047R. The lack of associations sug-
1052 and 1053 (T1052I and T1053I) were never pub- gests that alteration of PIK3CA is an event that occurs
lished before, nor are described in the COSMIC database, early in a subset of gastric cancers that progresses
despite the large number of studies investigating the towards malignancy through other mechanisms. In fact,
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Table 3: Distribution of Clinical-pathological covariates according to the presence of PI3KCA mutations in 264 gastric
cancers.
Parameter Categories Wt Mutated Odds Ratio P
(95% CI)
Gender F 74 (83.1%) 15 (16.9%) 1 0.766
M 148 (84.6%) 27 (15.4%) 0.9 (0.5 - 1.8)
Age mean 67.47 66.81 0.771
pT 2 88 (88.9%) 11 (11.1%) 1 0.077
3 108 (83.7%) 21 (16.3%) 1.6 (0.7 - 3.5)
4 26 (72.2%) 10 (27.8%) 3.1 (1.2 - 8.1)
pN 0 42 (80.8%) 10 (19.2%) 1 0.840
1 86 (86.0%) 14 (14.0%) 0.7 (0.3 - 1.7)
2 67 (83.8%) 13 (16.2%) 0.8 (0.3 - 2.1)
3 26 (86.7%) 4 (13.3%) 0.6 (0.2 - 2.2)
pM 0 182 (85.0%) 32 (15.0%) 1 0.298
1 24 (77.4%) 7 (22.6%) 1.7 (0.6 - 4.0)
Lauren Intestinal 147 (86.5%) 23 (13.5%) 1 0.275
Mixed 22 (81.5%) 5 (18.5%) 1.5 (0.5 - 4.0)
Diffuse 49 (77.8%) 14 (22.2%) 1.8 (0.9 - 3.8)
Location Antrum 93 (86.9%) 14 (13.1%) 1 0.394
Body 58 (79.5%) 15 (20.5%) 1.7 (0.8 - 3.9)
Fundus 59 (85.5%) 10 (14.5%) 1.1 (0.5 - 2.7)
Grading G1 13 (86.7%) 2 (13.3%) 1 0.652
G2 76 (87.4%) 11 (12.6%) 0.9 (0.2 - 6.5)
G3 117 (83.0%) 24 (17.0%) 1.3 (0.3 - 8.9)
Microsatellite MSI 31 (79.5%) 8 (20.5%) 1 0.408
instability
MSS 191 (84.9%) 34 (15.1%) 0.7 (0.3 - 1.7)
Survival rate at 2 46.7% (40.5%- 46.9% (32.4%- 0.941
years (95% CI) 53.9%) 67.8%)
in a multivariate survival model there was no evident cancer, exon 9 is significantly more hit than exon 20. This
effect of the presence of mutation on prognosis. confirms suggestions from previous studies [8,23,27]. The
Based on our meta-analysis, the ratio between muta- opposite mutational pattern was consistently found in
tion prevalences in exons 9 and 20 can be generally con- studies regarding endometrial cancer with exon 20 largely
sidered a signature of cancer type. In particular, we found more hit than exon 9. This peculiarity was already
a significant exon bias for colon cancer, breast cancer pointed out and suggests a specific mechanism of
with ductal histotype and endometrium cancer. In colon PI3KCA involvement for endometrial cancer [28-30].
6. Barbi et al. Journal of Experimental & Clinical Cancer Research 2010, 29:32 Page 6 of 8
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Table 4: Multivariate Cox survival analysis of 245 gastric cancer patients.
Parameter Category HR (95% CI) P-Value
PI3KCA status wt 1.0 0.630
mutated 1.1 (0.7-1.7)
Stage I 1.0 <0.001
II 3.1 (1.1-9.1)
III 11.6 (4.2-31.8)
IV 19.1 (6.8- 53.2)
Age (10 years increment) 1.3 (1.1-1.5) <0.001
Tumor Location Antrum 1.0 0.004
Body 1.1 (0.7-1.5)
Fundus 1.8 (1.3-2.6)
MSI status MSI 1.0 0.077
MSS 1.7 (0.9-3.0)
It is less clear whether an exon bias exists in breast can- ductal histotypes as already suggested [15]. For ductal
cer as many studies are apparently contradictory (see Fig- histotype, exon 20 was significantly more hit compared to
ure 1). However, for studies that did furnish the exon 9, whereas a slight but inverse tendency was found
information about the histotype of each sample, we in series of lobular breast cancers. This pattern is not evi-
observed a different exon preference between lobular and dent in studies where the information about histotype is
Table 5: Overall frequency and pooled prevalence ratio of mutations affecting the two hot spots of PIK3CA located in Exon
9 and exon 20 in 36 series grouped by cancer type
Tumor Type nr. series total cases Exon 9 Exon 20 Ex20/Ex9 P-value
Prevalence
Ratio
(95% CI)
Breast Cancer 6 788 101 105 1.0 (0.8 -1.4) 0.7805
(histotype not
specified)
Breast Cancer 4 99 25 15 0.6 (0.3 -1.1) 0.1178
(lobular
histotype)
Breast Cancer 5 499 41 64 1.6 (1.1 -2.3) 0.0260
(ductal
histotype)
Endometrial 5 263 7 29 4.1 (1.9 -10.3) 0.0007
Cancer
Colon Cancer 6 1292 134 80 0.6 (0.5 -0.8) 0.0003
Gastric Cancer 5 602 17 46 2.7 (1.6 -4.9) 0.0005
Head and Neck 3 175 7 2 0.3 (0.0 -1.2) 0.1182
squamous
Cancer
Glioblastoma 4 203 3 5 1.7 (0.4 -8.1) 0.4842
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0.8
0.6 exon 9
Mutation Prevalence
exon 20
0.4
0.2
0.0
Figure 1 Point and 95% confidence interval estimates of prevalence of mutations affecting exon 9 and 20 of PI3KCA in 36 series. Mutations
affecting exon 9 and 20 are shown as solid filled boxes and empty diamonds, respectively. The pooled estimates for each group are shown in grey.
not available, possibly as an result of mixing different genetic background in which tumours develop may
kinds of tumours together. require and select specific altered activities of p110-
For squamous head and neck tumors a slight tendency alpha.
to a greater prevalence of exon 9 mutations was observed
among series, although the low incidence of PIK3CA Conclusions
mutations in this kind of neoplasm has probably pre- We found a relatively high prevalence of PIK3CA somatic
vented this tendency to stand out. For glioblastoma, there mutations further supporting the role of PIK3CA as a
was no evidence of exon-selectivity, due to the fact that a major oncogene in gastric cancer. Such prevalence was
high percent of non hot-spot mutations are frequently highly biased towards exon 20, in particular, in MSI cases
found in this disease [8,31]. which seem to carry only one type of exon 20 mutations.
Finally, in stomach cancer series, exon 20 resulted to be By analysis of the mutations occurring in the two stan-
more involved than exon 9, although a common trend dard hot-spot regions of PIK3CA in 27 published papers
among the series was substantially missing. The hetero- on six major cancer types (colorectal, breast ductal,
geneity in both overall prevalence and exon-selectivity in breast lobular, stomach, endometrium, head and neck
stomach cancer may be due to the strong influence that and glioblastoma), we found that exon-selectivity is an
specific etio-pathologic, genetic and environmental fac- important signature of cancer type and subtype reflecting
tors have on this disease. different contexts in which tumours arise.
Although several of the observations presented in our
meta-analysis were sporadically suggested or demon- Additional material
strated in single papers, this approach allows to gather
more convincing evidences by pooling similar studies. Additional file 1 Supplementary Material and Methods. Supplemen-
tary Material and Methods
Moreover, the meta-analysis has the further advantage of
Additional file 2 Metanalysis references. List of papers analyzed for the
providing an outlook and an estimate of PIK3CA exon- presence of PI3KCA mutations
selectivity and standardized rate of mutation in different
cancer types, although this might be affected by the limi- Competing interests
tations derived from retrospective studies. The authors declare that they have no competing interests.
The association of specific mutations with either can- Authors' contributions
cer type or subtype is in line with recent findings about SB performed data analysis and manuscript drafting; IC partecipated in manu-
different mechanisms through which these mutations script drafting and revising; GDM contributed to conception and design, col-
lected specimens and provided clinical informations; SB performed
exert their oncogenic potential. In fact, it has been shown microdissection and DNA purification and carried out microsatellite analysis; SL
that mutations occurring at the kinasic domain are and SM performed PI3KCA mutation analysis; AB contributed to conception
dependent upon binding with p85, another component of and design of experiments and supervised molecular analysis; AS contributed
to conception and design of experiments and approved the final version of the
PI3K, to be fully oncogenic, whereas mutations in the manuscript. All authors read and approved the final manuscript.
helical domain are dependent upon RAS-GTP binding
[14]. The dependence of PIK3CA mutations on other sig- Acknowledgements
This study is supported by the AIRC, Associazione Italiana Ricerca sul Cancro,
nalling components is in keeping with the fact that the Milan, Italy; Fondazione Cariparo, Padova, Italy; Fondazione Monte dei Paschi di