This document discusses a study comparing CD8+ lymphocyte distribution and apoptosis in typical medullary breast carcinoma (TMC) and atypical medullary breast carcinoma (AMC). The study found that TMC had significantly more CD8+ lymphocytes within tumor nests compared to AMC. It also found that CD8+ lymphocytes in both tumor types tended to accumulate along the margins of lymphocyte tracts adjoining tumor nests. The study observed apoptosis of lymphocytes in contact with tumor cells and of tumor cells in contact with lymphocytes in both TMC and AMC tumor nests, but did not find significant differences in apoptosis between the two tumor types. The findings are consistent with CD8+ cytotoxic lymphocyte-mediated immunity contributing to the
This proposal outlines a thesis project to investigate the role of chemokines CCL19b and CCL25b in recruiting T cells into melanoma tumors. The student hypothesizes that inducing expression of these chemokines in melanoma cell lines transplanted into an animal model will increase T cell recruitment and reduce tumor burden. The proposal provides background on melanoma, the immune system response to tumors, and current immunotherapy strategies including adoptive T cell transfer and immune checkpoint inhibitors. If successful, the research could provide a new treatment option or complement existing therapies to improve patient survival rates.
Gastroenterology Medicine & Research-Crimson Publishers: Can we Optimize Immu...CrimsonGastroenterology
Immunotherapy is revolutionizing oncology, with a simple guiding principle: the host immune system has the potential to eradicate cancer, treatment consisting in optimizing immune actors' functions. Although significant results were demonstrated in patients with melanoma or lung cancer, objective response rate (ORR) is only 20% in digestive oncology. However, we can improve this situation by a better knowledge of anti-tumor immunity. For example, ORR is multiplied by two to three in case of PD-L1 (programmed death-ligand 1) overexpression or microsatellite instability (MSI). In a near future, we will certainly be able to take into account other biomarkers for building composite scores for assigning to each patient with digestive cancer an 'immune identity card' able to strongly predict immunotherapy efficacy.
This document describes a study that conducted an RNA interference screening in breast cancer cells to identify epigenetic factors regulating the mesenchyme to epithelium transition (MET). Researchers designed a siRNA library targeting 729 chromatin modification genes and screened it in the mesenchymal breast cancer cell line MDA-MB-231. They identified 70 candidate genes involved in MET, including known genes like ZEB1, G9a, SMAD5 and SMARCD3, as well as DOT1L which has been implicated in MET. They also identified KAT5 as a novel gene linked to maintaining the mesenchymal phenotype for the first time. The screening approach involved measuring E-cadherin induction and cell
This document describes the process of constructing tissue microarrays (TMAs). TMAs allow high-throughput analysis of molecular markers in hundreds of tissue samples by taking small cores from donor tissue blocks and arranging them in a recipient block. The key steps are:
1. Selecting donor tissue blocks to sample based on the research question and reviewing H&E slides of each block.
2. Creating a TMA map that assigns a unique position to each tissue core and records metadata about each sample.
3. Using a manual tissue arrayer, punching cores from the donor blocks and inserting them into an ordered array in the recipient block according to the map. This allows parallel analysis of markers across many samples
HDAC4 and HDAC7 Promote Breast and Ovarian Cancer Cell Migration by Regulatin...CrimsonpublishersCancer
Breast and ovarian cancer have been remained as a highly malignant tumor among women, posing a serious threat to women health worldwide. In this study, we were aimed to investigate the underlying mechanism of breast and ovarian cancer cell migration. Wound healing assay showed that MDA-MB-231and C13* have higher migration potential compare with MCF-7 and OV2078 cells, as well as regulated epithelial-mesenchymal transition (EMT) marker. We found that HDAC4 and HADC7 mRNA are up regulated in MDA-MB-231 and C13* cells. Moreover, target HDAC4 and HDAC7 by TSA or shRNA block MDA-MB-231and C13* migration. These results reveal a new link between HDACs and EMT in the regulation of breast and ovarian cancer migration.
The document describes a new ex vivo platform called CANScript that aims to predict patient responses to anticancer drugs. It does this by:
1. Engineering personalized tumour ecosystems from patient tumour biopsies that conserve tumour heterogeneity and microenvironment by culturing thin tumour sections on defined tumour-specific matrix proteins and in autologous patient serum.
2. Testing the response of over 100 such tumour ecosystems to anticancer drugs and correlating it to actual patient outcomes to train a machine learning algorithm.
3. Validating the algorithm on an independent group of 55 patients, where it achieved 100% sensitivity in predicting responses while maintaining high specificity.
The authors believe this platform, which contextualizes the native tumour environment
The study compared gene expression profiles between breast and prostate tumor stromas using microarray data and gene set enrichment analysis (GSEA). GSEA identified pathways that were commonly up-regulated or down-regulated in both tumor stromas, as well as pathways that were differentially regulated between them. Specifically, 9 pathways showed common regulation, while others like ABC transporters and oxidative phosphorylation differed in their regulation between tumor types. Certain genes and transcription factors also demonstrated heterogeneous expression patterns between breast and prostate tumor stroma. The results reveal genomic heterogeneity between tumor microenvironments and identify candidate signatures relevant to cancer progression.
Cord Blood Mesenchymal Stem Cells Conditioned Media Suppress Epithelial Ovari...ijtsrd
MSC CM suppresses epithelial ovarian cancer cells in vitro in a concentration-dependent manner. When ovarian cancer cells were treated with MSC CM at concentrations of 100%, 75%, 50%, and 25% for 72 hours, cell morphology changes were observed including cell shrinkage, debris and reduced cell numbers compared to control. MTT assays showed reduced proliferation and Annexin V testing demonstrated increased early and late apoptosis. Cell cycle analysis found an increased sub-G1 phase, indicating apoptosis. Expression of embryonic stemness genes was also progressively suppressed in cancer cells treated with MSC CM compared to control. Therefore, MSC CM has potential as an ovarian cancer inhibitor by creating new treatment modalities.
This proposal outlines a thesis project to investigate the role of chemokines CCL19b and CCL25b in recruiting T cells into melanoma tumors. The student hypothesizes that inducing expression of these chemokines in melanoma cell lines transplanted into an animal model will increase T cell recruitment and reduce tumor burden. The proposal provides background on melanoma, the immune system response to tumors, and current immunotherapy strategies including adoptive T cell transfer and immune checkpoint inhibitors. If successful, the research could provide a new treatment option or complement existing therapies to improve patient survival rates.
Gastroenterology Medicine & Research-Crimson Publishers: Can we Optimize Immu...CrimsonGastroenterology
Immunotherapy is revolutionizing oncology, with a simple guiding principle: the host immune system has the potential to eradicate cancer, treatment consisting in optimizing immune actors' functions. Although significant results were demonstrated in patients with melanoma or lung cancer, objective response rate (ORR) is only 20% in digestive oncology. However, we can improve this situation by a better knowledge of anti-tumor immunity. For example, ORR is multiplied by two to three in case of PD-L1 (programmed death-ligand 1) overexpression or microsatellite instability (MSI). In a near future, we will certainly be able to take into account other biomarkers for building composite scores for assigning to each patient with digestive cancer an 'immune identity card' able to strongly predict immunotherapy efficacy.
This document describes a study that conducted an RNA interference screening in breast cancer cells to identify epigenetic factors regulating the mesenchyme to epithelium transition (MET). Researchers designed a siRNA library targeting 729 chromatin modification genes and screened it in the mesenchymal breast cancer cell line MDA-MB-231. They identified 70 candidate genes involved in MET, including known genes like ZEB1, G9a, SMAD5 and SMARCD3, as well as DOT1L which has been implicated in MET. They also identified KAT5 as a novel gene linked to maintaining the mesenchymal phenotype for the first time. The screening approach involved measuring E-cadherin induction and cell
This document describes the process of constructing tissue microarrays (TMAs). TMAs allow high-throughput analysis of molecular markers in hundreds of tissue samples by taking small cores from donor tissue blocks and arranging them in a recipient block. The key steps are:
1. Selecting donor tissue blocks to sample based on the research question and reviewing H&E slides of each block.
2. Creating a TMA map that assigns a unique position to each tissue core and records metadata about each sample.
3. Using a manual tissue arrayer, punching cores from the donor blocks and inserting them into an ordered array in the recipient block according to the map. This allows parallel analysis of markers across many samples
HDAC4 and HDAC7 Promote Breast and Ovarian Cancer Cell Migration by Regulatin...CrimsonpublishersCancer
Breast and ovarian cancer have been remained as a highly malignant tumor among women, posing a serious threat to women health worldwide. In this study, we were aimed to investigate the underlying mechanism of breast and ovarian cancer cell migration. Wound healing assay showed that MDA-MB-231and C13* have higher migration potential compare with MCF-7 and OV2078 cells, as well as regulated epithelial-mesenchymal transition (EMT) marker. We found that HDAC4 and HADC7 mRNA are up regulated in MDA-MB-231 and C13* cells. Moreover, target HDAC4 and HDAC7 by TSA or shRNA block MDA-MB-231and C13* migration. These results reveal a new link between HDACs and EMT in the regulation of breast and ovarian cancer migration.
The document describes a new ex vivo platform called CANScript that aims to predict patient responses to anticancer drugs. It does this by:
1. Engineering personalized tumour ecosystems from patient tumour biopsies that conserve tumour heterogeneity and microenvironment by culturing thin tumour sections on defined tumour-specific matrix proteins and in autologous patient serum.
2. Testing the response of over 100 such tumour ecosystems to anticancer drugs and correlating it to actual patient outcomes to train a machine learning algorithm.
3. Validating the algorithm on an independent group of 55 patients, where it achieved 100% sensitivity in predicting responses while maintaining high specificity.
The authors believe this platform, which contextualizes the native tumour environment
The study compared gene expression profiles between breast and prostate tumor stromas using microarray data and gene set enrichment analysis (GSEA). GSEA identified pathways that were commonly up-regulated or down-regulated in both tumor stromas, as well as pathways that were differentially regulated between them. Specifically, 9 pathways showed common regulation, while others like ABC transporters and oxidative phosphorylation differed in their regulation between tumor types. Certain genes and transcription factors also demonstrated heterogeneous expression patterns between breast and prostate tumor stroma. The results reveal genomic heterogeneity between tumor microenvironments and identify candidate signatures relevant to cancer progression.
Cord Blood Mesenchymal Stem Cells Conditioned Media Suppress Epithelial Ovari...ijtsrd
MSC CM suppresses epithelial ovarian cancer cells in vitro in a concentration-dependent manner. When ovarian cancer cells were treated with MSC CM at concentrations of 100%, 75%, 50%, and 25% for 72 hours, cell morphology changes were observed including cell shrinkage, debris and reduced cell numbers compared to control. MTT assays showed reduced proliferation and Annexin V testing demonstrated increased early and late apoptosis. Cell cycle analysis found an increased sub-G1 phase, indicating apoptosis. Expression of embryonic stemness genes was also progressively suppressed in cancer cells treated with MSC CM compared to control. Therefore, MSC CM has potential as an ovarian cancer inhibitor by creating new treatment modalities.
Defect in recruiting effector memory CD8+ T-cells in malignant pleural effusi...Enrique Moreno Gonzalez
Malignant pleural effusions (MPE) are a common and fatal complication in cancers including lung or breast cancers, or malignant pleural mesothelioma (MPM). MPE animal models and immunotherapy trials in MPM patients previously suggested defects of the cellular immunity in MPE. However only few observational studies of the immune response were done in MPM patients, using questionable control groups (transudate…).
Determining the intrinsic quality of a summary (for Automatic Summarization E...Nishita Jaykumar
The document discusses factors that contribute to the quality of summaries generated by an automatic summarization system. It examines how the topic being summarized, source documents, and summarization method all impact the results. The system is evaluated by comparing summary content to curated medical resources to determine how well the high-level information is conveyed in a condensed format.
Oncogenes can reprogram tumor cells early in cancer development, establishing tumor-specific cell fates. This tumoral stem cell reprogramming hypothesis proposes that oncogenic lesions act on stem/progenitor cells, imposing a specific tumor-differentiated cell fate. Experimental evidence in mouse models of chronic myeloid leukemia and multiple myeloma support this hypothesis by showing oncogene expression restricted to stem cells results in cancer. This challenges the classical view that oncogenes uniformly alter differentiated cells and suggests reprogramming cancer stem cells could be a therapeutic target.
ResQu: A Framework for Automatic Evaluation of Knowledge-Driven Automatic Sum...Nishita Jaykumar
Automatic generation of summaries that capture the salient aspects of a search resultset
(i.e., automatic summarization) has become an important task in biomedical research. Automatic
summarization offers an avenue for overcoming the information overload problem
prevalent in large online digital libraries. However, across many of the knowledge-driven
approaches for automatic summarization it is not always clear which features highly impact
or influence the quality of a summary. Instead, there has been considerable focus on
utilizing schema knowledge to facilitate browsing and exploration of generated summaries
a posteriori. Informative features should not be ignored, since they could be utilized to
help optimize the models that generate these semantic summaries in the first place.
In this research, we adopt a leave-one-out approach to assess the impact of various
features on the quality of automatically generated summaries that contain structured background
knowledge. We first create the gold standard summaries, using information-theoretic
methods, by extraction and validation, then the semantic summaries are transformed into
an equivalent textual format. Finally, various similarity metrics, such as cosine similarity,
euclidean distance, and Jensen-Shannon divergence are computed under different feature
combinations, to assess summary quality against the textual gold standard. We report on
the relative importance of the various features used to automatically generate the semantic
summaries in a biomedical application. Our evaluation suggests that the proposed approach
is an effective automatic
Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement M Dominici1, K Le Blanc2, I Mueller3, I Slaper-Cortenbach4, FC Marini5, DS Krause6, RJ Deans7, A Keating8, DJ Prockop9 and EM Horwitz10
Odontogenic ameloblast-associated protein (ODAM) inhibits growth and migratio...Enrique Moreno Gonzalez
The Odontogenic Ameloblast-associated Protein (ODAM) is expressed in a wide range of
normal epithelial, and neoplastic tissues, and we have posited that ODAM serves as a novel
prognostic biomarker for breast cancer and melanoma. Transfection of ODAM into breast
cancer cells yields suppression of cellular growth, motility, and in vivo tumorigenicity.
Herein we have extended these studies to the effects of ODAM on cultured melanoma cell
lines.
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.
Opportunities and challenges provided by crosstalk between signalling pathway...Anirudh Prahallad
This document summarizes opportunities and challenges in exploiting crosstalk between signaling pathways for cancer treatment. It discusses how inhibition of one pathway can activate a secondary survival pathway, conferring resistance. The review evaluates using genetic approaches to identify pathway crosstalk and develop combination therapies. It provides examples where targeting two interacting pathways showed stronger effects than single agents, including combinations of BRAF/EGFR inhibitors for BRAF mutant colon cancer and MEK/ERBB3 inhibitors for KRAS mutant cancers.
This document discusses immunohistochemistry (IHC), which is used to identify tissue antigens through antigen-antibody interactions. It provides details on the IHC process, common antibodies and their targets, and tumor markers. IHC is useful for tumor diagnosis, narrowing differential diagnoses, and detecting unexpected diagnoses. The antibody panels discussed can help determine the primary site of cancers and differentiate between tumor types.
This research article examines the expression of RhoA and Rac1 in fibroblasts found at primary breast tumor sites and corresponding lymph node metastases. Immunohistochemistry on tissue microarrays revealed that 59% of fibroblasts at primary tumors and 41% at lymph node metastases expressed RhoA. Similarly, 57.1% at primary tumors and 42.9% at lymph node metastases expressed Rac1. Since expression levels were similar between primary and metastatic sites, the researchers suggest that fibroblasts actively participate in cancer cell invasion to lymph nodes and that metastatic cells continue relying on their microenvironment. Primary cell cultures were used to validate differences in focal adhesion pathways between carcinoma-associated fibroblasts and normal fibroblasts previously found via genomic profiling.
This document discusses tumor markers and their use in cancer screening and care. It defines tumor markers as substances produced by tumor cells or other cells in response to tumors that can be detected in blood, fluids, or tissues. The document describes how tumor markers are used to aid in diagnosis, identify cancer type and stage, monitor treatment effectiveness, and screen high-risk populations. It also discusses different types of tumor markers and provides guidance on choosing markers for specific cancer types.
A physical sciences network characterization of non-tumorigenic and metastati...Shashaanka Ashili
To investigate the transition from non-cancerous to metastatic from a physical sciences perspective, the
Physical Sciences–Oncology Centers (PS-OC) Network performed molecular and biophysical comparative studies of the non-tumorigenic MCF-10A and metastatic DA-MB-231 breast epithelial cell lines, commonly used as models of cancer metastasis. Experiments were performed in 20 laboratories from 12 PS-OCs. Each laboratory was supplied with identical aliquots and common reagents and culture protocols. Analyses of these measurements revealed dramatic differences in their mechanics, migration, adhesion, oxygen response, and proteomic profiles. Model-based multi-omics approaches identified key differences between these cells’ regulatory networks involved in morphology and survival. These results provide a multifaceted description of cellular parameters of two widely used cell lines and demonstrate the value of the PS-OC Network approach for integration of diverse experimental observations to elucidate the phenotypes associated with cancer metastasis.
Growth Kinetics of 2- and 3-D Cell Models as Influenced by the MicroenvironmentТатьяна Гергелюк
The noncontact cocultivation system was developed for the study of the paracrine interactions
between MCF-7 (breast carcinoma cells) and MT-4 (a line of human T-cell leukemia). Viability and proliferation
rates were determined in the adhesion and suspension fractions of MCF-7 cells sampled from two model
systems: monolayer culture and multicellular tumor spheroids (MTS). Cocultivation with MT-4 reduced the
number of MCF-7 cells in the adhesion fraction and had no effect upon the suspension fraction, despite an
increase in the total population of MCF-7 cells. The two model systems displayed a substantial difference in
cell viability, alone and in the presence of MT-4 cells – the fraction of viable cells in the monolayers was greater
than in the spheroids. It is suggested that cocultivation with MT-4 stimulates proliferation of MCF-7 cells via
a paracrine mechanism, reduces adhesion to the substrate, and leads to MTS formation.
Chemotherapy Friends or Foe to Cancer Immunotherapy by Prof. Mohamed L. SalemProf. Mohamed Labib Salem
This talk is presented by Mohamed Labib Salem, Ph.D.; Prof. of Immunology; Director, Center of Excellence in Cancer Research, Tanta University, Egypt
at the 15TH INTERNATIONAL CONFERENCE ON CHEMISTRY AND ITS ROLE IN DEVELOPMENT (15TH ICCRD), August 9, 2021
Faculty of Science, Mansoura University, Egypt
This review article discusses the potential use of mesenchymal stem cells (MSCs) in cancer therapy. MSCs can be obtained from sources like bone marrow and adipose tissue. They have properties like homing to tumor sites and secreting factors that may help reduce tumor growth. However, there are challenges to using MSCs in cancer therapy. Extensive expansion of MSCs in vitro carries a risk of malignant transformation due to telomere shortening or manipulation. There is also a limited understanding of the molecular mechanisms underlying any potential malignant transformation. Overall, while MSCs show promise as delivery vehicles for anti-cancer agents due to their homing properties, more research is needed to fully understand and address the risks of their therapeutic
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.
The study aimed to analyze the molecular profiles of surgical margins and colorectal cancer (CRC) tumors to identify prognostic markers. The results showed that cancer stem-like cells (CSCs) were present in 84.84% of tumors but also enriched in the distal surgical margin in 63.63% of cases. CSCs in distal margins correlated with shorter resection lengths, with 81.8% of margins under 2cm positive for CSCs compared to 0% over 5cm. Additionally, genes related to drug resistance and stemness were overexpressed in distal margins versus normal tissue. While CSC presence did not impact survival rates, the results suggest CSCs in surgical margins may drive tumor recurrence and wider margins could help reduce recurrence risk
Alain Toledano : Test and genomic profile : what future in breast cancer trea...breastcancerupdatecongress
This document summarizes a study that used whole-genome sequencing and molecular pathological analysis to track the evolution of the lethal prostate cancer cell clone in a patient who died from metastatic prostate cancer. The analyses revealed that the lethal clone arose from a small, relatively low-grade cancer focus in the primary tumor, not the bulkier higher-grade primary tumor or a lymph node metastasis removed during prostatectomy. This highlights the importance of molecular markers to better predict cancer progression and underscores the need to longitudinally sample metastatic lesions to understand clonal evolution during disease progression. Similar comprehensive studies of additional prostate cancer cases are needed.
1. The study found that ADAM8, a protein highly expressed in triple-negative breast cancers, regulates the expression of miRNAs, including miR-720.
2. Experiments showed that ADAM8 induces miR-720 expression via activation of the β1-integrin/ERK signaling pathway.
3. Modulating miR-720 levels in triple-negative breast cancer cells revealed that miR-720 promotes migratory and invasive abilities, suggesting it plays a role in the aggressive phenotype driven by ADAM8.
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 discusses tumor markers and their use in monitoring tumor response to therapy. It provides information on different types of tumor markers including proteins, enzymes, hormones, genetic markers and circulating tumor cells. Ideal tumor markers are highly sensitive and specific, correlate with tumor stage and prognosis, and can be used for screening, diagnosis, prognosis, monitoring treatment and detecting recurrence. Examples discussed include CEA, AFP, PSA, CA125 and circulating tumor cells. The Oncotype DX 21-gene recurrence score test and tissue polypeptide specific antigen are also summarized.
Role of Flow Cytometric Immunophenotyping in Plasma Cell DyscrasiasApollo Hospitals
Immunophenotyping is being routinely used for the diagnosis of leukemias. With the advent of specific markers for plasma cells, it has become possible to differentiate between benign and malignant plasma cells based on their immunophenotypic profile. The enhanced use of immunophenotyping in plasma cells dyscrasias may help to categorize the borderline cases which can not be done with morphology alone. Also the immunophenotypic profiling of plasma cells would help in Minimal Residual Disease (MRD) evaluation of patients on treatment of multiple myeloma (MM).
Defect in recruiting effector memory CD8+ T-cells in malignant pleural effusi...Enrique Moreno Gonzalez
Malignant pleural effusions (MPE) are a common and fatal complication in cancers including lung or breast cancers, or malignant pleural mesothelioma (MPM). MPE animal models and immunotherapy trials in MPM patients previously suggested defects of the cellular immunity in MPE. However only few observational studies of the immune response were done in MPM patients, using questionable control groups (transudate…).
Determining the intrinsic quality of a summary (for Automatic Summarization E...Nishita Jaykumar
The document discusses factors that contribute to the quality of summaries generated by an automatic summarization system. It examines how the topic being summarized, source documents, and summarization method all impact the results. The system is evaluated by comparing summary content to curated medical resources to determine how well the high-level information is conveyed in a condensed format.
Oncogenes can reprogram tumor cells early in cancer development, establishing tumor-specific cell fates. This tumoral stem cell reprogramming hypothesis proposes that oncogenic lesions act on stem/progenitor cells, imposing a specific tumor-differentiated cell fate. Experimental evidence in mouse models of chronic myeloid leukemia and multiple myeloma support this hypothesis by showing oncogene expression restricted to stem cells results in cancer. This challenges the classical view that oncogenes uniformly alter differentiated cells and suggests reprogramming cancer stem cells could be a therapeutic target.
ResQu: A Framework for Automatic Evaluation of Knowledge-Driven Automatic Sum...Nishita Jaykumar
Automatic generation of summaries that capture the salient aspects of a search resultset
(i.e., automatic summarization) has become an important task in biomedical research. Automatic
summarization offers an avenue for overcoming the information overload problem
prevalent in large online digital libraries. However, across many of the knowledge-driven
approaches for automatic summarization it is not always clear which features highly impact
or influence the quality of a summary. Instead, there has been considerable focus on
utilizing schema knowledge to facilitate browsing and exploration of generated summaries
a posteriori. Informative features should not be ignored, since they could be utilized to
help optimize the models that generate these semantic summaries in the first place.
In this research, we adopt a leave-one-out approach to assess the impact of various
features on the quality of automatically generated summaries that contain structured background
knowledge. We first create the gold standard summaries, using information-theoretic
methods, by extraction and validation, then the semantic summaries are transformed into
an equivalent textual format. Finally, various similarity metrics, such as cosine similarity,
euclidean distance, and Jensen-Shannon divergence are computed under different feature
combinations, to assess summary quality against the textual gold standard. We report on
the relative importance of the various features used to automatically generate the semantic
summaries in a biomedical application. Our evaluation suggests that the proposed approach
is an effective automatic
Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement M Dominici1, K Le Blanc2, I Mueller3, I Slaper-Cortenbach4, FC Marini5, DS Krause6, RJ Deans7, A Keating8, DJ Prockop9 and EM Horwitz10
Odontogenic ameloblast-associated protein (ODAM) inhibits growth and migratio...Enrique Moreno Gonzalez
The Odontogenic Ameloblast-associated Protein (ODAM) is expressed in a wide range of
normal epithelial, and neoplastic tissues, and we have posited that ODAM serves as a novel
prognostic biomarker for breast cancer and melanoma. Transfection of ODAM into breast
cancer cells yields suppression of cellular growth, motility, and in vivo tumorigenicity.
Herein we have extended these studies to the effects of ODAM on cultured melanoma cell
lines.
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.
Opportunities and challenges provided by crosstalk between signalling pathway...Anirudh Prahallad
This document summarizes opportunities and challenges in exploiting crosstalk between signaling pathways for cancer treatment. It discusses how inhibition of one pathway can activate a secondary survival pathway, conferring resistance. The review evaluates using genetic approaches to identify pathway crosstalk and develop combination therapies. It provides examples where targeting two interacting pathways showed stronger effects than single agents, including combinations of BRAF/EGFR inhibitors for BRAF mutant colon cancer and MEK/ERBB3 inhibitors for KRAS mutant cancers.
This document discusses immunohistochemistry (IHC), which is used to identify tissue antigens through antigen-antibody interactions. It provides details on the IHC process, common antibodies and their targets, and tumor markers. IHC is useful for tumor diagnosis, narrowing differential diagnoses, and detecting unexpected diagnoses. The antibody panels discussed can help determine the primary site of cancers and differentiate between tumor types.
This research article examines the expression of RhoA and Rac1 in fibroblasts found at primary breast tumor sites and corresponding lymph node metastases. Immunohistochemistry on tissue microarrays revealed that 59% of fibroblasts at primary tumors and 41% at lymph node metastases expressed RhoA. Similarly, 57.1% at primary tumors and 42.9% at lymph node metastases expressed Rac1. Since expression levels were similar between primary and metastatic sites, the researchers suggest that fibroblasts actively participate in cancer cell invasion to lymph nodes and that metastatic cells continue relying on their microenvironment. Primary cell cultures were used to validate differences in focal adhesion pathways between carcinoma-associated fibroblasts and normal fibroblasts previously found via genomic profiling.
This document discusses tumor markers and their use in cancer screening and care. It defines tumor markers as substances produced by tumor cells or other cells in response to tumors that can be detected in blood, fluids, or tissues. The document describes how tumor markers are used to aid in diagnosis, identify cancer type and stage, monitor treatment effectiveness, and screen high-risk populations. It also discusses different types of tumor markers and provides guidance on choosing markers for specific cancer types.
A physical sciences network characterization of non-tumorigenic and metastati...Shashaanka Ashili
To investigate the transition from non-cancerous to metastatic from a physical sciences perspective, the
Physical Sciences–Oncology Centers (PS-OC) Network performed molecular and biophysical comparative studies of the non-tumorigenic MCF-10A and metastatic DA-MB-231 breast epithelial cell lines, commonly used as models of cancer metastasis. Experiments were performed in 20 laboratories from 12 PS-OCs. Each laboratory was supplied with identical aliquots and common reagents and culture protocols. Analyses of these measurements revealed dramatic differences in their mechanics, migration, adhesion, oxygen response, and proteomic profiles. Model-based multi-omics approaches identified key differences between these cells’ regulatory networks involved in morphology and survival. These results provide a multifaceted description of cellular parameters of two widely used cell lines and demonstrate the value of the PS-OC Network approach for integration of diverse experimental observations to elucidate the phenotypes associated with cancer metastasis.
Growth Kinetics of 2- and 3-D Cell Models as Influenced by the MicroenvironmentТатьяна Гергелюк
The noncontact cocultivation system was developed for the study of the paracrine interactions
between MCF-7 (breast carcinoma cells) and MT-4 (a line of human T-cell leukemia). Viability and proliferation
rates were determined in the adhesion and suspension fractions of MCF-7 cells sampled from two model
systems: monolayer culture and multicellular tumor spheroids (MTS). Cocultivation with MT-4 reduced the
number of MCF-7 cells in the adhesion fraction and had no effect upon the suspension fraction, despite an
increase in the total population of MCF-7 cells. The two model systems displayed a substantial difference in
cell viability, alone and in the presence of MT-4 cells – the fraction of viable cells in the monolayers was greater
than in the spheroids. It is suggested that cocultivation with MT-4 stimulates proliferation of MCF-7 cells via
a paracrine mechanism, reduces adhesion to the substrate, and leads to MTS formation.
Chemotherapy Friends or Foe to Cancer Immunotherapy by Prof. Mohamed L. SalemProf. Mohamed Labib Salem
This talk is presented by Mohamed Labib Salem, Ph.D.; Prof. of Immunology; Director, Center of Excellence in Cancer Research, Tanta University, Egypt
at the 15TH INTERNATIONAL CONFERENCE ON CHEMISTRY AND ITS ROLE IN DEVELOPMENT (15TH ICCRD), August 9, 2021
Faculty of Science, Mansoura University, Egypt
This review article discusses the potential use of mesenchymal stem cells (MSCs) in cancer therapy. MSCs can be obtained from sources like bone marrow and adipose tissue. They have properties like homing to tumor sites and secreting factors that may help reduce tumor growth. However, there are challenges to using MSCs in cancer therapy. Extensive expansion of MSCs in vitro carries a risk of malignant transformation due to telomere shortening or manipulation. There is also a limited understanding of the molecular mechanisms underlying any potential malignant transformation. Overall, while MSCs show promise as delivery vehicles for anti-cancer agents due to their homing properties, more research is needed to fully understand and address the risks of their therapeutic
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.
The study aimed to analyze the molecular profiles of surgical margins and colorectal cancer (CRC) tumors to identify prognostic markers. The results showed that cancer stem-like cells (CSCs) were present in 84.84% of tumors but also enriched in the distal surgical margin in 63.63% of cases. CSCs in distal margins correlated with shorter resection lengths, with 81.8% of margins under 2cm positive for CSCs compared to 0% over 5cm. Additionally, genes related to drug resistance and stemness were overexpressed in distal margins versus normal tissue. While CSC presence did not impact survival rates, the results suggest CSCs in surgical margins may drive tumor recurrence and wider margins could help reduce recurrence risk
Alain Toledano : Test and genomic profile : what future in breast cancer trea...breastcancerupdatecongress
This document summarizes a study that used whole-genome sequencing and molecular pathological analysis to track the evolution of the lethal prostate cancer cell clone in a patient who died from metastatic prostate cancer. The analyses revealed that the lethal clone arose from a small, relatively low-grade cancer focus in the primary tumor, not the bulkier higher-grade primary tumor or a lymph node metastasis removed during prostatectomy. This highlights the importance of molecular markers to better predict cancer progression and underscores the need to longitudinally sample metastatic lesions to understand clonal evolution during disease progression. Similar comprehensive studies of additional prostate cancer cases are needed.
1. The study found that ADAM8, a protein highly expressed in triple-negative breast cancers, regulates the expression of miRNAs, including miR-720.
2. Experiments showed that ADAM8 induces miR-720 expression via activation of the β1-integrin/ERK signaling pathway.
3. Modulating miR-720 levels in triple-negative breast cancer cells revealed that miR-720 promotes migratory and invasive abilities, suggesting it plays a role in the aggressive phenotype driven by ADAM8.
Clinical and experimental studies regarding the expression and diagnostic val...Enrique Moreno Gonzalez
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Engineered T Cell Therapy for
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Breast cancer immune niche is a busy chatty neighbourhood with innumerable cross-talks, millions of mutual coded messages are in a dynamic flow among cancer cells and their neighbours, nonetheless among all these endless details, the most important message by far is how to evaluate, translate and thus utilise such cross talks into a substantial protocol within legitimate evidenced based background. This talk was created to wrap up this enormous field of knowledge by focusing on its harvested fruits
JTM-Functional characterization of human Cd33+ And Cd11b+ myeloid-derived sup...Karolina Megiel
This study examined the ability of human tumor cell lines to induce myeloid-derived suppressor cells (MDSC) from healthy donor peripheral blood mononuclear cells (PBMC) using in vitro co-cultures. Two distinct MDSC subsets were identified and characterized: CD33+ HLA-DRlow HIF1a+/STAT3+ MDSC and CD11b+ HLA-DRlow C/EBPb+ MDSC. The induction of CD33+ MDSC depended on overexpression of IL-1b, IL-6, TNFa, VEGF, and GM-CSF by tumor cells, while CD11b+ MDSC induction correlated with FLT3L and TGF
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tumor apoptosis. The molecular mechanism identified may serve as a platform for involving calcarea
carbonica into immunotherapeutic strategies for effective tumor regression
Construction and Validation of Prognostic Signature Model Based on Metastatic...daranisaha
Colorectal Cancer (CRC) is a common malignant cancer with a poor prognosis. Liver metastasis is the dominant cause of death in CRC patients, and it often involves changes in various gene expression profiling. This study proposed to construct and validate a risk model based on differentially expressed genes between the primary and liver metastatic tumors from CRC for prognostic prediction.
Molecular med tricon 2017 poster printedRandyLyEIT
This document summarizes the development of an automated filter-based system for isolating and detecting circulating tumor cells (CTCs) from blood samples. The system uses size- and deformability-based filtration to recover over 90% of CTCs while depleting over 99.99% of white blood cells. It also allows identification of protein markers on CTCs through immunostaining and detection of as few as 5 CTCs through quantitative RT-PCR analysis. Optimal sample storage conditions of 23°C for up to 72 hours was also determined.
maintrac liquid biopsy on circulating epithelial tumor cells Peter Pachmann
This document summarizes a study on monitoring the response of circulating epithelial tumor cells (CETCs) to adjuvant chemotherapy in breast cancer patients. The study found that CETCs can be quantified from blood samples of patients before, during, and after chemotherapy. Three typical response patterns were observed: a decrease of more than 10-fold in CETC numbers correlated with a good prognosis; marginal changes in CETC numbers correlated with a medium prognosis; and an increase of more than 10-fold in CETC numbers, even after an initial decrease, correlated with a poor prognosis and high risk of early relapse. Patients with increasing CETC numbers had a significantly worse relapse-free survival compared to the other groups. Therefore,
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This study found that colon cancer cells express the chemokine receptor CCR4, which mediates migration of the cells in response to its ligand CCL17 (TARC) through the RhoA/Rho kinase signaling pathway. Quantitative RT-PCR and flow cytometry showed that the colon cancer cell lines HT-29 and AZ-97 expressed CCR4 at both the mRNA and protein levels. Stimulation with CCL17 induced dose-dependent migration of the colon cancer cells, which was inhibited by blocking CCR4 with an antibody or antagonist. CCL17 also increased mRNA levels of RhoA proteins and RhoA activation in the cells. Inhibition of Rho kinase or isoprenylation blocked CCL17-induced cell migration
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ABSTRACT
Background: Chemotherapy is a mainstay of tumor therapy, however, it is predominantly applied according to empiri- cally developed recommendations derived from statistical relapse rates occurring years after the treatment in the adju- vant situation and from progression-free interval data in the metastatic situation, without any possibility of individually determining the efficacy in the adjuvant situation and with loss of time and quality of life in the metastatic situation if the drugs chosen are not effective. Here, we present a method to determine the efficiency of chemotherapeutic drugs using tumor cells circulating in blood as the part of the tumor actually available in the patient’s body for chemosensitiv- ity testing. Methodology/Principal Findings: After only red blood cell lysis, omitting any enrichment (analogous to other blood cell enumeration methods, including rare CD34 cells), the white cells comprising the circulating epithelial tumor cells (CETC) are exposed to the drugs in question in different concentrations and for different periods of time. Staining with a fluorescence-labeled anti-epithelial antibody detects both vital and dying tumor cells, distinguishing vital from dying cells through membrane permeability and nuclear staining with propidium iodide. Increasing percent- ages of dying tumor cells are observed dependent on time and concentration. The sensitivity can vary during therapy and was correlated with decrease or increase in CETC and clinical outcome. Conclusions/Significance: Thus, we are able to show that chemosensitivity testing of circulating tumor cells provides real-time information about the sensitivity of the tumor present in the patient, even at different times during therapy, and correlates with treatment success.
Infiltration, accumulation, and survival of chimeric antigen receptor T (CAR-T) cells in solid tumors are crucial for tumor clearance. T cell infiltration assays ensure the functional T cells are located in tumor microenvironment to display humoral or cellular immunity both in vitro and in vivo. https://www.creative-biolabs.com/car-t/enhancement-or-inhibition-of-t-cell-response-assays.htm
2. 124 I. Nurlaila et al. / Immunology Letters 156 (2013) 123–126
tumour cells within tumour nests, in TMC and AMC as a paired
model for studying tumour immunity.
2. Materials and methods
2.1. Tumour specimens
TMC and AMC samples were obtained from the Department of
Pathology’s archive at the Raja Isteri Pengiran Anak Saleha (RIPAS)
Hospital Brunei Darussalam in the form of formalin-fixed paraffin
embedded (FFPE) blocks from surgical resections performed in the
period 2004–2011 [10]. The FFPE blocks were cut into 4 m thick
sections using a microtome, affixed to silanized slides (Electron
Microscopy Science, USA) and prepared for immunohistochemical
staining as described [10].
2.2. Detection of CD8+ cells
Haematoxylin and eosin was used as a counter-stain for
immunohistochemical staining and to examine the morphological
features of TMC and AMC as previously described [10]. CD8+ cells
were identified by immunohistochemical staining using a mon-
oclonal mouse anti-human CD8 antibody clone C8/144B (Dako,
Germany) followed by a secondary goat anti-mouse IgG conju-
gated to peroxidase-labelled polymer solution (Dako, Denmark).
Diaminobenzidine was then used as a peroxidase substrate. The
TMC and AMC specimens were derived from six and eight dif-
ferent tumours respectively. Between five and seven fields were
examined per tumour under a light microscope (Olympus DP25,
Japan) at 600× magnification. Positively stained lymphocytes were
enumerated as a proportion of all lymphocytes in the same fields.
2.3. Detection of apoptotic cells
Apoptotic cells were detected by immunohistochemical stain-
ing with a rabbit monoclonal antibody to cleaved caspase-3
(Cell Signaling Technology, UK), followed by a secondary F(ab )2
peroxidase-conjugated goat antibody to rabbit IgG (Santa Cruz
Biotechnology, USA). The primary antibody detected the large frag-
ment of activated caspase-3 resulting from cleavage adjacent to
Asp175. A blocking peptide of cleaved caspase-3 (Cell Signaling
Technology, UK) was pre-mixed with the primary antibody before
application in order to establish the specificity of the primary anti-
body. Etoposide-treated Jurkat cell lines (Cell Signaling Technology,
UK) were employed as positive controls.
Apoptotic cells were enumerated by light microscopy (Olympus
DP25, Japan) at 600× magnification in six different TMC and five
different AMC samples. Between five to seven randomly selected
fields containing tumour nests were examined in each sample and
the percentage of apoptotic lymphocytes in contact with tumour
cells or apoptotic tumour cells in contact with lymphocytes in the
respective total lymphocyte or tumour cell populations in the fields
determined.
2.4. Statistical analysis
A two-tailed non-parametric Mann Whitney U-tailed test was
performed to determine the significance of differences between the
proportions of CD8+ and apoptotic cells in TMC and AMC.
3. Results
3.1. CD8+ lymphocytes in tumour nests and lymphocyte tracts
The CD8+ cells were abundant in both TMC and AMC (Fig. 1).
However, instead of being evenly distributed within the lympho-
cyte tract, CD8+ cells tend to accumulate in the periphery of the
tracts adjoining tumour nests (Fig. 1).
The mean percentages of CD8+ cells in the lymphocyte tracts
of TMC and AMC were 33.4% ± 6.6 (mean ± standard deviation)
and 25.1% ± 11.3 respectively. The results were not significantly
different (z = −1.48, p = 0.14). However the percentage of CD8+ lym-
phocytes within tumour nests of TMC (66.4% ± 14.3) was higher
than AMC (45.0% ± 16.2) with the difference being statistically sig-
nificant (z = −2.26, p = 0.02).
3.2. Apoptosis in tumour nests
Etoposide-treated Jurkat cell lines show prominent apoptotic
cells, indicated by dense brown staining (Fig. 2A). Fig. 2C and D
show apoptotic cells in representative experimental samples of
TMC and AMC respectively. In an AMC sample used as a negative
control, where cleaved caspase-3 blocking peptide was preincu-
bated with the primary antibody, some cells show characteristic
hyperchromicity, nuclear shrinkage and the presence of apoptotic
bodies (arrowed in Fig. 2B) but no brown staining (Fig. 2B). This
result confirms the specificity of detection of activated caspase-3.
The results also provide evidence to suggest that direct con-
tact between tumour cells and lymphocytes within the tumour
nest may lead to apoptosis. Fig. 3A shows an apoptotic tumour
cell (arrowed) in direct contact with an adjacent lymphocyte. Its
nucleus is condensed and hyperchromatic with a shrunken shape.
Fig. 3B shows apoptosis in two adjacent lymphocytes (arrowed)
that are in contact with a tumour cell. The upper lymphocyte has
Fig. 1. Localization of CD8+ lymphocytes in TMC and AMC. Panels show the location of CD8+ lymphocytes stained brown in (A) TMC and (B) AMC (100×). The full and dotted
lines delineate lymphocyte tracts (lt) and tumour nests (tn).
3. I. Nurlaila et al. / Immunology Letters 156 (2013) 123–126 125
Fig. 2. Apoptotic cells in TMC and AMC. Apoptotic cells stained brown were detected using a primary rabbit monoclonal antibody to cleaved caspase-3 in (A) Etoposide-
treated Jurkat cells as a positive control (200×), (B) AMC sample reacted with primary antibody that was pre-treated with cleaved caspase-3 blocking peptide as a negative
control (200×), (C) TMC (400×) and (D) AMC (400×). In the AMC sample used as a negative control (B), apoptotic tumour cells are morphologically observed (black arrows)
but no staining for cleaved caspase-3 is seen in them.
Fig. 3. Contact-mediated apoptosis of tumour cells and lymphocytes in TMC and AMC. The panels show apoptosis in a tumour cell in contact with a lymphocyte (A) and two
lymphocytes in contact with a tumour cell (B) at 600× magnification. The apoptotic cells are indicated with white arrowheads.
undergone nuclear shrinkage and condensation and a decrease in
size. The other lymphocyte has already formed an apoptotic body
since its organelles, especially the nucleus, has degraded into small
granules.
Apoptotic tumour cells within tumour nests that were in direct
contact with lymphocytes as a percentage of all tumour cells in
the fields examined were 0.8% ± 0.6 (mean ± standard deviation)
and 0.6% ± 0.5 in TMC and AMC respectively. The difference was
not statistically significant (p > 0.05). Apoptotic lymphocytes that
were in direct contact with tumour cells as a percentage of all lym-
phocytes in the fields examined were 7.4% ± 5.9 and 12.5% ± 21.7
in TMC and AMC respectively. The difference was not statistically
significant (p > 0.05).
4. Discussion
Despite the anaplastic cytological feature and high mitotic rate,
the prognosis for patients diagnosed with MBC, particularly TMC,
is better than for other types of DIC [1–8]. A positive correlation
between the intensity of lymphoid infiltration and patient survival
suggests that the immune system may be involved in restraining
the spread of this type of breast cancer [4].
4. 126 I. Nurlaila et al. / Immunology Letters 156 (2013) 123–126
CD8+ CTLs are a component of the adaptive immune system.
The capacity for rapid expansion and the ability of a single CD8+
CTL to destroy more than one target cell, while sparing ‘innocent’
bystanders, make CD8+ CTLs efficient antigen-specific effector cells.
Destruction of target cells by CD8+ CTLs typically requires cell con-
tact mediated by the recognition of peptide antigen presented on
MHC Class 1 molecules on the target cell by the T cell antigen recep-
tor, followed by target cell killing through the release of cytotoxic
granules or Fas/FasL interaction [11]. In a previous study on MBC in
Brunei, a higher proportion of CD8+ lymphocytes and a lower pro-
portion of CD20+ B-lineage cells were observed to be characteristic
of TMC in comparison to AMC [5]. Observations in the present and
previous studies [5,7] are consistent with close contact between
CD8+ lymphocytes and tumour cells in TMC. They suggest that the
better tumour control in TMC might be mediated by CD8+ CTLs.
However, the comparative distribution of CD8+ cells within tumour
nests and lymphocytic tracts of TMC and AMC had previously not
been reported. The present findings suggests that CD8+ lympho-
cytes in lymphocyte tracts tend to localize close to tumour nests
in MBC and that tumour nests of TMC had a significantly greater
percentage of CD8+ lymphocytes among the infiltrating lympho-
cytes than AMC. The lymphocyte tracts in TMC also tended to have
a greater proportion of CD8+ lymphocytes than AMC but statisti-
cal significance could not be established possibly due to the small
number of samples studied. These findings are however consistent
with CD8+ CTLs being responsible for the better tumour control in
TMC compared to AMC.
Apoptosis is a form of programmed cell death that plays an
essential role in many biological processes including normal cell
turnover, immune response, embryonic development and hor-
mone dependent atrophy [12,13]. Apoptosis in tumour cells has
been associated with the better prognosis in TMC [6,7]. A study
of 50 cases of MBC and 50 cases of non-medullary DIC utilizing
the terminal deoxynucleotidyl transferase-mediated dUTP-biotin
nick end-labelling (TUNEL) method for detecting apoptotic tumour
cells and immunohistochemistry for detecting p53, bcl-2, and Ki-
67 showed that tumour cells in MBC had higher apoptotic and
proliferative indices and significantly lower positivity for the anti-
apoptotic protein Bcl-2 than matched DIC controls [6]. A similar
independent study confirmed that tumour cells in both TMC and
AMC had higher apoptotic indices than matched cases of DIC [7].
No study to date has definitively established the cause of increased
apoptosis in MBC.
Taking into account previous observations of close contacts
between CD8+ lymphocytes and tumour cells in TMC [5,7], it was
expected that the better prognosis for TMC compared with AMC,
might be reflected in more tumour cells and the fewer lymphocytes
in TMC than AMC undergoing contact mediated-apoptosis within
tumour nests. However, while apoptosis in lymphocytes in contact
with tumour cells and in tumour cells in contact with lymphocytes
was observed within the tumour nests in both TMC and AMC, the
proportions of apoptotic cells were small and significant differences
could not be established between the two MBC types.
At least two strategies used by tumours to evade rejection by the
immune system are related to apoptosis [9,14]. Firstly, malignant
cells can alter the expression of molecules involved in apopto-
sis signalling, resulting in resistance to immune cell mediated
killing mechanisms. Secondly, tumours may adopt a mechanism
to delete attacking anti-tumour lymphocytes for example through
the expression of Fas ligand (CD95L) [9,14]. Tumour cells can
resist apoptosis at the membrane receptor and intracellular levels
[9,14]. Tumour cells down-regulate membrane Fas receptor (CD95)
expression thus inhibiting engagement with Fas ligand on immune
effector cells that can cause apoptosis in Fas-expressing tumour
cells. At the intracellular level, apoptosis resistance can be caused
by up-regulation of anti-apoptotic molecules or down-regulation
or loss of pro-apoptotic molecules. Higher levels of anti-apoptotic
Bcl-2 for example protects tumour cells against an immune attack
and promotes tumour survival and proliferation [6,13,14]. Details
of such possible mechanisms need to be investigated in parallel in
TMC and AMC. Additional roles for CD4+ T cells [15], other effector
cells such as NK cells [5], and antibodies in tumour immunity also
warrant further comparative investigation in TMC and AMC.
The present study underscores the previously proposed impor-
tance of TMC and AMC as a paired model system for studying
immune mechanisms in cancer [5]. Because Brunei has a popula-
tion of approximately 400,000 persons [10], and therefore only a
limited number of MBC cases, a larger number of samples from a
multi-centre investigation will be helpful in improving the statis-
tical power of such studies.
Conflict of interest statement
The authors declare no conflict of interest.
Acknowledgements
This study was supported by a graduate research scholarship to
IN from the Universiti Brunei Darussalam.
Author contributions: IN performed experiments; PUT provided
tumour specimens; RR and PUT conceived, designed and coordi-
nated the study; IN, RR and PUT drafted the manuscript. All authors
read and approved the final manuscript.
References
[1] Ridolfi RL, Rosen PP, Port A, Kinne D, Mike V. Medullary carcinoma of the breast:
a clinicopathology study with a 10-year follow up. Cancer 1977;40:1365–85.
[2] Pedersen L, Zedeler K, Holck S, Schiodt T, Mouridsen HT. Medullary carcinoma
of the breast: prevalence and prognostic importance of classical risk factors in
breast cancer. Eur J Cancer 1995;31:2289–95. A(13-14).
[3] Wargotz ES, Silverberg SG. Medullary carcinoma of the breast: a clinico-
pathology study with appraisal of current diagnostic criteria. Hum Pathol
1988;19(11):1340–6.
[4] Malyuchik SS, Kiyamova RG. Medullary breast carcinoma. Exp Oncol
2008;30(2):96–101.
[5] Lim KHJ, Telisinghe PU, Abdullah MS, Ramasamy R. Possible significance of
differences in proportions of cytotoxic T cells and B-lineage cells in the tumour-
infiltrating lymphocytes of typical and atypical medullary carcinomas of the
breast. Cancer Immunity 2010;10:3.
[6] Kajiwara M, Toyoshima S, Yao T, Tanaka M, Tsuneyoshi M. Apoptosis and
cell proliferation in medullary carcinoma of the breast: a comparative study
between medullary and non-medullary carcinoma using the TUNEL method
and immunohistochemistry. J Surg Oncol 1999;70(4):209–16.
[7] Yakirevich E, Maroun L, Cohen O, Ben Izhak O, Rennert G, Resnick MB. Apo-
ptosis, proliferation, and Fas (APO-1, CD95)/Fas ligand expression in medullary
carcinoma of the breast. J Pathol 2000;192:166–73.
[8] Yakirevich E, Izhak OB, Rennert G, Kovacs ZG, Resnick MB. Cytotoxic phenotype
of tumour infiltrating lymphocytes in medullary carcinoma of the breast. Mod
Pathol 1999;12(11):1050–6.
[9] Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveil-
lance: immunoselection and immunosubvertion. Nature Rev Immunol
2006;6:715–27.
[10] Tan S, Abdullah MS, Telisinghe PU, Ramasamy R. Breast cancer in Brunei
Darussalam—incidence and the role of evaluation of molecular markers. Brunei
Int Med J 2011;7(5):250–9.
[11] Broere F, Apasov SG, Sitkovsky MV, van Eden W. Principles of immunophar-
macology, 3rd
edition. T cell subsets and T cell-mediated immunity. Basel,
Switzerland: Springer; 2011.
[12] Cohen GM. Caspase: the executioners of apoptosis. Biochem J 1997;326:1–16.
[13] Strasser A, Cory S, Adams JM. Deciphering the rules of programmed cell death
to improve therapy of cancer and other diseases. EMBO J 2011;30:3667–83.
[14] Igney FH, Krammer PH. Immune escape of tumours: apoptosis resistance and
tumour counterattack. J Leukoc Biol 2002;71:907–20.
[15] Perez-Diez A, Joncker NT, Choi K, Chan WFN, Anderson CC, Lantz O, et al.
CD4 cells can be more efficient at tumour rejection than CD8 cells. Blood
2007;109(12):5346–53.