El 27 de noviembre de 2014, la Fundación Ramón Areces celebró una nueva conferencia del ciclo que organiza sobre 'Envejecimiento, Sociedad y Salud: envejecimiento y enfermedad' en colaboración con el Centro de Estudios del Envejecimiento. En esta ocasión, la investigadora María Blasco, directora del Centro Nacional de Investigaciones Oncológicas (CNIO), habló sobre 'El origen de la enfermedad'.
88 24-1853 051.812.955.17 folder to Tax ReturnSandro Suzart
This study examined the association between genetic polymorphisms in glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) and N-acetyltransferase 2 (NAT2) genes and the risk of developing asbestos-related pulmonary disorders in Finnish construction workers with high asbestos exposure. The risk of developing malignant mesothelioma or nonmalignant pulmonary disorders was not significantly associated with GSTM1 or GSTT1 genotypes. However, individuals with the NAT2 slow acetylator genotype had over a two-fold increased risk of developing asbestos-related pulmonary disorders compared to those with the fast acetylator genotype. Those with both the GSTM1 null genotype and NAT2 slow acetyl
CONFERENCE
ON
Multiple Hereditary Exostoses
Insights Into Pathogenesis
November 3-5, 2005
Shriners Hospital of Houston
6977 Main Street
Houston, Texas
and the
Houston Marriott Medical Center
6580 Fannin Street
Houston, Texas
Sponsored By:
The Shriners Hospital
The National Institutes of Health
American Association of Enchondroma Diseases
March of Dimes Birth Defects Foundation
The Orthopaedic Research Society
The MHE Coalition
Gene Dx, DNA Diagnostic Services
The Mizutani Foundation for Glycoscience
Organizers: Dan Wells, Ph.D., Jacqueline Hecht, Ph.D., Sarah Ziegler
This document summarizes several case studies using mesenchymal stem cells (MSCs) for regenerative medicine applications:
1. A pre-clinical study using ovine MSCs implanted in a critical-sized bone defect in sheep tibias showed effective bone regeneration compared to autograft or no cell controls.
2. A large animal study treating induced osteonecrosis of the femoral head in sheep with ovine MSCs implanted at the lesion site showed persistence of cells differentiating into bone and effective treatment compared to controls.
3. A Phase I/IIa clinical trial in humans with osteonecrosis of the femoral head treated with implanted human MSCs showed safety and potential efficacy based on imaging follow-up
Neuroblastomas are rare extracranial tumors of the pediatric population arising from cells of the embryological sympathetic nervous system. These malignancies most commonly occur in the abdomen, but other sites include the chest, neck, and pelvis with a predisposition for lymphatic and hematogenous
spread. Metastasis to the bone is a poor prognostic indicator, requiring surgical excision and other extensive medical management.
This document discusses cancer stem cells in brain tumors. It begins by providing background on brain tumors and their treatment challenges. It then discusses the cancer stem cell hypothesis, which proposes that tumors contain a cellular hierarchy with a subpopulation of stem-like cancer cells that can maintain and propagate the tumor. Studies have identified these cancer stem cells in various brain tumors through their ability to self-renew, proliferate, and initiate new tumors. However, there is still debate around this hypothesis due to inconsistencies across cancer types and lack of universal stem cell markers. The document focuses on research characterizing brain tumor stem cells and their roles in tumor biology and therapeutic resistance.
Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neu...Gul Muneer
Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neutrophils. Lung tumors disrupt bone homeostasis and increase osteoblast activity and bone formation. Osteoblasts amplify tumor-associated SiglecFhigh neutrophils that promote tumor growth through angiogenesis, immunosuppression and other mechanisms. Serum from tumor-bearing mice increases osteoblast activity through elevated sRAGE, which stimulates neutrophil maturation. SiglecFhigh neutrophils correlate with poor survival in lung cancer patients. Therefore, lung tumors communicate with bone through factors like sRAGE to modulate osteoblasts and promote neutrophil-driven tumor progression.
Manuel Salto-Tellez on Personalised medicine and the future of tissue pathologyCirdan
Personalised / Precision Medicine has revolutionized cancer treatment and, in parallel, is also deeply transforming the way we practice tissue pathology. The aim of this talk is to briefly review the status of molecular diagnostic tests applicable to tissues and cells, as well as the main technical and conceptual areas that, in my opinion, will be dictating the evolution of tissue pathology and its integration with the molecular era. These areas are, among others – a) digital pathology in the pipeline of therapeutic pathology; b) tissue-based NGS and its integration in routine diagnostics; c) the promise of liquid biopsy diagnostics and its necessary “partnership” with tissue molecular testing; d) Pathology IT, databases and bioinformatics; and e) the training of future tissue pathologists. In the process of this review, it may be apparent that a solid, integrated, morpho-molecular approach to pathology may serve our patients better.
This document discusses genomic oncology and personalized medicine, using lung cancers as a model. It summarizes several key technologies that enable genomic oncology like cDNA microarrays, array CGH, and next generation sequencing. It provides examples of how these technologies have been used to classify cancers like diffuse large B-cell lymphoma and myelodysplastic syndrome, and identify genetic mutations that can guide targeted therapies for cancers like EGFR-mutated lung cancer.
88 24-1853 051.812.955.17 folder to Tax ReturnSandro Suzart
This study examined the association between genetic polymorphisms in glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) and N-acetyltransferase 2 (NAT2) genes and the risk of developing asbestos-related pulmonary disorders in Finnish construction workers with high asbestos exposure. The risk of developing malignant mesothelioma or nonmalignant pulmonary disorders was not significantly associated with GSTM1 or GSTT1 genotypes. However, individuals with the NAT2 slow acetylator genotype had over a two-fold increased risk of developing asbestos-related pulmonary disorders compared to those with the fast acetylator genotype. Those with both the GSTM1 null genotype and NAT2 slow acetyl
CONFERENCE
ON
Multiple Hereditary Exostoses
Insights Into Pathogenesis
November 3-5, 2005
Shriners Hospital of Houston
6977 Main Street
Houston, Texas
and the
Houston Marriott Medical Center
6580 Fannin Street
Houston, Texas
Sponsored By:
The Shriners Hospital
The National Institutes of Health
American Association of Enchondroma Diseases
March of Dimes Birth Defects Foundation
The Orthopaedic Research Society
The MHE Coalition
Gene Dx, DNA Diagnostic Services
The Mizutani Foundation for Glycoscience
Organizers: Dan Wells, Ph.D., Jacqueline Hecht, Ph.D., Sarah Ziegler
This document summarizes several case studies using mesenchymal stem cells (MSCs) for regenerative medicine applications:
1. A pre-clinical study using ovine MSCs implanted in a critical-sized bone defect in sheep tibias showed effective bone regeneration compared to autograft or no cell controls.
2. A large animal study treating induced osteonecrosis of the femoral head in sheep with ovine MSCs implanted at the lesion site showed persistence of cells differentiating into bone and effective treatment compared to controls.
3. A Phase I/IIa clinical trial in humans with osteonecrosis of the femoral head treated with implanted human MSCs showed safety and potential efficacy based on imaging follow-up
Neuroblastomas are rare extracranial tumors of the pediatric population arising from cells of the embryological sympathetic nervous system. These malignancies most commonly occur in the abdomen, but other sites include the chest, neck, and pelvis with a predisposition for lymphatic and hematogenous
spread. Metastasis to the bone is a poor prognostic indicator, requiring surgical excision and other extensive medical management.
This document discusses cancer stem cells in brain tumors. It begins by providing background on brain tumors and their treatment challenges. It then discusses the cancer stem cell hypothesis, which proposes that tumors contain a cellular hierarchy with a subpopulation of stem-like cancer cells that can maintain and propagate the tumor. Studies have identified these cancer stem cells in various brain tumors through their ability to self-renew, proliferate, and initiate new tumors. However, there is still debate around this hypothesis due to inconsistencies across cancer types and lack of universal stem cell markers. The document focuses on research characterizing brain tumor stem cells and their roles in tumor biology and therapeutic resistance.
Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neu...Gul Muneer
Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neutrophils. Lung tumors disrupt bone homeostasis and increase osteoblast activity and bone formation. Osteoblasts amplify tumor-associated SiglecFhigh neutrophils that promote tumor growth through angiogenesis, immunosuppression and other mechanisms. Serum from tumor-bearing mice increases osteoblast activity through elevated sRAGE, which stimulates neutrophil maturation. SiglecFhigh neutrophils correlate with poor survival in lung cancer patients. Therefore, lung tumors communicate with bone through factors like sRAGE to modulate osteoblasts and promote neutrophil-driven tumor progression.
Manuel Salto-Tellez on Personalised medicine and the future of tissue pathologyCirdan
Personalised / Precision Medicine has revolutionized cancer treatment and, in parallel, is also deeply transforming the way we practice tissue pathology. The aim of this talk is to briefly review the status of molecular diagnostic tests applicable to tissues and cells, as well as the main technical and conceptual areas that, in my opinion, will be dictating the evolution of tissue pathology and its integration with the molecular era. These areas are, among others – a) digital pathology in the pipeline of therapeutic pathology; b) tissue-based NGS and its integration in routine diagnostics; c) the promise of liquid biopsy diagnostics and its necessary “partnership” with tissue molecular testing; d) Pathology IT, databases and bioinformatics; and e) the training of future tissue pathologists. In the process of this review, it may be apparent that a solid, integrated, morpho-molecular approach to pathology may serve our patients better.
This document discusses genomic oncology and personalized medicine, using lung cancers as a model. It summarizes several key technologies that enable genomic oncology like cDNA microarrays, array CGH, and next generation sequencing. It provides examples of how these technologies have been used to classify cancers like diffuse large B-cell lymphoma and myelodysplastic syndrome, and identify genetic mutations that can guide targeted therapies for cancers like EGFR-mutated lung cancer.
This study compares the detection of residual multiple myeloma (MM) in bone marrow biopsy specimens using immunoperoxidase staining with noninvasive studies using serum protein electrophoresis (SPE) and urine protein electrophoresis (UPE). The study analyzed 83 bone marrow biopsies and found that SPE and UPE were sensitive methods for detecting residual disease. Negative SPE and UPE results made bone marrow biopsies unnecessary for monitoring residual MM.
What's In a Genotype?: An Ontological Characterization for the Integration of...mhb120
This document discusses challenges in integrating genetic variation data and summarizes efforts by the Monarch Initiative to address these challenges. Specifically, it discusses (1) reconciling genetic variation data associated with different levels (e.g. allele, gene), (2) integrating non-genomic forms of variation, and (3) creating semantic links to related biological data. The Monarch Initiative is developing the GENO ontology and using it in their data integration pipeline to standardize genetic variation data and infer new genotype-phenotype associations.
BACKGROUND: Sequential Epstein-Barr virus (EBV)–positive B cell lymphoma to the initial diagnosis of angioimmunoblastic T cell lymphoma (AITL) is very rare, the exact mechanism and standard therapy of which is still being explored. CASE: A 50-year-old man was admitted to our hospital in January 2014 with a three-week history of enlargement of multiple lymph nodes. His initial pathological evaluation indicated AILT. The reactivation of EBV was observed during the immunosuppression therapy for AITL, accompanied by onset of subcutaneous nodules proven to be EBV-positive diffuse large B cell lymphoma (DLBCL) based on the pathological findings of rebiopsy. The patient was successfully treated with chidamide, a histone deacetylase (HDAC) inhibitor, and rituximab.
Conclusion: The sufficient surveillance for serum EBV and repeat biopsy is necessary for patients with AITL, and this treatment modality may become an active option.
Keywords: angioimmunoblastic T cell lymphoma, Epstein-Barr virus, HDAC inhibitor, non-Hodgkin lymphoma, peripheral T cell lymphoma
- Multiple myeloma is the second most common hematological malignancy and remains largely incurable despite improved treatments.
- Phenotypic profiling of plasma cells can identify distinct subclones within patients' bone marrow that often have different genomic profiles and drug sensitivities.
- Monitoring of minimal residual disease using sensitive techniques can identify patients with higher-risk subclones who may be at greater risk of relapse.
- Achieving the deepest possible response including elimination of all detectable minimal residual disease may be needed for long-term disease control or cure.
This document traces the history of research on teratomas and embryonic carcinoma (EC) cells from ancient times to present day, including several key discoveries and advances:
1) Rudolph Virchow coined the term "teratoma" in the 19th century to describe tumors containing tissues from all three germ layers.
2) In the 1950s-60s, mouse EC cells were discovered and shown to be pluripotent cancer stem cells capable of generating complex teratomas, resembling the early embryo.
3) The first human EC cell lines were established in the 1970s, though they differed from mouse EC cells. Surface antigens helped characterize both mouse and human EC cells and embryonic stem cells
The document discusses various technologies used at the House Ear Institute including genomics, proteomics, and imaging. It describes how researchers are using these tools to study diseases like neurofibromatosis type 2 (NF2) at the molecular level in order to develop personalized treatments and therapies. Maintaining high quality biospecimens is important for enabling various types of research.
Alternative lengthening of telomeres is enriched in, and impacts survival of ...Joshua Mangerel
This study investigated the prevalence and significance of alternative lengthening of telomeres (ALT) in pediatric brain tumors. The researchers screened 517 pediatric brain tumor samples for ALT using the C-circle assay and validated the results with other assays. They found that ALT was detected in a subset of malignant pediatric brain tumors, especially primitive neuroectodermal tumors, choroid plexus carcinomas, and high-grade gliomas. Somatic mutations in TP53 were strongly associated with ALT. ALT attenuated the poor prognosis associated with TP53 mutations in some tumor types. ALT positive tumors had higher survival rates than ALT negative tumors for children with TP53 mutant malignant gliomas and choroid plexus carcinomas. This suggests ALT may impact survival
Metastatic Tumors of the Spinal Column George Sapkas
This document discusses metastatic tumors of the spinal column, including their diagnosis and management. Some key points:
- The thoracolumbar region is the most common location for skeletal metastases, affecting around 70% of patients. The lumbar and sacral spine make up around 20% while the cervical spine is around 10%.
- Treatment options include medical therapies like chemotherapy, hormone therapy, biophosphonates and radiotherapy. Surgical options include decompression, debulking, or excision with or without stabilization. Factors like life expectancy, tumor type and location help determine the best treatment approach.
- Systems like Tokuhashi and Tomita aim to evaluate prognosis and help decide between palliative
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.
Objective: The association between telomerase reverse transcriptase (TERT) promoter mutation and outcome of melanoma is unclear and controversial. We aim to conduct a meta-analysis and investigate whether the TERT promoter mutation is a prognostic factor of melanoma.
Study Design: Appropriate studies were searched in 3 databases: PubMed, Web of Science, and Embase. Pooled hazard ratios (HRs) were counted through random effects model.
Results: Heterogeneity was moderate in overall survival (OS) (I2=43.7%, p=0.059) and low in disease-free survival (DFS) (I2=0.0%, p=0.587). Sensitivity analysis indicated that the removal of any of the study did not affect the final results. Evidence for publication bias was not found (Begg’s test, p=0.281; Egger’s test, p=0.078). The pooled OS HRs from combined effects analysis was determined (HR 1.07; 95% CI 0.83–1.39, p=0.585), together with the pooled HRs of DFS (HR 1.65; 95% CI 1.02–2.66, p=0.042). TERT promoter mutation predicted a good outcome in meta-static melanoma patients (HR 0.66; 95% CI 0.46–0.96, p=0.042). The pooled HRs of combined mutation in TERT promoter and BRAF (HR 6.27; 95% CI 2.7–14.58, p=0.000) predicted a bad outcome in melanoma patients.
Conclusion: TERT promoter mutation significantly predicted poor DFS outcome but, on the contrary, predicted a good outcome in metastatic melanoma patients. The combined TERT promoter and BRAF mutation was a significant independent factor of OS in melanoma patients.
Keywords: melanoma; meta-analysis; mutation; prognosis; promoter regions, genetic; skin neoplasms; telomerase; TERT promoter mutation; TERT protein, human
Martin Pera stem cells and the future of medicineigorod
This document discusses stem cell research and regenerative medicine. It begins by defining regenerative medicine and stem cells. It describes different types of stem cells including tissue stem cells and embryonic stem cells. It discusses some clinical uses of tissue stem cells and limitations. It then covers the discovery of human embryonic stem cells in 1998 and their potential uses and challenges. The rest of the document discusses various stem cell research projects at USC including using stem cells to study disease, induced pluripotent stem cells, and stem cell-based therapies for conditions like macular degeneration and HIV/AIDS.
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.
From 3D Cell Culture System to Personalized Medicine in Osteosarcoma_Crimson ...CrimsonpublishersITERM
Osteosarcoma is the most common primary bone malignancy presenting typically during childhood and adolescence. However, few improvements of the survival outcomes for osteosarcoma patients have been achieved since the last three decades. Despite the rarity of the diagnosis, the complexity of tumor microenvironment and the genetic heterogeneity of osteosarcoma remain the major obstacles to understanding the mechanisms involved in tumor progression and metastasis, and to screening the pharmacologically active molecules for better drugs. Compared to the 2D cell culture system, 3D cell culture system is much closer to the in vivo physiological condition in tumor. Thus, 3D cell culture system could be a powerful technique to screen therapeutic agent towards personalized medicine in osteosarcoma.
https://netrf.org/pancreatic-nets
Neuroendocrine tumors that arise in the pancreas are called “pancreatic neuroendocrine tumors” or “islet cell
tumors.”
Role of autophagy in tumor necrosis factor-α- induced apoptosis of osteoblast...KarlFrank99
This study investigated the role of tumor necrosis factor-α (TNF-α) in inducing autophagy and apoptosis in mouse osteoblast MC3T3-E1 cells. The study found that TNF-α inhibited cell viability in a dose- and time-dependent manner and induced both autophagy and apoptosis. Modulating autophagy levels with inducers and inhibitors affected the degree of TNF-α-induced apoptosis, indicating autophagy protects cells by reducing apoptosis. Studying the interaction between TNF-α, autophagy and apoptosis may provide insights into bone disease pathogenesis and new therapeutic targets.
Cervical cancer prevention current scenarioNilesh Kucha
Cervical cancer prevention requires a multi-pronged approach including screening, vaccination, and treatment. Screening begins at age 30 through pap smears or HPV testing every 5-10 years and helps detect pre-cancerous lesions early. HPV vaccination targets girls aged 9-13 and has shown nearly 100% efficacy against HPV types 16 and 18, which cause 70% of cervical cancers. Treatment of pre-cancerous lesions can prevent progression to invasive cancer. A comprehensive cervical cancer prevention program should include building healthcare infrastructure, increasing screening coverage, assessing impact, and conducting targeted education campaigns.
Hairy cell leukemia and magnetic resonance imaging in diffuse malignant bone ...TCHF
This document discusses a study examining the use of magnetic resonance imaging (MRI) to evaluate diffuse involvement of the bone marrow in cases of various hematopoietic disorders and malignancies. Thirty-six patients with malignant bone marrow diseases and 8 patients with reactive bone marrow were examined using spin-echo MRI at 0.35T and 0.5T magnetic field strengths. Regions of interest were analyzed to estimate T1 and T2 relaxation times, which were found to correlate with the cellularity of the bone marrow as assessed by histology. Among patients with near 100% cellular bone marrow, MRI was unable to distinguish between different malignancies or malignant versus reactive bone marrow. MRI was determined to be useful for assessing bone marrow cellularity
Objective: The prognostic indictors of age-related poor outcomes in patients with acute myeloid leukemia (AML) are still controversial. The aim of this work was to provide comprehensive insights into the effect of different hemocytes and to investigate the association between age and clinical features in adult patients with AML.
Study Design: A retrospective study was performed to determine the role of age in the therapeutic outcomes of AML. A total of 166 newly diagnosed adult patients’ data from January 2015 to November 2019 in Zhongshan Hospital of Xiamen University were collected and analyzed.
Results: Older patients presented a poorer prognosis (p=0.001) with shorter overall survival, which is served as age-related outcomes. Binary logistic regression demonstrated that cytogenetic risk (OR=4.508, 95% CI 2.733–7.435), leukocyte (OR=7.410, 95% CI 1.139–5.910), and bone marrow blast cells (OR=3.261, 95% CI 1.075–5.615) were independent indictors for age-related prognosis. In addition, Kaplan-Meier curve also revealed that the above factors were associated with overall survival (all p values <0.001).
Conclusion: Cytogenetic risk, leukocyte, and bone marrow blast cells are dominant factors which account for the age-related poor outcomes and shorter overall survival in AML.
Keywords: acute myeloid leukemia, adult, cytogenetic risk, hemocyte, leukemia, overall survival
Telomeros, envejecimiento y prevencion Dr.A.Fernandez-Cruz - Barcelona - apr...Life Length
Telomeres, aging and prevention. Telomere length decreases with each cell division and can be used as a biomarker for biological aging. While telomerase helps maintain telomere length in embryonic development, it is normally silenced after birth. Cancer cells are able to reactivate telomerase to become immortal. Studies show that increased telomerase through genetic modifications in mice can increase healthspan and longevity while reducing aging effects and slightly increasing cancer risk. Precision medicine approaches using telomere length and other biomarkers may help predict disease risks and develop new prevention and treatment strategies.
The document discusses rare types of genital cancers. It mentions that rare genital cancers make up around 1% of cases, and includes cancers like sertoli cell tumors, granulosa cell tumors, and von Leydig cell tumors. It provides some key details about each type of rare cancer, including typical patient demographics, associated symptoms, treatment approaches, and prognosis.
We report a series of 10 patients with thalamic high HGGs with extensive clinical, neuro-radiological, and pathologic analyses. Moreover, we attempted to correlate survival with some of the clinical data and reviewed the literature with regards to the management of thalamic HGGs.
This study compares the detection of residual multiple myeloma (MM) in bone marrow biopsy specimens using immunoperoxidase staining with noninvasive studies using serum protein electrophoresis (SPE) and urine protein electrophoresis (UPE). The study analyzed 83 bone marrow biopsies and found that SPE and UPE were sensitive methods for detecting residual disease. Negative SPE and UPE results made bone marrow biopsies unnecessary for monitoring residual MM.
What's In a Genotype?: An Ontological Characterization for the Integration of...mhb120
This document discusses challenges in integrating genetic variation data and summarizes efforts by the Monarch Initiative to address these challenges. Specifically, it discusses (1) reconciling genetic variation data associated with different levels (e.g. allele, gene), (2) integrating non-genomic forms of variation, and (3) creating semantic links to related biological data. The Monarch Initiative is developing the GENO ontology and using it in their data integration pipeline to standardize genetic variation data and infer new genotype-phenotype associations.
BACKGROUND: Sequential Epstein-Barr virus (EBV)–positive B cell lymphoma to the initial diagnosis of angioimmunoblastic T cell lymphoma (AITL) is very rare, the exact mechanism and standard therapy of which is still being explored. CASE: A 50-year-old man was admitted to our hospital in January 2014 with a three-week history of enlargement of multiple lymph nodes. His initial pathological evaluation indicated AILT. The reactivation of EBV was observed during the immunosuppression therapy for AITL, accompanied by onset of subcutaneous nodules proven to be EBV-positive diffuse large B cell lymphoma (DLBCL) based on the pathological findings of rebiopsy. The patient was successfully treated with chidamide, a histone deacetylase (HDAC) inhibitor, and rituximab.
Conclusion: The sufficient surveillance for serum EBV and repeat biopsy is necessary for patients with AITL, and this treatment modality may become an active option.
Keywords: angioimmunoblastic T cell lymphoma, Epstein-Barr virus, HDAC inhibitor, non-Hodgkin lymphoma, peripheral T cell lymphoma
- Multiple myeloma is the second most common hematological malignancy and remains largely incurable despite improved treatments.
- Phenotypic profiling of plasma cells can identify distinct subclones within patients' bone marrow that often have different genomic profiles and drug sensitivities.
- Monitoring of minimal residual disease using sensitive techniques can identify patients with higher-risk subclones who may be at greater risk of relapse.
- Achieving the deepest possible response including elimination of all detectable minimal residual disease may be needed for long-term disease control or cure.
This document traces the history of research on teratomas and embryonic carcinoma (EC) cells from ancient times to present day, including several key discoveries and advances:
1) Rudolph Virchow coined the term "teratoma" in the 19th century to describe tumors containing tissues from all three germ layers.
2) In the 1950s-60s, mouse EC cells were discovered and shown to be pluripotent cancer stem cells capable of generating complex teratomas, resembling the early embryo.
3) The first human EC cell lines were established in the 1970s, though they differed from mouse EC cells. Surface antigens helped characterize both mouse and human EC cells and embryonic stem cells
The document discusses various technologies used at the House Ear Institute including genomics, proteomics, and imaging. It describes how researchers are using these tools to study diseases like neurofibromatosis type 2 (NF2) at the molecular level in order to develop personalized treatments and therapies. Maintaining high quality biospecimens is important for enabling various types of research.
Alternative lengthening of telomeres is enriched in, and impacts survival of ...Joshua Mangerel
This study investigated the prevalence and significance of alternative lengthening of telomeres (ALT) in pediatric brain tumors. The researchers screened 517 pediatric brain tumor samples for ALT using the C-circle assay and validated the results with other assays. They found that ALT was detected in a subset of malignant pediatric brain tumors, especially primitive neuroectodermal tumors, choroid plexus carcinomas, and high-grade gliomas. Somatic mutations in TP53 were strongly associated with ALT. ALT attenuated the poor prognosis associated with TP53 mutations in some tumor types. ALT positive tumors had higher survival rates than ALT negative tumors for children with TP53 mutant malignant gliomas and choroid plexus carcinomas. This suggests ALT may impact survival
Metastatic Tumors of the Spinal Column George Sapkas
This document discusses metastatic tumors of the spinal column, including their diagnosis and management. Some key points:
- The thoracolumbar region is the most common location for skeletal metastases, affecting around 70% of patients. The lumbar and sacral spine make up around 20% while the cervical spine is around 10%.
- Treatment options include medical therapies like chemotherapy, hormone therapy, biophosphonates and radiotherapy. Surgical options include decompression, debulking, or excision with or without stabilization. Factors like life expectancy, tumor type and location help determine the best treatment approach.
- Systems like Tokuhashi and Tomita aim to evaluate prognosis and help decide between palliative
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.
Objective: The association between telomerase reverse transcriptase (TERT) promoter mutation and outcome of melanoma is unclear and controversial. We aim to conduct a meta-analysis and investigate whether the TERT promoter mutation is a prognostic factor of melanoma.
Study Design: Appropriate studies were searched in 3 databases: PubMed, Web of Science, and Embase. Pooled hazard ratios (HRs) were counted through random effects model.
Results: Heterogeneity was moderate in overall survival (OS) (I2=43.7%, p=0.059) and low in disease-free survival (DFS) (I2=0.0%, p=0.587). Sensitivity analysis indicated that the removal of any of the study did not affect the final results. Evidence for publication bias was not found (Begg’s test, p=0.281; Egger’s test, p=0.078). The pooled OS HRs from combined effects analysis was determined (HR 1.07; 95% CI 0.83–1.39, p=0.585), together with the pooled HRs of DFS (HR 1.65; 95% CI 1.02–2.66, p=0.042). TERT promoter mutation predicted a good outcome in meta-static melanoma patients (HR 0.66; 95% CI 0.46–0.96, p=0.042). The pooled HRs of combined mutation in TERT promoter and BRAF (HR 6.27; 95% CI 2.7–14.58, p=0.000) predicted a bad outcome in melanoma patients.
Conclusion: TERT promoter mutation significantly predicted poor DFS outcome but, on the contrary, predicted a good outcome in metastatic melanoma patients. The combined TERT promoter and BRAF mutation was a significant independent factor of OS in melanoma patients.
Keywords: melanoma; meta-analysis; mutation; prognosis; promoter regions, genetic; skin neoplasms; telomerase; TERT promoter mutation; TERT protein, human
Martin Pera stem cells and the future of medicineigorod
This document discusses stem cell research and regenerative medicine. It begins by defining regenerative medicine and stem cells. It describes different types of stem cells including tissue stem cells and embryonic stem cells. It discusses some clinical uses of tissue stem cells and limitations. It then covers the discovery of human embryonic stem cells in 1998 and their potential uses and challenges. The rest of the document discusses various stem cell research projects at USC including using stem cells to study disease, induced pluripotent stem cells, and stem cell-based therapies for conditions like macular degeneration and HIV/AIDS.
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.
From 3D Cell Culture System to Personalized Medicine in Osteosarcoma_Crimson ...CrimsonpublishersITERM
Osteosarcoma is the most common primary bone malignancy presenting typically during childhood and adolescence. However, few improvements of the survival outcomes for osteosarcoma patients have been achieved since the last three decades. Despite the rarity of the diagnosis, the complexity of tumor microenvironment and the genetic heterogeneity of osteosarcoma remain the major obstacles to understanding the mechanisms involved in tumor progression and metastasis, and to screening the pharmacologically active molecules for better drugs. Compared to the 2D cell culture system, 3D cell culture system is much closer to the in vivo physiological condition in tumor. Thus, 3D cell culture system could be a powerful technique to screen therapeutic agent towards personalized medicine in osteosarcoma.
https://netrf.org/pancreatic-nets
Neuroendocrine tumors that arise in the pancreas are called “pancreatic neuroendocrine tumors” or “islet cell
tumors.”
Role of autophagy in tumor necrosis factor-α- induced apoptosis of osteoblast...KarlFrank99
This study investigated the role of tumor necrosis factor-α (TNF-α) in inducing autophagy and apoptosis in mouse osteoblast MC3T3-E1 cells. The study found that TNF-α inhibited cell viability in a dose- and time-dependent manner and induced both autophagy and apoptosis. Modulating autophagy levels with inducers and inhibitors affected the degree of TNF-α-induced apoptosis, indicating autophagy protects cells by reducing apoptosis. Studying the interaction between TNF-α, autophagy and apoptosis may provide insights into bone disease pathogenesis and new therapeutic targets.
Cervical cancer prevention current scenarioNilesh Kucha
Cervical cancer prevention requires a multi-pronged approach including screening, vaccination, and treatment. Screening begins at age 30 through pap smears or HPV testing every 5-10 years and helps detect pre-cancerous lesions early. HPV vaccination targets girls aged 9-13 and has shown nearly 100% efficacy against HPV types 16 and 18, which cause 70% of cervical cancers. Treatment of pre-cancerous lesions can prevent progression to invasive cancer. A comprehensive cervical cancer prevention program should include building healthcare infrastructure, increasing screening coverage, assessing impact, and conducting targeted education campaigns.
Hairy cell leukemia and magnetic resonance imaging in diffuse malignant bone ...TCHF
This document discusses a study examining the use of magnetic resonance imaging (MRI) to evaluate diffuse involvement of the bone marrow in cases of various hematopoietic disorders and malignancies. Thirty-six patients with malignant bone marrow diseases and 8 patients with reactive bone marrow were examined using spin-echo MRI at 0.35T and 0.5T magnetic field strengths. Regions of interest were analyzed to estimate T1 and T2 relaxation times, which were found to correlate with the cellularity of the bone marrow as assessed by histology. Among patients with near 100% cellular bone marrow, MRI was unable to distinguish between different malignancies or malignant versus reactive bone marrow. MRI was determined to be useful for assessing bone marrow cellularity
Objective: The prognostic indictors of age-related poor outcomes in patients with acute myeloid leukemia (AML) are still controversial. The aim of this work was to provide comprehensive insights into the effect of different hemocytes and to investigate the association between age and clinical features in adult patients with AML.
Study Design: A retrospective study was performed to determine the role of age in the therapeutic outcomes of AML. A total of 166 newly diagnosed adult patients’ data from January 2015 to November 2019 in Zhongshan Hospital of Xiamen University were collected and analyzed.
Results: Older patients presented a poorer prognosis (p=0.001) with shorter overall survival, which is served as age-related outcomes. Binary logistic regression demonstrated that cytogenetic risk (OR=4.508, 95% CI 2.733–7.435), leukocyte (OR=7.410, 95% CI 1.139–5.910), and bone marrow blast cells (OR=3.261, 95% CI 1.075–5.615) were independent indictors for age-related prognosis. In addition, Kaplan-Meier curve also revealed that the above factors were associated with overall survival (all p values <0.001).
Conclusion: Cytogenetic risk, leukocyte, and bone marrow blast cells are dominant factors which account for the age-related poor outcomes and shorter overall survival in AML.
Keywords: acute myeloid leukemia, adult, cytogenetic risk, hemocyte, leukemia, overall survival
Telomeros, envejecimiento y prevencion Dr.A.Fernandez-Cruz - Barcelona - apr...Life Length
Telomeres, aging and prevention. Telomere length decreases with each cell division and can be used as a biomarker for biological aging. While telomerase helps maintain telomere length in embryonic development, it is normally silenced after birth. Cancer cells are able to reactivate telomerase to become immortal. Studies show that increased telomerase through genetic modifications in mice can increase healthspan and longevity while reducing aging effects and slightly increasing cancer risk. Precision medicine approaches using telomere length and other biomarkers may help predict disease risks and develop new prevention and treatment strategies.
The document discusses rare types of genital cancers. It mentions that rare genital cancers make up around 1% of cases, and includes cancers like sertoli cell tumors, granulosa cell tumors, and von Leydig cell tumors. It provides some key details about each type of rare cancer, including typical patient demographics, associated symptoms, treatment approaches, and prognosis.
We report a series of 10 patients with thalamic high HGGs with extensive clinical, neuro-radiological, and pathologic analyses. Moreover, we attempted to correlate survival with some of the clinical data and reviewed the literature with regards to the management of thalamic HGGs.
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.
The document discusses various types of primary and metastatic brain tumors. It provides statistics on the annual incidence of different brain tumors in the US. It then describes several specific tumor types in more detail, including meningiomas, vestibular schwannomas, craniopharyngiomas, gliomas such as glioblastoma, and brain metastases. For each tumor type, it discusses epidemiology, presentation, imaging, histopathology, treatment including surgery and radiotherapy techniques and dose/fractionation schedules.
1. Aging and limited lifespan are caused by the cost of complexity maintenance. Lifespan is determined by the functional stem cell output to tissue damage. Cancer arises when the size functional stem cell pool is small, which may take place in the early life stage or during aging stem cell decline. Changing life history can modify stem cell aging and cancer spectrum. Decelerating tissue damage and stem cell decline may delay cancer.
2. Immunity maintains somatic tissue integrity. Tumors may continuously form but are kept asymptomatic by immunosurveillance. Immune decline or suppression allows small tumors to outbreak and become symptomatic, promoting cancer. Allocating resources away from immunity through lifestyle causes immune suppression.
3. Evolutionary and life history
This study evaluated thyroid nodules in 35 patients with acromegaly using ultrasound elastography. The study found a high prevalence (56.7%) of stiff thyroid nodules in acromegaly, especially in patients with active disease. However, cytological analysis found that these stiff nodules were not malignant and were likely fibrotic in nature. Therefore, ultrasound elastography appears to have limited value for diagnosing thyroid cancer in patients with acromegaly.
FNAC & Histopathology correlation of various thyroid esionsiosrjce
IOSR Journal of Dental and Medical Sciences is one of the speciality Journal in Dental Science and Medical Science published by International Organization of Scientific Research (IOSR). The Journal publishes papers of the highest scientific merit and widest possible scope work in all areas related to medical and dental science. The Journal welcome review articles, leading medical and clinical research articles, technical notes, case reports and others.
Robert P. Edwards, MD, Chair of OB/GYN/RS, Co-Director of Women's Cancer Program at University of Pittsburgh, offers information about the current state of immunotherapy for recurrent ovarian cancer patients.
Alberto Pappo, MD, St. Jude Children’s Hospital, Memphis TN
Presented at the 2010 Texas Adolescent and Young Adult Oncology Conference hosted by Methodist Healthcare-San Antonio. October 2010.
1) Using high resolution telomere fluorescent in situ hybridization, the study found that intratubular germ cell neoplasia and most pure seminomas exhibited short telomeres, while non-seminoma subtypes generally had longer telomeres and a worse prognosis.
2) Among non-seminomas, embryonal carcinoma had the highest proportion of long telomeres and was the only subtype to display an alternative lengthening of telomeres phenotype.
3) The findings indicate that telomere anomalies are an early event in testicular germ cell tumor carcinogenesis and may contribute to tumor initiation and progression. Further investigation of telomeric aberrations could provide new pathways for
prognostic and predictive biomarkers of canine osteosarcomaJ.L. Gall
The document discusses prognostic and predictive biomarkers for canine osteosarcoma. It begins by providing background on canine osteosarcoma, including that it is an aggressive bone tumor that is difficult to treat and has a poor prognosis. It then discusses the potential use of biomarkers for diagnosing osteosarcoma subtypes, predicting patient outcomes, and assessing response to therapies. Several potential prognostic biomarkers are mentioned, such as tumor grade, size, location, and serum alkaline phosphatase levels, but it notes that no single biomarker has been validated to enhance prognosis. The review explores using molecular profiling to identify new prognostic and predictive biomarkers that could help tailor treatment for canine osteosarcoma.
This document provides an overview of thyroid cancer, including the anatomy and physiology of the thyroid gland, epidemiology, risk factors, clinical presentation, diagnostic evaluation, staging, surgical management, and role of radioactive iodine treatment. Key points include that thyroid cancer is most commonly diagnosed through incidental finding of a thyroid nodule, surgical removal of the thyroid (total thyroidectomy) is the primary treatment, and radioactive iodine ablation may be used post-operatively depending on risk level. Prognostic factors include histologic classification and cancer stage at diagnosis.
Presentazione a cura del Dottor Gabriele Capurso - "HOT TOPICS IN GASTROENTEROLOGIA - I TUMORI DELL'APPARATO DIGERENTE: cosa è cambiato e cosa bisogna sapere" - Roma 10/11/2018
This document summarizes a study on Pap smear screening conducted in Bagalkot, India between 2015-2016. 240 women ages 20-60 received Pap smears. The most common finding was reactive cellular changes associated with inflammation (75.8% of cases). Other findings included low-grade squamous intraepithelial lesions (4.5%), atypical squamous cells of undetermined significance (3.3%), high-grade squamous intraepithelial lesions (2.1%), and atrophy (1.3%). The average age of women with epithelial abnormalities was 40 years old. Cases with abnormal findings received follow-up colposcopy and biopsy. This study aims to increase awareness of Pap smears and
Medullary carcinoma of thyroid genene m. bekele, md, faceGofasefer
1) This document describes the case of a patient with metastatic medullary thyroid carcinoma (MTC) who underwent multiple surgeries and treatments over several years as their disease progressed and calcitonin levels increased.
2) Vandetanib, a drug that targets the RET gene mutation often present in MTC, was approved by the FDA in 2011 based on results of the ZETA clinical trial showing it significantly increased progression-free survival compared to placebo.
3) The ZETA trial involved 331 patients randomized to receive either vandetanib 300mg daily or placebo, with the primary endpoint being progression-free survival assessed by independent review. Vandetanib was found to nearly halve the risk of progression or death
The document summarizes a study that aimed to predict clinical failure in patients with metastatic prostate cancer by identifying genes related to prostate cancer. Researchers analyzed gene expression levels of androgen receptor, estrogen receptor, and stem cell markers in cancer and stromal cells collected via laser capture microdissection from biopsy samples of 76 patients. Logistic regression analysis showed that expression of Sox2, Her2, and CRP in cancer cells and AR and ER in stromal cells highly predicted prostate-specific antigen recurrence. Ten factors were identified as prognostic for cancer-specific survival, including expression of Oct1, TRIM36, Sox2, c-Myc, AR, Klf4, ER, and clinical parameters. Patients were divided into risk
The document summarizes a study that aimed to predict clinical failure in patients with metastatic prostate cancer by identifying genes related to prostate cancer. Researchers analyzed gene expression levels of androgen receptor, estrogen receptor, and stem cell markers in cancer and stromal cells collected via laser capture microdissection from biopsy samples of 76 patients. Logistic regression analysis showed that expression of Sox2, Her2, and CRP in cancer cells and AR and ER in stromal cells highly predicted prostate-specific antigen recurrence. Ten factors were identified as prognostic for cancer-specific survival, including expression of Oct1, TRIM36, Sox2, c-Myc, AR, Klf4, ER, as well as PSA, Gleason score
Plasmacytoma is a rare plasma cell neoplasm that can present as a solitary bone plasmacytoma (SBP) or extramedullary plasmacytoma (EMP). SBP most commonly involves the axial skeleton and presents with bone pain. EMP typically involves the upper aerodigestive tract and presents with symptoms related to site of involvement. Diagnosis involves biopsy and ruling out multiple myeloma. Radiotherapy is the primary treatment for both SBP and EMP and provides high rates of local control. Prognosis is generally good but some patients may progress to multiple myeloma.
This document discusses thyroid carcinoma and provides details on the anatomy, histology, types, staging, treatment, and prognosis of different thyroid cancers. It covers the embryology, blood supply, innervation and drainage of the thyroid gland. The main types discussed are papillary carcinoma, follicular carcinoma, hurthle cell carcinoma, and medullary carcinoma. Staging systems like TNM, University of Chicago, and MAICS scoring are explained. Treatment typically involves surgical excision and radioactive iodine for differentiated cancers. Prognosis depends on factors like age, histology, tumor size and invasion.
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Explore the benefits of combining Ayurveda with conventional Parkinson's treatments. Learn how a holistic approach can manage symptoms, enhance well-being, and balance body energies. Discover the steps to safely integrate Ayurvedic practices into your Parkinson’s care plan, including expert guidance on diet, herbal remedies, and lifestyle modifications.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of the physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar lead (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
6. Describe the flow of current around the heart during the cardiac cycle
7. Discuss the placement and polarity of the leads of electrocardiograph
8. Describe the normal electrocardiograms recorded from the limb leads and explain the physiological basis of the different records that are obtained
9. Define mean electrical vector (axis) of the heart and give the normal range
10. Define the mean QRS vector
11. Describe the axes of leads (hexagonal reference system)
12. Comprehend the vectorial analysis of the normal ECG
13. Determine the mean electrical axis of the ventricular QRS and appreciate the mean axis deviation
14. Explain the concepts of current of injury, J point, and their significance
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. Chapter 3, Cardiology Explained, https://www.ncbi.nlm.nih.gov/books/NBK2214/
7. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
- Video recording of this lecture in English language: https://youtu.be/kqbnxVAZs-0
- Video recording of this lecture in Arabic language: https://youtu.be/SINlygW1Mpc
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
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Histololgy of Female Reproductive System.pptxAyeshaZaid1
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Local Advanced Lung Cancer: Artificial Intelligence, Synergetics, Complex Sys...Oleg Kshivets
Overall life span (LS) was 1671.7±1721.6 days and cumulative 5YS reached 62.4%, 10 years – 50.4%, 20 years – 44.6%. 94 LCP lived more than 5 years without cancer (LS=2958.6±1723.6 days), 22 – more than 10 years (LS=5571±1841.8 days). 67 LCP died because of LC (LS=471.9±344 days). AT significantly improved 5YS (68% vs. 53.7%) (P=0.028 by log-rank test). Cox modeling displayed that 5YS of LCP significantly depended on: N0-N12, T3-4, blood cell circuit, cell ratio factors (ratio between cancer cells-CC and blood cells subpopulations), LC cell dynamics, recalcification time, heparin tolerance, prothrombin index, protein, AT, procedure type (P=0.000-0.031). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and N0-12 (rank=1), thrombocytes/CC (rank=2), segmented neutrophils/CC (3), eosinophils/CC (4), erythrocytes/CC (5), healthy cells/CC (6), lymphocytes/CC (7), stick neutrophils/CC (8), leucocytes/CC (9), monocytes/CC (10). Correct prediction of 5YS was 100% by neural networks computing (error=0.000; area under ROC curve=1.0).
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8. TTeelloommeerreess aarree lloosstt eevveerryyttiimmee tthhaatt aa cceellll ddiivviiddeess……
telomere telomere
Chromosome
(parent cell)
“the end-replication problem”
DNA is lost from the ends
Chromosome
(daughter cell #1)
Chromosome
(daughter cell #2)
12. Telomere length as a biomarker with
prognostic value?
Lower percentiles of telomere length=
higher risk of diseases (cardiovascular,
neurodegenerative, death by infections)
cancer
(> 95% of cancers
activate telomerase)
high
Telomere length
TTeelloommeerreess,, tteelloommeerraassee aanndd aaggiinngg
Tissues and organs (including stem cells)
Mutations in telomerase & health
telomere proteins
disease
age
Human pathologies due to telomere defects
(“TELOMERE SYNDROMES”)
dysqueratosis congenita (DKC1, Terc, Tin2)
aplastic anemia (Terc, Tert, Tin2)
idiophatic pulmonary fibrosis (Terc, Tert)
GI tract diseases (Terc,Tert)
loss of the regenerative capacity of the skin
lungs, bone marrow, intestine…
13. TTeelloommeerreess ppoowweerrffuullllyy qquuaannttiiffyy lliiffee´ss iinnssuullttss
Blackburn Blackburn & & E Eppeel,l ,N Naatuturere, ,2 2001122
# Life habits influence telomere length : smoking, exercise, obesity, nutrition
# Perceived stress as adults shortens telomeres (Epel et al., PNAS, 2004)
# Stress as children and stress suffered by the mother during pregnancy shortens
telomeres (Shalev et al, Mol Psychiatry, 2012; Entringer et al., PNAS, 2011)
# Personality disorders shorten telomeres(Elvsashagen et al., J. Affect. Disord., 2011)
14. WWee ddeevveellooppppeedd aa hhiigghhtthhrroouugghhppuutt mmeetthhoodd ttoo qquuaannttiiffyy sshhoorrtt tteelloommeerreess
1) Obtaining blood sample (5 ml) 2) HT Q-FISH 3) Confocal microscopy
6) Data analysis 5) Data processing 4) Capture of individual telomeres
Canela et al., PNAS, 2007
0 5 10 15 20
60
40
20
0
mean telomere length (kb)
frequency
Mean TL
% Short telomeres
15. Current collaborations to aasssseessss tthhee pprrooggnnoossttiicc vvaalluuee ooff tteelloommeerree lleennggtthh
Infarct, CVD
(CNIC, Madrid &
University Hospital,
Salamanca)
Fertility
(IVI, Madrid)
Bipolar & personality
dissorders
(University Hospital, Oslo)
Hepatic transplatation
tolerance
(Hospital Clínic, Barcelona)
AIDS
(Hospital Clínic,
Barcelona)
Toxicity of
breast cancer treatments
(CNIO, Madrid)
Risk of breast/ovarian
cancer (BRCA1/2 carriers)
(Familiar Cancer Consultancy
CNIO, Madrid)
16. Telomere lleennggtthh iinn ppeerrssoonnaalliizzeedd aanndd pprreevveennttiivvee mmeeddiicciinnee
INHERITED
Genetic tests: genes as risk factors for disease
but do not reflect on the environment or life habits
Telomere length: indication of the degree of
cellular aging (reflect environment, life habits)
INHERITED ENVIRONMENT
MORE POWERFUL PREDICTIONS
OF RISKS AND TIME OF ONSET
DEVELOPMENT OF
NEW TREATMENTS TO
PREVENT DISEASE
DEVELOPMENT OF
NEW TREATMENTS TO
PREVENT DISEASE
# aging is the highest risk factor for all diseases
# telomere length integrates both inheritance & life habits & environmental factors
17. Short telomeres as preditors ooff oonnsseett ooff hheerreeddiittaarryy bbrreeaasstt && oovvaarriiaann ccaanncceerr
BRCA1/BRCA2 carriers
breast/ovarian cancer
Martínez-Delgado et al., PLoS Genetics, 2011
Martínez-Delgado et al., J. Medical Genetics, 2012
Telomere length
Collaboration with Javier Benítez,
Human Cancer Genetics Group, CNIO
Age
healthy
20. telo Does telommeerraassee aaccttiivvaattiioonn ddeellaayy pphhyyssiioollooggiiccaall aaggiinngg??
TERT transgenic mice (K5-TERT)
Wild-type “Triple”
Less aging
Only minor increase in survival owing to slightly more cancer
González-Suarez et al., EMBO J. (2001)
TERT transgenic mice + increased tumor supressor genes
(Sp53+Sp16+Sp19ARF): “triple” mice
Less cancer
Less aging: better glucose tolerance, neuromuscular coordination,
bone density, skin fitness…
Longer telomeres & less DNA damage with aging
40% increase in lifespan
Tomás-Loba et al., Cell (2008)
21. IInnccrreeaasseedd ““hheeaalltthh ssppaann”” && lloonnggeevviittyy iinn TTRRIIPPLLEE mmiiccee
Overall survival Cancer-free survival
100
80
60
40
20
0
Sp53 (n=25)
Triple (p=0.003; n=6)
0 60 80 100 120 140 160 180
survival (%)
age (weeks)
+50%
Control (n=25)
100
80
60
40
20
0
Sp53 (n=49)
Triple (p<0.001; n=12)
0 60 80 100 120 140 160 180
survival (%)
age (weeks)
+40%
Control (n=49)
60
40
20
0
p=0.003
n=25
n=6
60
40
20
0
p<0.001
n=49
n=12
Control Triple
Survival at 3 years (%)
Control Triple
Survival at 3 years (%)
Tomás-Loba et al., Cell (2008)
23. WWhhaatt iiff wwee wwoouulldd ddoouubbllee hheeaalltthh ssppaann iinn hhuummaannss??
Heath-span
4400 y yeeaarsrs
Average life span (85 years)
Maximum life span (120 years)
survival
health diseases
age
Heath-span
Average life span (115 years)
Maximum life span (120 years ?)
survival
age
intervention
diseases
health
8800 y yeeaarsrs
25. TThheerraappeeuuttiicc ssttrraatteeggyy ffoorr tteelloommeerraassee aaccttiivvaattiioonn
Bernardes de Jesus et al, EMBO Mol Med (2012)
Aging is produced, at least in part, due to telomerase
deficiency in adult life.
We have used gene therapy to deliver TERT late in life (1 & 2
year old mice): gene therapy of aging.
We have used state-of-the art gene therapy vectors (AAV),
currently used in clinical trials owing to their safety: non-integrative,
non immunogenic.
More than 700 individuals have been already treated with
these vectors for different genetic diseases in clinical trials.
30. AA ssiinnggllee AAAAVV99--mmTTEERRTT ttrreeaattmmeenntt llaattee eexxtteennddss mmoouussee lliiffeessppaann
~1 yr old group
13% median lifespan
20% maximum lifespan
V.I. – Viral injection
AAV9-eGFP n=12
AAV9-mTERT n=21
Control n=33
eGFP vs mTERT
p= 0,02 (Log Rank test)
Control vs mTERT
p= 0,02 (Log Rank test)
Weeks
Percent Survival
V. I.
24%
13%
24% median lifespan
13% maximum lifespan
Weeks
Percent Survival
V. I.
~2 yrs old group
V.I. – Viral injection
AAV9-eGFP n=14
13%
20%
eGFP vs mTERT
p= 0,05 (Log Rank test)
Control vs mTERT
p= 0,007 (Log Rank test)
AAV9-mTERT n=23
Control n=25
Bernardes et al. , EMBO Molecular Medicine, 2012
39. The Telomeres & Telomerase GGrroouupp,, CCNNIIOO,, MMaaddrriidd
Christian Bär Aksinya Derevyanko Juanma Povedano Mercedes Gallardo
Bruno Bernardes
Agueda Tejera Maria Garcia Martina Stagno Miguel Foronda Paula Martinez
Ralph Schneider Gina de Bonis Nani Marion
Isabel L. Silanes
Fabian Beier
Elsa Vera
Iole Ferrara
Alicia Lemus
Nora Soberon
Ben Kumfmüller
Elisa Varela
Rosa Serrano
Ianire Garrobo
40. Effects ooff bbrreeaasstt ccaanncceerr ttrreeaattmmeenntt oonn tteelloommeerree lleennggtthh
Collaboration with Javier Benítez,
Human Cancer Genetics Group, CNIO
AC+T₁: Doxorrubicine/ cyclophosphamide + Paclitaxel
T+AC₂: Paclitaxel+ Doxorrubicine/ cyclophosphamide
T+FEC90₄: Paclitaxel+ (5-Fluoracile/Epirrubicine/ cyclophosphamide)
41. TTeelloommeerree lleennggtthh hheetteerrooggeenneeiittyy iinn hhuummaann ccaanncceerrss
basal cell carcinoma
long telomeres
short telomeres
Single cell quantitative telomere FISH
Schneider et al., unpublished
(“telomapping”)
Flores et al., G&D, 2008
58. Transient TRF1 deletion iinn aadduulltt mmoouussee ttiissssuueess ddooeess nnoott iimmppaaiirr mmoouussee vviiaabbiilliittyy
n.s
Tamoxifen diet start
point
Mice with the
phenotype
Trf1+/+ Trf1Δ/Δ
SKIN -Low cellularity of basal
layer
-Hair follicle cysts
0/4
0/4
3/4
3/4
INTESTINE -Atrophy of microvilli
-Increased mitotic
figures
0/4
0/4
0/4
4/4
BONE
MARROW
-Moderate aplasia
-Megacaryocytes with
reduced cytoplasm
0/4
0/4
1/4
4/4
García-Beccaria et al., submitted
59. TTrraannssiieenntt TTRRFF11 ddeelleettiioonn iinn aadduulltt mmoouussee ttiissssuueess ddooeess nnoott iimmppaaiirr ttiissssuuee ffuunnccttiioonn
Transient Trf1 systemic abrogation generates minor histological alterations in
Trf1+/+ Trf1Δ/Δ
200 μm 200 μm
SKIN
Normal epithelium and
hair follicle
Hair follicle cyst and
anisocaryosis
100 μm 100 μm
Low cellularity in basal skin
and normal hair follicle
100 μm
the skin (ie., low cellularity)
García-Beccaria et al., submitted
60. TTrraannssiieenntt TTRRFF11 ddeelleettiioonn iinn aadduulltt mmoouussee ttiissssuueess ddooeess nnoott iimmppaaiirr ttiissssuuee ffuunnccttiioonn
Transient Trf1 systemic abrogation generates minor histological alterations in
Trf1+/+ Trf1Δ/Δ
200 μm 200 μm
INTESTINE
Increased mitotic
figures. normal nuclei
Giant nuclei
50 μm 50 μm
n.s
Trf1+/+ Trf1Δ/Δ
450
350
250
150
50
microvilli length (pixels)
the gut (ie. normal microvilli, aberrant nuclei, increased mitosis)
García-Beccaria et al., submitted
61. TTrraannssiieenntt TTRRFF11 ddeelleettiioonn iinn aadduulltt mmoouussee ttiissssuueess ddooeess nnoott iimmppaaiirr ttiissssuuee ffuunnccttiioonn
Transient Trf1 systemic abrogation generates minor histological alterations in
BM, that do not compromise viability nor tissue function
Trf1+/+ Trf1Δ/Δ
400 μm 400 μm
*
50 μm 50 μm
BONE MARROW
50 μm
BONE MARROW
Moderate aplasia and
platelets with small cytoplasm
Normal cellularity and platelets Normal cellularity and platelets
* n.s n.s
García-Beccaria et al., submitted
64. TTRRFF11 rreeppoorrtteerr mmoouussee:: TTRRFF11--eeGGFFPP ““kknnoocckk--iinn”” mmiiccee
TRF1 endogenous locus
ATG
EGFP
ATG
Exon1
Exon2
Exon1
Exon2
neo
eGFP-TRF1 KI
Neo T
Inframe linking sequence loxP loxP
EGFP
eGFP-TRF1 KI
Neo -
Inframe linking sequence loxP
Recombinational
knock-in
+CRE
F R
eGFP-TRF1
+/+ +/KI KI/KI
eGFP-TRF1
endogenous TRF1
live visualization of telomere foci (eGFP) in a single cell nucleus
Schneider et al., Nature Communications, 2013
65. HT screening to identify compounds tthhaatt ddiissrruupptt TTRRFF11 tteelloommeerree bbiinnddiinngg
IN COLLABORATION WITH EXPERIMENTAL THERAPEUTICS PROGRAM CNIO
Screening using eGFP-Trf1ki/ki Induced Pluripotent Stem Cells (iPS)
(very high eGFP-TRF1 levels)
eGFP-Trf1 DAPI
eGFP-Trf1ki/ki
Sh-scramble ShTrf1
Positive
Control
Inhibition
Control
Treatment with
chemical library
(640
compounds)
Opera High Content
Screening system
Quantification by
High-speed
image
Analysis
Schneider et al., Nature Communications, 2013
Méndez et al., unpublished
66. HT screening to identify ccoommppoouunnddss tthhaatt ddiissrruupptt TTRRFF11 tteelloommeerree bbiinnddiinngg
IN COLLABORATION WITH EXPERIMENTAL THERAPEUTICS PROGRAM CNIO
Quantification setups
eGFP-Trf1ki/ki
LI HI LI: Low Intensity
Cut-off
Intensity (a.u.f.)
Q1 Q2 Q3
Foci with intensity ≤ cut-off
HI: High Intensity
Foci with intensity ≥ cut-off
Quartile (Q) distribution
Proof of concept
Z factor (0.5-1): high reproducibility
eGFP-Trf1ki/ki vs eGFP-Trf1ki/ki
Z**=0.75
eGFP-Trf1ki/ki vs shTrf1
Z**=0.86
Identification of hit compounds inhibiting Trf1 binding to telomeres
Méndez et al., unpublished
Control ETP-
47228
ETP-
47037
1.2
1
0.8
0.6
0.4
0.2
0
DMSO sh-TRF1 ETP-
47228
ETP-
47037
Mean e-GFP-Trf1 foci
intensity (a.u.f)
***
***
**
67. HT screening to identify compounds tthhaatt ddiissrruupptt TTRRFF11 tteelloommeerree bbiinnddiinngg
Mechanism of action: do compounds affect TRF1 binding to the
FRAP: fluorescence recovery after photobleaching of eGFP-TRF1 in
living cells
E. Varela
% and time of recovery
telomere in vivo?
68. E. Varela
1,6
1,4
1,2
1
0,8
0,6
0,4
0,2
0
FRAP oonn iinnddiivviidduuaall tteelloommeerreess ooff eeGGFFPP--TTRRFF11 iiPPSS cceellllss
0 50 100 150 200 250 300 350 400
DMSO, 11 movies
47228, 11 movies
50946, 14 movies
47361, 12 movies
Time (s) Relative fluorescence intensity
75. In conclusion: it is possible to ttaarrggeett sshheelltteerriinn pprrootteeiinnss
We targeted telomere “capping” by inhibition of TRF1
Deletion of TRF1 in lung cancer mouse models impairs lung
cancer and metastasis, independently of telomere length
Transient systemic deletion of TRF1 in adult mice does not
affect organismal viability and only has minor defects in
tissues, which are corrected upon release fromTRF1 inhibition
We found small molecules that dysrupt TRF1 binding to
telomeres in vivo
TRF1 inhibitors induce DNA damage at telomeres and impair
proliferation of iPS cells and cancer cell lines
86. SShheelltteerriinn:: tthhee pprrootteeiinn ccoommpplleexx tthhaatt pprrootteeccttss cchhrroommoossoommee eennddss
TTAGGG TTAGGG
AATCCC AATCCC
TTAGGG TTAGGG
AATCCC AATCCC
genes telomeres
genes telomeres
TTAGGG
TTAGGG
AATCCC AATCCC
TRF1
TRF2
cell death
cell senescence
aging
TTAGGG AATCCC AATCCC
Pot1
TPP1
“shelterin”
Pot1
Tin2 TPP1
Rap1
Epithelial abnormalities are characteristic of
“telomere syndromes”:
Skin hyperpigmentation
Nail dystrophy
Oral leukoplakia
More skin cancer
TPP1 is also necessary for telomerase binding to telomeres
(Tejera, Stagno d´Alcontres et al., Dev. Cell, 2010)
TPP1
Martínez & Blasco, Nature Reviews Cancer, 2011
87. We generated conditional mmoouussee mmooddeellss ffoorr TTRRFF22,, TTRRFF11,, TTPPPP11,, TTIINN22 aanndd RRAAPP11
hyperpigmentatio
n
Martínez et al., Genes & Dev (2009)
Tejera, Stagno et al., Dev Cell (2010)
Martínez et al., Nature Cell Biology (2010)
Martinez et al., Cell Reports (2013)
Martínez et al., Aging Cell (2014)
TRF1Δ⁄Δ K5-Cre
hyperpigmentation
All dead by 6 days
TRF1
TPP1 Δ⁄Δ K5-cre
All dead by 9 days
Tpp1
Pot1
Rap1D/D K5-Cre
normal survival
obesity & metabolic
syndrome
WT
RAP1
TRF1
TRF2
Tpp1
Pot1
RAP1 Tin2 TRF2
TRF2Δ⁄Δ K5-Cre
All dead by 1 day
Tin2
Tinf2 D/D-K5-Cre
All dead by 1 day
89. Permanent TRF1 deletion in mouse tissues lleeaaddss ttoo lloossss ooff ttiissssuuee
hhoommeeoossttaassiiss && rreeccaappiittuullaatteess tthhee ppaatthhoollooggiieess ooff tteelloommeerree ssyynnddrroommeess
TRF1Δ/Δ
Lack of hair follicles
Lack of sebaceus glands
Hyperpigmentation
Hyperkeratosis
Leukoplakia
Nail distrophy
TRF1flox/flox K5-Cre
Martínez et al., Genes & Dev (2009)
skin
TRF1flox/flox Mx1-Cre
Beier et al., Blood (2012)
BM failure
Cellular senescence
BM Short telomeres
TRF1lox/lox; Villin-CreERT2+/T
Schneider et al., Nature Communications (2013)
small
intestine
Colapse of villi/crypts
Apoptosis at SCs
Endoreduplication at SCs
lung
TRF1Δ/Δ KFP+/T SPC-CreERT2 +/T
Pulmonary fibrosis
Povedano et al., unpublished
90. TRF1 deletion in the BM as aa mmooddeell ffoorr DDKKCC && aappllaassttiicc aanneemmiiaa
……aanndd ffoorr tteessttiinngg tthheerraappeeuuttiicc tteelloommeerraassee aaccttiivvaattiioonn
0 5 10 15
50
40
30
20
10
Telomere length in kb
Time (w)
TRF1flox/flox
Mx1-wt (n=6)
TRF1flox/flox
Mx1-Cre
(n=8)
0 1 2 3
25
20
15
10
5
0
Survival (w) after last measurement
Percentage of telomeres <15 kb
r= -0.80
p=0.02
20
15
10
5
p=0.61
n=8
p=0.04
n=6
n=6
n=5
p=0.37
n=8
n=6
0 1 2 3
30
20
10
0
r=0.90
p=0.002
Survival (w) after last measurement
Telomere length in kb
Telomeres <15 kb
HT-Q-FISH
0
Week 0 Week 4 Week 8
Percentage of telomeres <15 kb
TRF1flox/flox
Mx1-wt
TRF1flox/floxM
x1-Cre
Fabian Beier
Beier et al., Blood (2012)
91. AAV9-TERT treatment as a therapeutic ssttrraatteeggyy ffoorr BBMM aappllaassiiaa
Christian Bär
TRF1
deletion
92. AAV9-TERT ttrreeaattmmeenntt iiss eeffffeeccttiivvee iinn ddeellaayyiinngg ddeeaatthh bbyy aappllaassttiicc aanneemmiiaa
n=4
AAV9-Tert
survival
AAV9-empty n=16
Percent p=0.0006 (Log-rank)
0 20 40 60 80 100
Christian Bär
n=31
p=0.0025 (Log-rank)
87%
55%
n=36
0 20 40 60 80 100
16
AAV9-empty
100
80
60
40
20
0
AAV9-Tert
AA related
other
% AA related death
100
80
60
40
AAV9-Tert
AAV9-empty
Days after AAV treatment
100
80
60
40
20
20
15
10
5
AAV9-Tert
AAV9-empty
0
number of AA deaths
n=4
n=16
0
Days after AAV treatment
n=31 n=36
4
27
20
93. TTeelloommeerree lleennggtthh aass aa bbiioommaarrkkeerr ooff ttooxxiicciittyy ttoo ttrreeaattmmeennttss
Sporadic breast cancer cases cancer treated (T) with taxanes (n=242)
Ti 6 m Tf 1.5 years post-T
Telomere length
Collaboration with Javier Benítez,
Human Cancer Genetics Group, CNIO
100. How to dysrupt
telomere “capping”
to kill cancer cells?
101. TTeelloommeerree lleennggtthh hheetteerrooggeenneeiittyy iinn hhuummaann ccaanncceerrss
basal cell carcinoma
long telomeres
short telomeres
Single cell quantitative telomere FISH
Schneider et al., unpublished
(“telomapping”)
Flores et al., G&D, 2008
107. TTRRFF11 rreeppoorrtteerr mmoouussee:: TTRRFF11--eeGGFFPP ““kknnoocckk--iinn”” mmiiccee
TRF1 endogenous locus
ATG
EGFP
ATG
Exon1
Exon2
Exon1
Exon2
neo
eGFP-TRF1 KI
Neo T
Inframe linking sequence loxP loxP
EGFP
eGFP-TRF1 KI
Neo -
Inframe linking sequence loxP
Recombinational
knock-in
+CRE
F R
eGFP-TRF1
+/+ +/KI KI/KI
eGFP-TRF1
endogenous TRF1
live visualization of telomere foci (eGFP) in a single cell nucleus
Schneider et al., Nature Communications, 2013
108. In conclusion: it is possible to ttaarrggeett sshheelltteerriinn pprrootteeiinnss
We targeted telomere “capping” by inhibition of TRF1
Deletion of TRF1 in lung cancer mouse models impairs lung
cancer and metastasis
Transient systemic deletion of TRF1 in adult mice does not
affect organismal viability and has minor defects in tissues,
which are corrected upon release fromTRF1 inhibition
We found small molecules that dysrupt TRF1 binding to
telomeres in vivo
We are studying these compounds
109. h Development & validation of a hiigghhtthhrroouugghhppuutt mmeetthhoodd ttoo qquuaannttiiffyy sshhoorrtt tteelloommeerreess
Canela et al., PNAS (2007)
HT-QFISH
Median telomere length (Kb)
≤20 21-30 31-40 41-50 51-60 >60
n= 16 n= 45 n= 78 n= 74 n= 32 n= 35
n= 16 n= 45 n= 78 n= 74 n= 32 n= 35
Age (years)
Q1 Q2 Q3 Q4
15
60
50
10
40
30
5
20
10
0
% short telomeres (<3kb)
≤20 21-30 31-40 41-50 51-60 >60
Age (years)
0
TThhee ppoowweerr ooff sshhoorrtt tteelloommeerreess……
SSnnyyddeerr ccaarrrriieess aa TTEERRTT mmuuttaattiioonn aassssoocciiaatteedd
ttoo aappllaassttiicc aanneemmiiaa
Chen et al., Cell ( 2012) Q5 Q6 Q7 Q8
111. IInnccrreeaasseedd ““hheeaalltthh ssppaann”” && lloonnggeevviittyy iinn TTRRIIPPLLEE mmiiccee
Overall survival Cancer-free survival
100
80
60
40
20
0
Sp53 (n=25)
Triple (p=0.003; n=6)
0 60 80 100 120 140 160 180
survival (%)
age (weeks)
+50%
Control (n=25)
100
80
60
40
20
0
Sp53 (n=49)
Triple (p<0.001; n=12)
0 60 80 100 120 140 160 180
survival (%)
age (weeks)
+40%
Control (n=49)
60
40
20
0
p=0.003
n=25
n=6
60
40
20
0
p<0.001
n=49
n=12
Control Triple
Survival at 3 years (%)
Control Triple
Survival at 3 years (%)
Tomás-Loba et al., Cell (2008)
112. o Pot1, a component off sshheelltteerriinn,, iiss mmuuttaatteedd
iinn CChhrroonniicc LLyymmpphhooccyyttiicc LLeeuukkeemmiiaa ((CCLLLL))
Carlos López-Otín Elías Campo
Miguel Foronda
Spanish Participation in the International Cancer Genome Consortium
113. FFiirrsstt ddeessccrriippttiioonn ooff sshheelltteerriinn mmuuttaattiioonnss iinn hhuummaann ccaanncceerr ((CCLLLL))
POT1
DNA binding domain
Q94R
M1L Y36N Y66* K90E Q94R Y223C S250* H266L G272V C591W
OOBB11 OOBB22
K39E I78T R137C G205D G274E L343F P475L
Splicing
N24S
NOTCH1 ~12% of CLL patients
SF3B1 ~10% of CLL patients
POT1 ~9% of CLL IGHV-unmutated patients
NOTCH1 ~12% of CLL patients
SF3B1 ~10% of CLL patients
POT1 ~9% of CLL IGHV-unmutated patients
127 exome seq
214 Sanger seq
12 different mutations (3,5%)
9/12 in the OB folds (ssDNA binding)
Prediction truncated protein
Ramsay*, Quesada*, Foronda* et al., Nature Genetics (2013)
Highlighted in Nature Reviews Cancer, “Gimme Shelter”
(C2h0a1n3g), S. “News & views”, Nature Genetics, (2013)
114. Mutations in Pot1 iinn CChhrroonniicc LLyymmpphhooccyyttiicc LLeeuukkeemmiiaa ((CCLLLL))
Human
Rat
Mouse
Opossum
Chicken
Frog
Conservation
36
F K P P Y L S K G
F K P P Y L S K G
F K P P Y V S K G
F K P P Y Q S R G
F K P P Y I S K G
F K P P Y R S K G
90 94
K I Q V Y K K E T Q G I T
K I Q V Y K N E L Q G I N
K I Q V Y K N E L Q G I N
K I Q Q Y K N E I Q G V T
K I R E Y N G Q M Q G I T
K I Q K F N D E I Q G I N
223
D I L V Y D N H V
D I L V Y D N H V
D I L V Y D N H V
D I L V Y D N H V
D V L V Y D N H V
D V L V Y D N H V
266 272 591
F H L H G G T S Y G R G I
F H L H G G T S Y G R G I
F H L H G G T S Y G R G I
F H L H G G T C Y G R G I
F H L H G G T C Y G R G I
F H L H G G T C F G R G I
M D M F P P G I
M D M I P P G I
M D M I P P G I
M Y M L P P G K
M N T L P P G R
M D T L P P R K
C
C
C
C
S
C
Y223
H266
K90
Q94
Y36
Affect
conserved
residues
Predicted to
affect
DNA binding
Ramsay*, Quesada*, Foronda* et al., Nature Genetics (2013)
Highlighted in Nature Reviews Cancer, “Gimme Shelter”
(C2h0a1n3g), S. “News & views”, Nature Genetics, (2013)
115. MMuuttaattiioonnss iinn PPoott11 iinn CCLLLL aacctt aass ddoommiinnaanntt nneeggaattiivveess
Normal binding
to telomeres
ChIP
Defective
ssDNA binding Abnormal telomere elongation
Q-FISH
Ramsay*, Quesada*, Foronda* et al., Nature Genetics (2013)
Highlighted in Nature Reviews Cancer, “Gimme Shelter”
(C2h0a1n3g), S. “News & views”, Nature Genetics, (2013)
126. A TERT based gene therapy of aging: ssiinnggllee ttrreeaattmmeenntt wwiitthh AAAAVV99--TTEERRTT
Lung
p= 0,03
n=3
AAV9-
mTERT
n=3
AAV9-
eGFP
p= 0,003
n=3
AAV9-
mTERT
n=3
AAV9-
eGFP
~ 1 yr ~2 yr
Fold changes in telomerase activity
AAV9-mTERT #1 AAV9-mTERT #2 AAV9-mTERT #3 AAV9-eGFP #1 AAV9-eGFP #2
P rRotneians (em g ) - + - 1 - 3 - 5+ 5 - 1 - 3 - 5+ 5 - -1 - 3 + 5 5 - - 1 - 3 + 5 -5 - 1- +3 5 5
Could be used in the treatment of some cases of
pulmonary fibrosis caused by telomerase mutations
Bernardes et al. , EMBO Molecular Medicine, 2012
Lung (2-year old group)
H
el
a
IC
3 3
3 months PI
Could be used in the treatment of some cases of
pulmonary fibrosis caused by telomerase mutations
127. eeGGFFPP--TTRRFF11hhiigghh iiPPSS cceellllss aarree mmoorree pplluurriippootteenntt ((cchhiimmeerraass))
D
0 to 30% chimerism
30 to 70% chimerism
70 to100% chimerism
57 embr.
2 pups
57 embr.
4 pups
61 embr.
2 pups
66 embr.
17 pups
low high low high
eGFP-TRF1+/+ eGFP-TRF1+/KI
10
8
6
4
2
0
(% of transfered embryos)
Chimeras
Generation of chimeras
iPS cells (C57BL/6J x agouti) with Hsd:ICR(CD-1) morulae
iPS clone Embryos
Injected
Cells
injected
Embryos
Transfered
Pups born Chimeras
iPS eGFP-TRF1+/+ pool cl. 2-8/1-5 LOW 57 5 to 6 57 2 1M (50%)
iPS eGFP-TRF1+/+ pool cl. 2-8/1-5 HIGH 57 5 to 6 57 4+ 1 dead 1M (40%) 1F (30%)
iPS eGFP-TRF1+/KI pool cl. 2-1/1-6 LOW 61 5 to 6 61 2+ 1dead 0
iPS eGFP-TRF1+/KI pool cl. 2-1/1-6 HIGH 66 5 to 6 66 17+ 3 dead 1M (80%) 1F (70%) 1M (50%)
1M (40%) 1F (30%)
iPS eGFP-TRF1+/+ iPS eGFP-TRF1+/KI
iPS eGFP-TRF1KI/KI
Schneider et al., Nature Communications, 2013
128. TRF1 is essential for bbootthh aadduulltt sstteemm cceellllss aanndd pplluurriippootteenntt sstteemm cceellllss
3 day old
TRF1D/D K5-Cre wildtype
1.14 g 2.53 g
TRF1D/D K5-Cre
hyperpigmentation
basal cell layer
hair
follicles
primitive hair
follicles
primitive hair
follicles
wildtype TRF1D/D K5-Cre
Lack of hair follicle
stem cells!
Martínez et al., Genes & Dev (2009)
129. Telomere fragility Telomere fragility
80
60
40
20
0
Multitelomeric signals per metaphase
Wild type
Knock-out
Trf1 Tpp1 Rap1
……bbuutt ddooeess nnoott ccoorrrreellaattee wwiitthh ffrraaggiilliittyy
MTS: multitelomeric signals
(replication fork stalling at telomeres)
Martínez et al., Genes & Dev (2009)
Tejera, Stagno et al., Dev Cell (2010)
Martínez et al., Nature Cell Biology (2010)
Martinez et al., Cell Reports (2013)
Martínez et al., Aging Cell (2014)
130. Mouse models to uunnddeerrssttaanndd tthhee rroollee ooff tteelloommeerraassee iinn ccaanncceerr && aaggiinngg
Blasco et al., Science (1995)
Blasco, Lee, et al., Cell (1997)
Lee, Blasco, et al., Nature (1998)
Telomerase inactivation models
Telomerase-deficient mice (Terc-/-)
Stem cell dysfunction
Decreased regenerative capacity
Diaseases associated with aging including
heart dysfuction
Less cancer
González-Suarez et al., Nat Genet (2000)
Flores et al., Science (2005)
Telomerase activation models
TERT transgenic mice (K5-TERT)
Less aging
Slightly more cancer
TERT Tg+ Sp53+Sp16+Sp19ARF (“triple”)
Delayed cancer, delayed aging & 40%
increase in lifespan
Wild-type “Triple”
González-Suarez et al., EMBO J. (2001)
Tomás-Loba et al, Cell (2008)
142. ETP-00047363 ETP-00047228 8h
24h
Het
C DMSO
Het
C DMSO
Het
C DMSO
ETP-00047361
ETP-00041108
Het
C DMSO
Het
C DMSO
ETP-00047037
Mean fluorescence intensity
(Normalized to Control DMSO)
Mean fluorescence intensity
(Normalized to Control DMSO)
IIddeennttiiffiiccaattiioonn ooff aa ttoottaall ooff 2200--hhiittss
144. rem Increased remooddeelliinngg ppoosstt MMII aassssoocciiaatteedd ttoo TTEERRTT eexxpprreessssiioonn
ECM
rel. expression
I: infarct
IT: infarct + Tert treatment
AAV9
empty
AAV9
Tert
rel. expression
down up
FDR<10e-04
ECM
I IT
p=0.047
n=9
FGFR
n=9
FDR=0.075
FGFR
2.5
2.0
1.5
1.0
0.5
I IT
AAV9
empty
TGFß
AAV9
Tert
TGFß
rel. expression
down up
Fold change mRNA level
Fgfr3
2.5
2.0
1.5
1.0
0.5
0.0
p=0.002
n=6
n=6
AAV9-empty
AAV9-Tert
AAV9
empty
AAV9
Tert
down up
FDR=0.085
I IT
0.0
Fold change mRNA level
Bmprb1
Bär/Bernardes, unpublished
Editor's Notes
TRF1 downregulation is maintained in the subcutaneous tumors
Trf1-dowregulated subcutaneous tumors recapitulate Trf1-deficient tumors phenotype: with higher DNA damage etc
-decir que hay diferente eficacia de engraftment dependiente del clon (e independiente de los niveles de TRF1). (poner imágenes representativas X-gal staining).
-pero que a igual nivel de engraftment un KO ha presentado menor crecimiento que 5 wts (poner fotos representativas del pulmon ko 16 835 y del wt 16 826 y/o 16 833 y 16 825). Falta confirmar con más KOs. Tenemos 2 KO más que murieron pero fueron DIC (sin muestra).
Decir que la downregulacion se hace en el adulto y que es transient.