Cancer cells demonstrate altered cellular metabolism characterized by increased glucose uptake and fermentation via glycolysis, even in the presence of oxygen. This phenomenon, called the Warburg effect, is a general property of growing cells that becomes permanent in cancer cells. Tumor cells are also able to evade cell death pathways and grow indefinitely without triggering autophagy or entering replicative senescence. They stimulate angiogenesis to obtain nutrients and oxygen and metastasize through a series of steps involving local invasion, intravasation, transport, extravasation, and micrometastasis formation. Cancer cells evade immune surveillance through a variety of mechanisms and express antigens that induce an ineffective immune response or promote tumor growth.
This document discusses genetic diseases, including their causes and transmission patterns. It covers several key points:
1) Genetic diseases can be inherited from parents or caused by mutations in somatic cells. They include disorders caused by single gene mutations as well as chromosomal abnormalities.
2) Single gene mutations include point mutations and frameshifts, and can cause diseases like cystic fibrosis or phenylketonuria. These mutations may be dominant or recessive.
3) Chromosomal abnormalities include changes in number, like trisomies, or structure, like translocations. They can cause conditions such as Down syndrome. Chromosomal imbalances are generally more severe than single gene mutations.
This document provides an overview of neoplasia (new growth) and cancer. It discusses how cancer is caused by genetic mutations, and how cancer cells acquire properties called cancer hallmarks that allow for abnormalities in cell growth, invasion and metastasis. These properties are driven by mutations in cancer genes like oncogenes and tumor suppressor genes. The document outlines the characteristics of benign and malignant tumors, risk factors for cancer like age, environment and genetics, common precursor lesions, and describes the multistep process of carcinogenesis and the hallmarks of cancer like sustained proliferation and evading growth suppression. Key cancer genes discussed are cyclins/CDKs that regulate the cell cycle, RB which suppresses the cell cycle, and TP53 which
The document discusses various methods of immune regulation, including both immunosuppression and immunopotentiation. It describes several classes of immunosuppressive drugs like corticosteroids, thiopurines, alkylating agents, and monoclonal antibodies that can suppress the immune system. The document also discusses methods to potentiate the immune response through cytokines, adoptive immunotherapy, or vaccination. It outlines several immunological assays and techniques used to measure antibodies, cytokines, complement levels, and detect DNA sequences for diagnostic purposes.
Cell injury and Cellular Adaptation: PathologyHarshit Jadav
This document discusses various types of cell injury, including reversible and irreversible injury. It outlines several causes of cell injury, such as hypoxia, physical agents, chemicals/drugs, microbial agents, immunologic agents, and nutritional derangements. The document also discusses various cellular adaptations that cells undergo in response to stress, including atrophy, hypertrophy, hyperplasia, metaplasia, and dysplasia. Overall, the document provides an overview of the different forms of cell injury, causes of injury, and adaptive cellular responses.
This document summarizes different types of cellular adaptations to stress, including hypertrophy, hyperplasia, atrophy, metaplasia, and cellular aging. It describes hypertrophy as an increase in cell size without cell division. Hyperplasia is an increase in cell number through cell proliferation. Atrophy is a shrinkage in cell size due to loss of cell substance. Metaplasia is the replacement of one adult cell type with another. Cellular aging results from a progressive decline in cell lifespan and function over time.
The cell cycle is a series of events that leads to cell duplication and division. It consists of four main phases - G1 phase where the cell grows, S phase where DNA is replicated, G2 phase where the cell prepares for division, and M phase where mitosis and cytokinesis occur resulting in two daughter cells. Progress through the cell cycle phases is tightly regulated by cyclin-dependent kinases and other proteins to ensure accurate copying and distribution of genetic material between daughter cells. Deregulation of cell cycle control can lead to cancer if damaged DNA is not detected and repaired properly.
Cell injury, adaptation, and death can occur through various stimuli and stresses. Cells may undergo reversible or irreversible changes. Reversible changes include cellular adaptation through hypertrophy, hyperplasia, and metaplasia to stressors. Irreversible changes result in cellular atrophy and eventually cell death through necrosis or apoptosis. The morphology of reversible injury includes cellular swelling, fatty change, and changes to organelles. Necrosis is the degradative process of cell death where cellular contents are digested by enzymes.
Basic principles of cell injury and adaptationshivangimistry3
This document provides information on basic principles of cell injury and adaptation. It discusses various types of cellular adaptations including hypertrophy, hyperplasia, atrophy, metaplasia, and dysplasia. It also outlines several mechanisms of pathogenesis of cell injury including depletion of ATP, damage to mitochondria, influx of calcium, oxidative stress, defects in cell membrane permeability, and damage to DNA and proteins. Finally, it discusses various forms of intracellular accumulation that can occur including fatty change, cholesterol, proteins, glycogen, and pigments.
This document discusses genetic diseases, including their causes and transmission patterns. It covers several key points:
1) Genetic diseases can be inherited from parents or caused by mutations in somatic cells. They include disorders caused by single gene mutations as well as chromosomal abnormalities.
2) Single gene mutations include point mutations and frameshifts, and can cause diseases like cystic fibrosis or phenylketonuria. These mutations may be dominant or recessive.
3) Chromosomal abnormalities include changes in number, like trisomies, or structure, like translocations. They can cause conditions such as Down syndrome. Chromosomal imbalances are generally more severe than single gene mutations.
This document provides an overview of neoplasia (new growth) and cancer. It discusses how cancer is caused by genetic mutations, and how cancer cells acquire properties called cancer hallmarks that allow for abnormalities in cell growth, invasion and metastasis. These properties are driven by mutations in cancer genes like oncogenes and tumor suppressor genes. The document outlines the characteristics of benign and malignant tumors, risk factors for cancer like age, environment and genetics, common precursor lesions, and describes the multistep process of carcinogenesis and the hallmarks of cancer like sustained proliferation and evading growth suppression. Key cancer genes discussed are cyclins/CDKs that regulate the cell cycle, RB which suppresses the cell cycle, and TP53 which
The document discusses various methods of immune regulation, including both immunosuppression and immunopotentiation. It describes several classes of immunosuppressive drugs like corticosteroids, thiopurines, alkylating agents, and monoclonal antibodies that can suppress the immune system. The document also discusses methods to potentiate the immune response through cytokines, adoptive immunotherapy, or vaccination. It outlines several immunological assays and techniques used to measure antibodies, cytokines, complement levels, and detect DNA sequences for diagnostic purposes.
Cell injury and Cellular Adaptation: PathologyHarshit Jadav
This document discusses various types of cell injury, including reversible and irreversible injury. It outlines several causes of cell injury, such as hypoxia, physical agents, chemicals/drugs, microbial agents, immunologic agents, and nutritional derangements. The document also discusses various cellular adaptations that cells undergo in response to stress, including atrophy, hypertrophy, hyperplasia, metaplasia, and dysplasia. Overall, the document provides an overview of the different forms of cell injury, causes of injury, and adaptive cellular responses.
This document summarizes different types of cellular adaptations to stress, including hypertrophy, hyperplasia, atrophy, metaplasia, and cellular aging. It describes hypertrophy as an increase in cell size without cell division. Hyperplasia is an increase in cell number through cell proliferation. Atrophy is a shrinkage in cell size due to loss of cell substance. Metaplasia is the replacement of one adult cell type with another. Cellular aging results from a progressive decline in cell lifespan and function over time.
The cell cycle is a series of events that leads to cell duplication and division. It consists of four main phases - G1 phase where the cell grows, S phase where DNA is replicated, G2 phase where the cell prepares for division, and M phase where mitosis and cytokinesis occur resulting in two daughter cells. Progress through the cell cycle phases is tightly regulated by cyclin-dependent kinases and other proteins to ensure accurate copying and distribution of genetic material between daughter cells. Deregulation of cell cycle control can lead to cancer if damaged DNA is not detected and repaired properly.
Cell injury, adaptation, and death can occur through various stimuli and stresses. Cells may undergo reversible or irreversible changes. Reversible changes include cellular adaptation through hypertrophy, hyperplasia, and metaplasia to stressors. Irreversible changes result in cellular atrophy and eventually cell death through necrosis or apoptosis. The morphology of reversible injury includes cellular swelling, fatty change, and changes to organelles. Necrosis is the degradative process of cell death where cellular contents are digested by enzymes.
Basic principles of cell injury and adaptationshivangimistry3
This document provides information on basic principles of cell injury and adaptation. It discusses various types of cellular adaptations including hypertrophy, hyperplasia, atrophy, metaplasia, and dysplasia. It also outlines several mechanisms of pathogenesis of cell injury including depletion of ATP, damage to mitochondria, influx of calcium, oxidative stress, defects in cell membrane permeability, and damage to DNA and proteins. Finally, it discusses various forms of intracellular accumulation that can occur including fatty change, cholesterol, proteins, glycogen, and pigments.
This is a presentation on the topic of Adaptations, Cell injury and cell death, prepared by Dr Ashish Jawarkar, he is MD in pathology and a teacher at Parul institute of Medical sciences and research Vadodara.
Cell injury occurs when cells can no longer maintain homeostasis or adapt to stress. There are two types of cell injury: reversible and irreversible. Reversible injury allows cells to return to normal after stress is removed, while irreversible injury leads to cell death through necrosis or apoptosis. Causes of cell injury include hypoxia, chemicals, physical agents, infections, immunologic reactions, genetics, and nutrition. Mechanisms of injury involve depletion of ATP, mitochondrial damage, calcium dysregulation, oxidative stress, and membrane damage.
Angiogenesis is the formation of new blood vessels from pre-existing vessels. It involves sprouting, splitting, and remodeling of existing vessels. It supplies oxygen and nutrients and removes waste. Tumors stimulate angiogenesis to grow beyond 2mm3 by producing angiogenic factors like VEGF. Angiogenesis inhibitors like endostatin can restrict tumor growth. Anti-angiogenic therapies cut off the tumor blood supply, while vascular disrupting agents directly damage existing tumor vessels.
Metaplasia is a reversible change where one adult cell type replaces another in response to stress. For example, in smokers the ciliated trachea cells are often replaced with squamous cells. This change arises from the reprogramming of stem cells due to signals from cytokines, growth factors and the extracellular matrix. If the stress persists, metaplasia can predispose the tissue to malignant transformation.
This document discusses various types of cellular adaptations: atrophy, hypertrophy, hyperplasia, metaplasia, dysplasia. Atrophy is a reduction in cell size and number. Hypertrophy is an increase in cell size but not number. Hyperplasia is an increase in cell number. Metaplasia is a change from one adult cell type to another. Dysplasia refers to abnormal cell shapes and sizes that can progress to cancer. Cellular adaptations provide clues for pathologists to diagnose disease.
Cell injury , cell death and adaptation mdc 2021aliya yasir
This document discusses cell injury, cell death, and adaptation. It defines pathology as the study of structural, biochemical, and functional changes in cells using various techniques. Cell injury occurs when cells are exposed to damaging stimuli that exceed their limits of response. This can lead to either reversible cell injury or irreversible cell injury resulting in cell death via necrosis or apoptosis. The document describes various causes of cell injury and the morphological features and patterns of necrosis.
This document summarizes cellular pathology by discussing normal cell structure and function, as well as how cells adapt, become injured, and die in response to stress or disease. It states that understanding normal cells is crucial to appreciating abnormalities and outlines the basic organelles shared by most cells, including the plasma membrane, nucleus, mitochondria, endoplasmic reticulum, ribosomes, Golgi apparatus, lysosomes, and peroxisomes. It then defines homeostasis, cellular adaptation, reversible and irreversible cell injury, and the types of cell death including necrosis and apoptosis.
Cellular Adaptation
as cells encounter stresses they undergo functional or structural adaptations to maintain viability / homeostasis.
Injury - altered homeostasis
if limits of the adaptive response are exceeded or if adaptation not possible, a sequence of events called cell injury occurs.
Reversible Cell Injury
removal of stress results in complete restoration of structural & functional integrity.
b) Irreversible Cell Injury / Cell Death
if stimulus persists or is severe enough from the start, the cell suffers irreversible cell injury and death.
2 main morphologic patterns: necrosis & apoptosis.
Adaptations are reversible changes in the size, number, phenotype, metabolic activity, or functions of cells in response to changes in their environment.
Physiologic adaptations are responses of cells to normal stimulation by hormones or endogenous chemical mediators
Pathologic adaptations are responses to stress that allow cells to modulate their structure and function and thus escape injury.
Hypertrophy refers to an increase in the size of cells, that results in an increase in the size of the affected organ
The hypertrophied organ has no new cells, just larger cells.
Types:
a) physiologic b) pathologic
Causes:
a) increased functional demand b) hormonal stimulation
The document discusses various types of cellular adaptation:
1. Hypertrophy is an increase in cell size without an increase in cell number. Examples given include muscle and cardiac hypertrophy.
2. Atrophy is a decrease in cell size due to loss of cell substances. It can be caused by decreased workload, loss of innervation, or inadequate nutrition.
3. Hyperplasia is an increase in cell number, leading to organ or tissue enlargement. It can be physiological like endometrial growth, or pathological like prostate enlargement.
4. Metaplasia is a reversible change from one differentiated cell type to another in response to stimuli. Examples given include squamous metaplasia in the
1. Cells actively control their environment and internal conditions through homeostasis, but can undergo adaptation or injury in response to stresses.
2. If injury is too severe, it leads to irreversible injury and cell death. Common causes of cell injury include hypoxia, chemicals, physical agents, infections, and genetics.
3. In response to injury, cells exhibit general biochemical mechanisms like ATP depletion, mitochondrial damage, calcium imbalance, and free radical generation, which can damage cells through lipid peroxidation, DNA fragmentation, and protein crosslinking if not neutralized.
Adaptation of cellular growth & differentiationHrudi Sahoo
This document discusses the adaptation of cellular growth and differentiation in response to environmental stressors. It describes several mechanisms of adaptation, including altered cell surface receptor binding and protein synthesis. Adaptive disorders that can occur include atrophy (shrinkage), hypertrophy (enlargement), hyperplasia (increased cell number), metaplasia (cell type transformation), and dysplasia (abnormal cell development). Metaplasia can be epithelial or mesenchymal, and dysplasia can progress to carcinoma if the stimulus is not removed. Overall, the document outlines how cells can adapt their size, number, and type in response to physiological or pathological stimuli.
This document discusses mechanisms of cell injury. It describes how the cellular response to injury depends on factors like the nature, duration and severity of the injury. Small or brief injuries may cause reversible injury, while larger or more prolonged injuries can result in immediate or slow irreversible injury. The consequences also depend on the type, state and adaptability of the injured cell. Several mechanisms can cause cell injury, including depletion of ATP, mitochondrial damage, influx of calcium, and oxidative stress. Specific patterns of tissue necrosis are also described such as coagulative, liquefactive, gangrenous and caseous necrosis.
Homeostasis, feedback mechanism,cellular adaptations
cell injry..etiology...types and its pathogenesis..
morphology of cellinjury
necrosis
calcification
The document discusses various types of intracellular accumulations and pathologic calcification. It defines three categories of intracellular accumulations: (1) a normal cellular constituent accumulated in excess, (2) an abnormal substance that is either exogenous or endogenous, and (3) a pigment. It then describes specific examples of accumulations including lipids, cholesterol, proteins, glycogen, pigments, and minerals. It also discusses two types of pathologic calcification: dystrophic calcification which occurs in areas of necrosis and metastatic calcification which may occur in normal tissues with hypercalcemia.
This document discusses various cellular adaptations including physiological and pathological adaptations. It describes physiological adaptations like hypertrophy and hyperplasia that occur in response to increased needs. Pathological adaptations include atrophy, metaplasia, dysplasia, and cancerous changes. Atrophy is a reduction in cell size and number. Hypertrophy is an increased cell size while hyperplasia is an increased cell number. Metaplasia is the change of one cell type to another. Dysplasia shows disordered cellular development with potentially pre-cancerous changes. Examples and causes of each adaptation are provided along with morphological features.
This document outlines different types of cell injury and death. It begins by defining cell injury as occurring when stress exceeds a cell's ability to adapt. Reversible cell injury involves swelling while irreversible injury involves membrane damage, ultimately leading to cell death via either necrosis or apoptosis. Necrosis is unprogrammed cell death from pathology, resulting in inflammation, while apoptosis is genetically programmed single-cell death without inflammation. Various patterns of necrosis are described, including coagulative, liquefactive, and caseous necrosis. Apoptosis involves cell and nuclear shrinkage followed by organized nuclear fragmentation and removal of apoptotic bodies by macrophages.
This document discusses various cellular adaptations and injury. It defines atrophy, hypertrophy, hyperplasia, and metaplasia. Atrophy is a decrease in cell size and number. Hypertrophy is an increase in cell size. Hyperplasia is an increase in cell number. Metaplasia is the replacement of one cell type with another. Examples of each type of adaptation are given, including how squamous cell metaplasia in smokers replaces normal trachea and bronchial cells, and how warts represent skin hyperplasia.
This document discusses cell injury and pathogenesis. It defines cell injury as stress encountered by a cell due to changes in its internal or external environment. The mechanisms of cell injury include free radical formation, hypoxia and ATP depletion, and disruption of calcium homeostasis. Pathogenesis of cell injury can be reversible or irreversible. Reversible injury includes decreased ATP generation and damage to the plasma membrane, while irreversible injury involves membrane damage, hydrolytic enzyme damage, and damage from physical forces like radiation. Chemical injury can directly damage cell components or poison cellular processes like oxidative phosphorylation.
This document discusses various cellular adaptations that may occur in response to injury or stress, including hyperplasia, hypertrophy, atrophy, metaplasia, and intracellular accumulations. Hyperplasia is an increase in cell number, hypertrophy is an increase in cell size, and atrophy is a decrease in cell size. Metaplasia is a reversible change where one mature cell type replaces another. Cells may accumulate lipids, proteins, glycogen, or pigments like lipofuscin, melanin, or hemosiderin. Calcification can be dystrophic in nonviable tissue or metastatic in viable tissue during hypercalcemia. These adaptations can be physiologic or pathologic responses to stressors or
Robbins Chapter 1.. Cell as a unit of health and diseaseAshish Jawarkar
The document provides an overview of key cellular structures and functions, including the genome, plasma membrane, organelles, cellular communication, the extracellular matrix, cell division, and stem cells. It discusses how cells maintain essential housekeeping functions and how differentiation occurs at the epigenetic level despite all cells containing the same genetic material. Stem cells are described as being able to both self-renew and differentiate into specialized cell types to replace damaged or aging cells.
The document outlines the eight hallmarks of cancer that enable tumor growth and metastatic spread. These hallmarks include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprogramming energy metabolism, and evading immune destruction. The hallmarks represent biological capabilities that are acquired during the development and progression of cancer and provide an organizing framework for understanding the complexities of the disease.
Cancer is mainly caused by the conversion of proto-oncogenes into oncogenes. The process is known as oncogenesis.
This slide will help to get an idea about oncogenesis and also the proto-oncogenes which get converted.
This is a presentation on the topic of Adaptations, Cell injury and cell death, prepared by Dr Ashish Jawarkar, he is MD in pathology and a teacher at Parul institute of Medical sciences and research Vadodara.
Cell injury occurs when cells can no longer maintain homeostasis or adapt to stress. There are two types of cell injury: reversible and irreversible. Reversible injury allows cells to return to normal after stress is removed, while irreversible injury leads to cell death through necrosis or apoptosis. Causes of cell injury include hypoxia, chemicals, physical agents, infections, immunologic reactions, genetics, and nutrition. Mechanisms of injury involve depletion of ATP, mitochondrial damage, calcium dysregulation, oxidative stress, and membrane damage.
Angiogenesis is the formation of new blood vessels from pre-existing vessels. It involves sprouting, splitting, and remodeling of existing vessels. It supplies oxygen and nutrients and removes waste. Tumors stimulate angiogenesis to grow beyond 2mm3 by producing angiogenic factors like VEGF. Angiogenesis inhibitors like endostatin can restrict tumor growth. Anti-angiogenic therapies cut off the tumor blood supply, while vascular disrupting agents directly damage existing tumor vessels.
Metaplasia is a reversible change where one adult cell type replaces another in response to stress. For example, in smokers the ciliated trachea cells are often replaced with squamous cells. This change arises from the reprogramming of stem cells due to signals from cytokines, growth factors and the extracellular matrix. If the stress persists, metaplasia can predispose the tissue to malignant transformation.
This document discusses various types of cellular adaptations: atrophy, hypertrophy, hyperplasia, metaplasia, dysplasia. Atrophy is a reduction in cell size and number. Hypertrophy is an increase in cell size but not number. Hyperplasia is an increase in cell number. Metaplasia is a change from one adult cell type to another. Dysplasia refers to abnormal cell shapes and sizes that can progress to cancer. Cellular adaptations provide clues for pathologists to diagnose disease.
Cell injury , cell death and adaptation mdc 2021aliya yasir
This document discusses cell injury, cell death, and adaptation. It defines pathology as the study of structural, biochemical, and functional changes in cells using various techniques. Cell injury occurs when cells are exposed to damaging stimuli that exceed their limits of response. This can lead to either reversible cell injury or irreversible cell injury resulting in cell death via necrosis or apoptosis. The document describes various causes of cell injury and the morphological features and patterns of necrosis.
This document summarizes cellular pathology by discussing normal cell structure and function, as well as how cells adapt, become injured, and die in response to stress or disease. It states that understanding normal cells is crucial to appreciating abnormalities and outlines the basic organelles shared by most cells, including the plasma membrane, nucleus, mitochondria, endoplasmic reticulum, ribosomes, Golgi apparatus, lysosomes, and peroxisomes. It then defines homeostasis, cellular adaptation, reversible and irreversible cell injury, and the types of cell death including necrosis and apoptosis.
Cellular Adaptation
as cells encounter stresses they undergo functional or structural adaptations to maintain viability / homeostasis.
Injury - altered homeostasis
if limits of the adaptive response are exceeded or if adaptation not possible, a sequence of events called cell injury occurs.
Reversible Cell Injury
removal of stress results in complete restoration of structural & functional integrity.
b) Irreversible Cell Injury / Cell Death
if stimulus persists or is severe enough from the start, the cell suffers irreversible cell injury and death.
2 main morphologic patterns: necrosis & apoptosis.
Adaptations are reversible changes in the size, number, phenotype, metabolic activity, or functions of cells in response to changes in their environment.
Physiologic adaptations are responses of cells to normal stimulation by hormones or endogenous chemical mediators
Pathologic adaptations are responses to stress that allow cells to modulate their structure and function and thus escape injury.
Hypertrophy refers to an increase in the size of cells, that results in an increase in the size of the affected organ
The hypertrophied organ has no new cells, just larger cells.
Types:
a) physiologic b) pathologic
Causes:
a) increased functional demand b) hormonal stimulation
The document discusses various types of cellular adaptation:
1. Hypertrophy is an increase in cell size without an increase in cell number. Examples given include muscle and cardiac hypertrophy.
2. Atrophy is a decrease in cell size due to loss of cell substances. It can be caused by decreased workload, loss of innervation, or inadequate nutrition.
3. Hyperplasia is an increase in cell number, leading to organ or tissue enlargement. It can be physiological like endometrial growth, or pathological like prostate enlargement.
4. Metaplasia is a reversible change from one differentiated cell type to another in response to stimuli. Examples given include squamous metaplasia in the
1. Cells actively control their environment and internal conditions through homeostasis, but can undergo adaptation or injury in response to stresses.
2. If injury is too severe, it leads to irreversible injury and cell death. Common causes of cell injury include hypoxia, chemicals, physical agents, infections, and genetics.
3. In response to injury, cells exhibit general biochemical mechanisms like ATP depletion, mitochondrial damage, calcium imbalance, and free radical generation, which can damage cells through lipid peroxidation, DNA fragmentation, and protein crosslinking if not neutralized.
Adaptation of cellular growth & differentiationHrudi Sahoo
This document discusses the adaptation of cellular growth and differentiation in response to environmental stressors. It describes several mechanisms of adaptation, including altered cell surface receptor binding and protein synthesis. Adaptive disorders that can occur include atrophy (shrinkage), hypertrophy (enlargement), hyperplasia (increased cell number), metaplasia (cell type transformation), and dysplasia (abnormal cell development). Metaplasia can be epithelial or mesenchymal, and dysplasia can progress to carcinoma if the stimulus is not removed. Overall, the document outlines how cells can adapt their size, number, and type in response to physiological or pathological stimuli.
This document discusses mechanisms of cell injury. It describes how the cellular response to injury depends on factors like the nature, duration and severity of the injury. Small or brief injuries may cause reversible injury, while larger or more prolonged injuries can result in immediate or slow irreversible injury. The consequences also depend on the type, state and adaptability of the injured cell. Several mechanisms can cause cell injury, including depletion of ATP, mitochondrial damage, influx of calcium, and oxidative stress. Specific patterns of tissue necrosis are also described such as coagulative, liquefactive, gangrenous and caseous necrosis.
Homeostasis, feedback mechanism,cellular adaptations
cell injry..etiology...types and its pathogenesis..
morphology of cellinjury
necrosis
calcification
The document discusses various types of intracellular accumulations and pathologic calcification. It defines three categories of intracellular accumulations: (1) a normal cellular constituent accumulated in excess, (2) an abnormal substance that is either exogenous or endogenous, and (3) a pigment. It then describes specific examples of accumulations including lipids, cholesterol, proteins, glycogen, pigments, and minerals. It also discusses two types of pathologic calcification: dystrophic calcification which occurs in areas of necrosis and metastatic calcification which may occur in normal tissues with hypercalcemia.
This document discusses various cellular adaptations including physiological and pathological adaptations. It describes physiological adaptations like hypertrophy and hyperplasia that occur in response to increased needs. Pathological adaptations include atrophy, metaplasia, dysplasia, and cancerous changes. Atrophy is a reduction in cell size and number. Hypertrophy is an increased cell size while hyperplasia is an increased cell number. Metaplasia is the change of one cell type to another. Dysplasia shows disordered cellular development with potentially pre-cancerous changes. Examples and causes of each adaptation are provided along with morphological features.
This document outlines different types of cell injury and death. It begins by defining cell injury as occurring when stress exceeds a cell's ability to adapt. Reversible cell injury involves swelling while irreversible injury involves membrane damage, ultimately leading to cell death via either necrosis or apoptosis. Necrosis is unprogrammed cell death from pathology, resulting in inflammation, while apoptosis is genetically programmed single-cell death without inflammation. Various patterns of necrosis are described, including coagulative, liquefactive, and caseous necrosis. Apoptosis involves cell and nuclear shrinkage followed by organized nuclear fragmentation and removal of apoptotic bodies by macrophages.
This document discusses various cellular adaptations and injury. It defines atrophy, hypertrophy, hyperplasia, and metaplasia. Atrophy is a decrease in cell size and number. Hypertrophy is an increase in cell size. Hyperplasia is an increase in cell number. Metaplasia is the replacement of one cell type with another. Examples of each type of adaptation are given, including how squamous cell metaplasia in smokers replaces normal trachea and bronchial cells, and how warts represent skin hyperplasia.
This document discusses cell injury and pathogenesis. It defines cell injury as stress encountered by a cell due to changes in its internal or external environment. The mechanisms of cell injury include free radical formation, hypoxia and ATP depletion, and disruption of calcium homeostasis. Pathogenesis of cell injury can be reversible or irreversible. Reversible injury includes decreased ATP generation and damage to the plasma membrane, while irreversible injury involves membrane damage, hydrolytic enzyme damage, and damage from physical forces like radiation. Chemical injury can directly damage cell components or poison cellular processes like oxidative phosphorylation.
This document discusses various cellular adaptations that may occur in response to injury or stress, including hyperplasia, hypertrophy, atrophy, metaplasia, and intracellular accumulations. Hyperplasia is an increase in cell number, hypertrophy is an increase in cell size, and atrophy is a decrease in cell size. Metaplasia is a reversible change where one mature cell type replaces another. Cells may accumulate lipids, proteins, glycogen, or pigments like lipofuscin, melanin, or hemosiderin. Calcification can be dystrophic in nonviable tissue or metastatic in viable tissue during hypercalcemia. These adaptations can be physiologic or pathologic responses to stressors or
Robbins Chapter 1.. Cell as a unit of health and diseaseAshish Jawarkar
The document provides an overview of key cellular structures and functions, including the genome, plasma membrane, organelles, cellular communication, the extracellular matrix, cell division, and stem cells. It discusses how cells maintain essential housekeeping functions and how differentiation occurs at the epigenetic level despite all cells containing the same genetic material. Stem cells are described as being able to both self-renew and differentiate into specialized cell types to replace damaged or aging cells.
The document outlines the eight hallmarks of cancer that enable tumor growth and metastatic spread. These hallmarks include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprogramming energy metabolism, and evading immune destruction. The hallmarks represent biological capabilities that are acquired during the development and progression of cancer and provide an organizing framework for understanding the complexities of the disease.
Cancer is mainly caused by the conversion of proto-oncogenes into oncogenes. The process is known as oncogenesis.
This slide will help to get an idea about oncogenesis and also the proto-oncogenes which get converted.
This document provides an overview of cancer, including:
1) Cancer is caused by the accumulation of genetic damage over time that leads to uncontrolled cell growth and proliferation. This "multi-hit" model involves mutations in oncogenes and tumor suppressor genes.
2) Cancer cells exhibit altered growth signaling, immortality, invasion/metastasis, and evasion of apoptosis. Tumor progression involves additional mutations that increase aggressiveness.
3) Diagnosis involves examining tissue morphology and karyotyping to identify abnormal cancer cell characteristics. Advanced tumors develop blood vessels to grow larger than 2mm.
This document provides an overview of cancer biology. It discusses how cancer is caused by the accumulation of genetic mutations over time that disrupt normal cell growth regulation. Key points covered include: the genetic and molecular basis of cancer; common properties of cancer cells like uncontrolled growth; the role of oncogenes and tumor suppressor genes; how mutations in growth factors, receptors, and cell cycle regulators can cause cancer; and the multi-hit model of carcinogenesis. The document also examines specific cancer-causing mutations and molecular mechanisms.
This document provides an overview of cancer biology. It discusses how cancer is caused by the accumulation of genetic damage over time, leading to gain-of-function mutations in oncogenes and loss of function in tumor suppressor genes. This disrupts normal cell growth pathways. Cancer cells exhibit uncontrolled growth, loss of differentiation, ability to invade and metastasize. The "multi-hit" model explains how cancers develop through multiple mutations. Specific cancer-causing mutations in growth factors, receptors, cell cycle proteins and other genes are also summarized.
This document provides an overview of cancer biology. It discusses how cancer is caused by the accumulation of genetic mutations over time that disrupt normal cell growth regulation. Key points covered include: the genetic and molecular basis of cancer; common properties of cancer cells like uncontrolled growth; the role of oncogenes and tumor suppressor genes; how mutations in growth factors, receptors, and cell cycle regulators can cause cancer; and the multi-hit model of carcinogenesis. The document also examines specific cancer-causing mutations and molecular mechanisms.
This document provides an overview of cancer biology. It discusses how cancer is caused by the accumulation of genetic mutations over time that disrupt normal cell growth regulation. Key points covered include: the genetic and molecular basis of cancer; common properties of cancer cells like uncontrolled growth; the role of oncogenes and tumor suppressor genes; how mutations in growth factors, receptors, and cell cycle regulators can cause cancer; and the multi-hit model of carcinogenesis. The document also examines specific cancer-causing mutations and molecular mechanisms.
This document discusses cancer and its genetic basis. It begins by introducing cancer and how it is caused by the accumulation of genetic damage over time through mutations in genes that control cell growth. Key points include: cancers originate from mutations in somatic cells, not germ cells; carcinomas make up over 90% of cancers and originate from endodermal or ectodermal tissues; the ability of cancer cells to invade and metastasize distinguishes malignant from benign tumors. The document then covers specific genetic mutations and cellular processes involved in cancer development.
This document provides information about cancer genetics and cell biology. It defines cancer as uncontrolled cell growth and classifies tumors as benign or malignant. The main cancer types - carcinomas, sarcomas, and leukemias/lymphomas - are described based on their cell of origin. Key concepts in cancer development are discussed, including the roles of oncogenes, tumor suppressor genes, DNA repair genes, and failures in cell cycle control. Cancer results from mutations that disable normal controls on cell growth and division.
Carcinogenesis is the process by which normal cells are transformed into cancer cells due to mutations in DNA that disrupt the orderly processes regulating cell proliferation and death. This results in uncontrolled cell division. A series of mutations in proto-oncogenes that promote cell growth and tumor suppressor genes that discourage cell growth are required before a normal cell transforms into a cancer cell. The ras oncogene and p53 tumor suppressor gene are examples that are commonly mutated in cancer. Grading of cancers provides information on prognosis and treatment by assessing how differentiated the cancer cells are from normal cells.
Molecular Pathogenesis and mechanisms of carcinogenesis involve several key hallmarks and changes in cell physiology that drive cancer development and progression. The hallmarks include self-sufficiency in growth signals, evasion of growth suppression, resistance to cell death, replication immortality, induction of angiogenesis, activation of invasion and metastasis, immune evasion, microRNA involvement, and epigenetic alterations. Cancer results from dysregulation of oncogenes and tumor suppressor genes that control the normal cell cycle and proliferation.
The document discusses several topics related to oncology including:
1. The most common cancers worldwide affect the lungs, breast, colorectum, stomach, and liver. Incidence varies widely by geography due to genetic and environmental factors.
2. Cancer results from dysregulation of the cell cycle and accumulation of mutations that confer a growth advantage. This includes activation of oncogenes and inactivation of tumor suppressor genes.
3. The hallmarks of cancer include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprogramming energy metabolism, and evading immune destruction.
- HCC displays a high degree of molecular and histological heterogeneity. Morphological subtypes of hepatocellular carcinoma are strongly associated with tumour subclasses and gene mutations. Development of a morpho-molecular classification could improve precision medicine for patients with this highly aggressive malignancy. Although unlike lung or colorectal cancer, increasing knowledge of HCC subtypes has not yet resulted in biomarker discovery and improved clinical care. Integrative pathological and molecular studies are needed to define a consensus HCC morpho-molecular classification that could guide ongoing therapeutic trials.
1) Tumors exist within a complex microenvironment consisting of various cell types that influence tumor growth, progression, and metastasis.
2) Chronic inflammation can promote tumor development by increasing genetic mutations while also stimulating angiogenesis and tumor cell proliferation.
3) The tumor microenvironment interacts bidirectionally with cancer cells to encourage processes like angiogenesis, immune suppression, invasion, and metastasis through factors such as TGF-β, VEGF, and cytokines.
4) Therapies targeting the tumor microenvironment can impact its composition and make cancer cells more invasive, highlighting the need for combination treatments.
Its about cancer biology where it includes characteristics features of cancer, hallmarks of cancer, protooncogenes oncogenes, tumor suppressor genes, chromosomal translocation, oncogenic viruses, cellular transformation to induce cancer, molecular basis of diagnosis of cancer, development of cancer, carcinogenes, types of cancer, mutation in developing cancer, prevelance of cancer, conversion of proto-oncogenes to oncogenes, oncogene in human cancer, oncogene fusion protein, oncogene activation by chromosomal translocation, BRCA1 and BRCA2, p53, oncogene targeted drugs, CAR-T-cell therapy, Immunotherapy, Monoclonal antibodies.
Cancer is caused by uncontrolled cell growth and spread. Cancer cells form tumors and spread through the body. There are many types of cancer that can affect different parts of the body. Cancer development is influenced by both external factors like lifestyle and environment as well as internal genetic factors. Cancer progression occurs through multiple genetic mutations over time that allow cancer cells to evade control mechanisms and continue growing and spreading.
This document discusses tumor-host interactions and the systemic effects of neoplasms. It covers topics such as invasion and metastasis, the molecular mechanisms of invasion through the extracellular matrix, angiogenesis in cancer, evidence of anti-tumor immunity including immune surveillance and immune escape, systemic symptoms of cancer including cachexia, and paraneoplastic syndromes. Examples are provided throughout to illustrate key concepts and mechanisms.
This document discusses various strategies for targeting tumors, including passive and active targeting approaches. Passive targeting exploits the enhanced permeability and retention effect to preferentially deliver drug carriers to tumor tissues. Active targeting approaches conjugate targeting ligands like antibodies, peptides, vitamins and transferrin to carriers to recognize receptors overexpressed on cancer cells. Recent advances include molecular targeted therapies inhibiting key pathways, targeting tumor vasculature and angiogenesis, cancer immunotherapy, and multifunctional nanoparticle systems for combined diagnosis and therapy of cancer.
REVIEWCancer stem cells a new framework for the designo.docxjoellemurphey
REVIEW
Cancer stem cells: a new framework for the design
of tumor therapies
Boyan K. Garvalov & Till Acker
Received: 14 July 2010 /Revised: 27 August 2010 /Accepted: 16 September 2010
# Springer-Verlag 2010
Abstract Modern tumor therapy has achieved considerable
progress, but many tumors remain refractory to treatment or
relapse following initial remission. Recent evidence points
to one possible reason for this limited therapeutic efficiency:
that the design of anticancer agents so far may not have been
aimed at the right target. While conventional tumor therapies
have targeted the main mass of tumor cells, there is now
compelling evidence that tumor initiation and progression are
driven by a subpopulation of tumor cells that possess stem cell
properties and are resistant to traditional cancer treatments—
the cancer stem cells (CSCs). CSCs have been identified in
most types of cancer and can be separated from the rest of the
tumor cells using appropriate markers. CSCs are regulated by
molecular mechanisms and specific, perivascular, and hypox-
ic microenvironments, which largely overlap with those
controlling stem cells from normal tissues. Our improved
understanding of CSC biology has already provided a number
of novel targets and drug discovery platforms for the design of
specific therapies that aim to eradicate the CSC subpopula-
tion. Therapeutic approaches can be targeted either at
eliminating the CSCs themselves or at disrupting the niches
in which CSCs reside. Moreover, the importance of CSCs for
tumor growth, resistance, and progression implies that clinical
trials and preclinical studies of anticancer therapies should
include as a key element an assessment of the abundance and
persistence of CSCs. Thus, CSC research holds great promise
for providing important new impetus to the fields of tumor
biology and clinical oncology.
Keywords Cancer stem cell . Hypoxia .
Microenvironment . Angiogenesis . Antitumor therapy.
Metastasis
The hierarchy model and cancer stem cells (CSCs)
The classical view of tumor formation is based on the
“stochastic” or “clonal evolution” model [1, 2]. It perceives
the tumor as a mass of hyperproliferative cells with similar
potential for driving tumor growth. Tumor heterogeneity
and progression are seen as the result of variations in the
tumor microenvironment and genetic mutations in individ-
ual cells, followed by selection of those that are best
adapted to support the further growth of the tumor (Fig. 1a).
An alternative concept that has been gaining increasing
experimental support is the “hierarchy” or “cancer stem
cell” model [3]. This model posits that tumors are generated
and maintained in a manner similar to the physiological
stem cell system operating in normal tissues, i.e., by cells
with stem cell-like properties, which self-renew and
differentiate into the distinct cellular subtypes of the tumor
(Fig. 1b). The key novel features of this model are that only
a limited population of tumor cell ...
Cytokine Immunotherapy: A Forthcoming Visible Feature in Cancer TherapeuticsSachin K. S. Chauhan
The document discusses cytokine immunotherapy as a promising approach for cancer treatment. It notes that cytokines can stimulate the immune system to fight tumors, but that mono-cytokine therapy has limitations. Combined cytokine therapy or cytokine therapy combined with other treatments may be more effective by creating a specific immune response. The document advocates focusing research on combination therapies to help overcome drawbacks of traditional cancer treatments.
Fetal monitoring aims to assess fetal wellbeing during pregnancy and labor. This document provides guidelines for interpreting cardiotocography (CTG) traces and responding to patterns. CTGs should consider gestational age, fetal growth, movements, and any conditions affecting fetal wellbeing. Antenatally, reduced fetal movements or abnormal fundal height measurements may warrant further assessment. During labor, CTG is recommended for high-risk pregnancies and can identify non-reassuring patterns like late decelerations indicating possible hypoxia. Interpretation requires evaluating baseline rate, variability, decelerations, and accelerations in the context of the clinical situation.
This document provides guidance on antenatal care. It discusses the importance of preconception care, screening and risk assessment during pregnancy, and the essential components of antenatal visits. The goals of antenatal care are to ensure the best outcomes for women and babies by screening for problems, assessing risk, treating issues, providing medications and information. Key aspects covered include taking a medical history, conducting physical exams, estimating gestation, performing essential screening tests, discussing medications and vaccines, creating a management plan, and covering topics for subsequent routine prenatal visits.
This document provides guidelines for preventing mother-to-child transmission of HIV (PMTCT) in antenatal care settings. There are four key elements of PMTCT care: primary HIV prevention, preventing unintended pregnancies among HIV+ women, preventing transmission from mother to child, and treatment/support for HIV+ women and their families. The goals of PMTCT in antenatal care are to identify all HIV+ women, provide same-day ART to optimize health and prevent transmission, and ensure viral suppression through treatment. All pregnant women should be tested for HIV and receive counseling. HIV+ women initiate lifelong ART regardless of CD4 count or clinical stage, while HIV- women receive repeat testing during pregnancy and breastfeeding.
This document provides guidance on performing and managing caesarean deliveries. It discusses:
- The need for caesarean delivery capabilities 24/7 at district hospitals and ability to perform emergency c-sections within 1 hour.
- Testing fetal lung maturity before elective c-sections if gestational age is uncertain.
- Preparation steps like consent, blood availability, and ensuring an experienced surgeon.
- Precautions against hemorrhage like oxytocin administration and careful surgical technique.
- Managing hemorrhage through measures like massaging the uterus, giving uterotonics, exploring for bleeding sources, and considering compression sutures.
- Postoperative orders around analgesia, fluids, thrombosis
Induction of labour is the artificial initiation of labour to achieve a vaginal delivery. Common indications include post-term pregnancy, hypertension disorders, and pre-labour rupture of membranes. The document discusses assessing the need for induction and balancing risks to the mother and baby. It provides guidance on methods for induction including membranes sweeping, prostaglandins, misoprostol, and oxytocin administration. Risks like uterine hyperstimulation are addressed. Special considerations for fetal demise, ruptured membranes, and scarred uteruses are also covered.
This document provides guidance on diagnosing and treating infections during pregnancy and the postpartum period. It discusses abnormal vaginal discharge, sexually transmitted infections like candidiasis, gonorrhea, chlamydia and trichomoniasis. It also addresses genital warts, ulcers, syphilis, urinary tract infections, acute pyelonephritis, and malaria. For each condition, it describes signs and symptoms, recommended testing, and treatment guidelines. It emphasizes treating sexually transmitted infections syndromically and the importance of notifying partners for examination and treatment.
This document provides guidelines for managing medical disorders in pregnancy, including anemia, diabetes mellitus, and cardiac disease. For anemia, it outlines screening, prevention, and treatment protocols. It describes gestational and pregestational diabetes and their management. For cardiac disease, it discusses referral criteria and managing labor and delivery for high-risk patients. The overall aim is to provide optimal care for both mother and baby's health outcomes.
1) Tuberculosis (TB) is a major cause of maternal mortality in South Africa. All pregnant women, especially those with HIV, should be screened for TB at antenatal visits.
2) Symptom screening involves asking about cough, fever, night sweats, and weight loss. A TB test (GeneXpert) is also required for pregnant women with new HIV diagnoses or known HIV.
3) If TB is diagnosed, treatment should begin promptly according to national guidelines. For drug-resistant TB, consultation with infectious disease specialists is recommended due to high mortality risk.
1) Bleeding in early pregnancy, defined as before 22 weeks, can be caused by miscarriage, ectopic pregnancy, molar pregnancy, or other issues. A rapid assessment including vital signs and exam is needed.
2) Miscarriages are categorized as safe, unsafe, threatening, inevitable, incomplete, or septic and management depends on the category and gestational age. Manual vacuum aspiration is preferred for evacuating the uterus under 16 weeks.
3) Post-miscarriage care involves screening for physical and mental health issues, providing counseling and information, and discussing family planning options.
Pregnant and postpartum women with COVID-19 should receive supportive care. While pregnant women are not more likely to get infected, those who do contract COVID-19, especially in the third trimester, are at higher risk of severe outcomes. COVID-19 testing criteria are the same for pregnant women as non-pregnant adults. Preventative measures include vaccination, masks, distancing, and hygiene. COVID-19 vaccination is recommended in pregnancy to protect both mother and baby. Mild cases can be isolated at home but moderate or severe cases require hospital admission. Mode of delivery depends on obstetric needs and maternal stability.
This document provides guidance on the management of antepartum haemorrhage (APH), or bleeding during pregnancy prior to delivery. It discusses causes of APH including placental abnormalities, infections, trauma, and unknown causes. It provides recommendations for emergency management at clinics, community health centers, and hospitals. Specific guidance is given for managing placenta praevia, abruptio placentae, and APH of unknown origin. Recommendations include IV fluids, blood transfusions, ultrasound exams, monitoring vital signs, and determining need for transfer or delivery.
Hypertensive disorders in pregnancy (HDP) are a common cause of maternal and infant health problems and death. HDP include gestational hypertension, preeclampsia, and eclampsia. Risk factors include being young, older than 35, having previous HDP, obesity, diabetes, or kidney disease. Symptoms of severe preeclampsia include headaches, vision issues, low platelets, elevated liver enzymes, pain in the upper right abdomen, HELLP syndrome, or high creatinine. All pregnant people should take calcium and those at higher risk may benefit from low-dose aspirin. HDP requires frequent monitoring, control of blood pressure, delivery by 38 weeks for gestational hypertension or earlier for pre
This document discusses gender-based violence and provides guidance for health workers in responding to GBV. It begins by defining GBV and noting that 1 in 4 women in South Africa experience GBV during pregnancy. It then outlines the negative health impacts of untreated GBV for women and children. The document describes possible signs that a woman is experiencing violence and provides a screening tool for health workers. It provides guidance on first line support, safety planning, and self-care for health workers responding to disclosures of GBV.
The document summarizes various abnormalities that can occur during labour and their management. It discusses prolonged latent phase of labour, poor progress in the active phase, meconium staining of amniotic fluid, prolonged second stage of labour, vacuum extraction, fetal distress, cord prolapse, and shoulder dystocia. For each issue, it provides details on how to assess and manage the situation, including administering drugs, changing positioning, accelerating delivery, or transferring to a hospital if needed. The goal is to safely resolve any problems and deliver a healthy baby.
1. The document discusses fetal maturity and intrauterine growth restriction (IUGR), including definitions, clinical symptoms, signs, biochemical markers, and fetal maturity tests. Fetal maturity tests assess surfactant levels in amniotic fluid to predict risk of respiratory distress syndrome in newborns.
2. IUGR is defined as fetal weight below the 10th percentile and can be symmetric or asymmetric, early or late onset. It increases risks of complications. Management depends on gestational age and Doppler ultrasound results, with delivery generally between 34-37 weeks.
3. There is no worldwide consensus on specific management strategies for IUGR, and guidelines from organizations like RCOG and ACOG have some differences.
The document discusses how the fetus is able to survive as a semi-allograft within the mother's uterus despite having different genetic material. It was first proposed in 1953 that the fetus is able to evade maternal immune detection through lack of fetal antigen expression or maternal lymphocyte suppression. The document then explores various mechanisms by which the fetal-maternal interface avoids rejection, including lack of MHC class I expression on trophoblast cells, shifts in maternal immune cell profiles toward anti-inflammatory responses, and expression of inhibitory ligands on trophoblasts. Immune cells in both the peripheral maternal system and local decidua are adapted to tolerate the semi-allogeneic fetus through these various mechanisms.
Teratology is the study of birth defects and their causes. Some key points:
- Around 5% of newborns have a detectable birth defect, though the cause is unknown for 70% of cases. Less than 1% are due to medications.
- Teratogens are agents that cause permanent changes to embryonic or fetal development, and can cause malformations (teratogen), altered growth (trophogen), or interference with organ maturation (hadegen).
- Studying teratogenicity in humans is difficult due to ethical concerns, so animal studies are also used but not definitive. Counseling women exposed to potential teratogens is important to avoid anxiety.
- Amniotic fluid serves several important roles in fetal development including allowing movement, swallowing, breathing and protecting the fetus.
- The normal volume of amniotic fluid increases throughout pregnancy reaching around 800mL by the mid-third trimester. Abnormally low (oligohydramnios) or high (hydramnios) volumes can occur.
- Hydramnios, which complicates 1-2% of pregnancies, has many potential causes including fetal anomalies, diabetes or infections. It can lead to pregnancy complications like cesarean delivery. Oligohydramnios also has various causes like renal abnormalities and medications and is associated with adverse outcomes such as pulmonary hypoplasia
This document discusses various fetal disorders, focusing on fetal anemia, hydrops fetalis, and thrombocytopenia. It describes the main causes of fetal anemia as red blood cell alloimmunization and various infections. Doppler evaluation and fetal blood sampling are used to identify and monitor anemia. Left untreated, anemia can lead to heart failure, hydrops, and death. However, intrauterine transfusions have dramatically improved survival rates. Hydrops fetalis refers to fluid accumulation and can result from immune or nonimmune causes. For immune hydrops, the main cause is red blood cell alloimmunization, while aneuploidy and infections are common nonimmune causes. Thrombocytopenia can
Genetics is the study of genes, heredity, and inherited traits. Medical genetics deals with genetic causes of human diseases. The document discusses several types of chromosomal abnormalities including trisomies like Down syndrome, Edwards syndrome, and Patau syndrome. It also discusses sex chromosome abnormalities such as Turner syndrome, Klinefelter syndrome, and other conditions. Structural abnormalities of chromosomes including deletions, duplications, translocations, and microdeletions are also summarized. Chromosomal abnormalities are a major cause of genetic diseases and pregnancy complications.
Rasamanikya is a excellent preparation in the field of Rasashastra, it is used in various Kushtha Roga, Shwasa, Vicharchika, Bhagandara, Vatarakta, and Phiranga Roga. In this article Preparation& Comparative analytical profile for both Formulationon i.e Rasamanikya prepared by Kushmanda swarasa & Churnodhaka Shodita Haratala. The study aims to provide insights into the comparative efficacy and analytical aspects of these formulations for enhanced therapeutic outcomes.
Histololgy of Female Reproductive System.pptxAyeshaZaid1
Dive into an in-depth exploration of the histological structure of female reproductive system with this comprehensive lecture. Presented by Dr. Ayesha Irfan, Assistant Professor of Anatomy, this presentation covers the Gross anatomy and functional histology of the female reproductive organs. Ideal for students, educators, and anyone interested in medical science, this lecture provides clear explanations, detailed diagrams, and valuable insights into female reproductive system. Enhance your knowledge and understanding of this essential aspect of human biology.
Integrating Ayurveda into Parkinson’s Management: A Holistic ApproachAyurveda ForAll
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.
Adhd Medication Shortage Uk - trinexpharmacy.comreignlana06
The UK is currently facing a Adhd Medication Shortage Uk, which has left many patients and their families grappling with uncertainty and frustration. ADHD, or Attention Deficit Hyperactivity Disorder, is a chronic condition that requires consistent medication to manage effectively. This shortage has highlighted the critical role these medications play in the daily lives of those affected by ADHD. Contact : +1 (747) 209 – 3649 E-mail : sales@trinexpharmacy.com
Muktapishti is a traditional Ayurvedic preparation made from Shoditha Mukta (Purified Pearl), is believed to help regulate thyroid function and reduce symptoms of hyperthyroidism due to its cooling and balancing properties. Clinical evidence on its efficacy remains limited, necessitating further research to validate its therapeutic benefits.
Does Over-Masturbation Contribute to Chronic Prostatitis.pptxwalterHu5
In some case, your chronic prostatitis may be related to over-masturbation. Generally, natural medicine Diuretic and Anti-inflammatory Pill can help mee get a cure.
Promoting Wellbeing - Applied Social Psychology - Psychology SuperNotesPsychoTech Services
A proprietary approach developed by bringing together the best of learning theories from Psychology, design principles from the world of visualization, and pedagogical methods from over a decade of training experience, that enables you to: Learn better, faster!
Osteoporosis - Definition , Evaluation and Management .pdfJim Jacob Roy
Osteoporosis is an increasing cause of morbidity among the elderly.
In this document , a brief outline of osteoporosis is given , including the risk factors of osteoporosis fractures , the indications for testing bone mineral density and the management of osteoporosis
- 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
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2. Altered Cellular Metabolism
• Even in the presence of ample oxygen, cancer cells demonstrate a
distinctive form of cellular metabolism characterized by high levels of
glucose uptake and increased conversion of glucose to lactose
(fermentation) via the glycolytic pathway
• This phenomenon, called the Warburg effect and also known as
aerobic glycolysis
• “Warburg metabolism” is not cancer specific, but instead is a general
property of growing cells that becomes “fixed” in cancer cells.
4. Autophagy
• Tumor cells often seem to be able to grow under marginal
environmental conditions without triggering autophagy,
• Suggesting that the pathways that induce autophagy are deranged.
• In keeping with this, several genes that promote autophagy are tumor
suppressors.
5. Evasion of Cell Death
• Tumor cells frequently contain mutations in genes that regulate
apoptosis, making the cells resistant to cell death.
• There are two pathways that lead to apoptosis: the extrinsic pathway,
triggered by the death receptors FAS and FAS-ligand; and the intrinsic
pathway (also known as the mitochondrial pathway
• Cancer cells are subject to a number of intrinsic stresses that can
initiate apoptosis, particularly DNA damage, but also metabolic
disturbances stemming from dysregulated growth as well as hypoxia
caused by insufficient blood supply
6. Immortality
• Tumor cells, unlike normal cells, are capable of limitless replication.
• Most normal human cells have a capacity of at most 70 doublings.
Thereafter, the cells lose the ability to divide and enter replicative
senescence.
• This phenomenon has been ascribed to progressive shortening of
telomeres at the ends of chromosomes
• Markedly eroded telomeres are recognized by the DNA repair
machinery as double-stranded DNA breaks, leading to cell cycle arrest
,mediated by TP53 and RB.
8. Sustained Angiogenesis
• Even if a solid tumor possesses all of the genetic aberrations that are
required for malignant transformation, it cannot enlarge beyond 1 to
2 mm in diameter unless it has the capacity to induce angiogenesis
• Growing cancers stimulate neoangiogenesis, during which vessels
sprout from previously existing capillaries.
• Neovascularization has a dual effect on tumor growth: perfusion
supplies needed nutrients and oxygen, and secreting growth factors
• Permitting tumor cells access to these abnormal vessels, angiogenesis
also contributes to metastasis.
9. Invasion and Metastasis
• Invasion, and metastasis, the major causes of cancer-related
morbidity and mortality, result from complex interactions involving
cancer cells, stromal cells, and the extracellular matrix (ECM)
• These interactions can be broken down into a series of steps
consisting of local invasion, intravasation into blood and lymph
vessels
• Transit through the vasculature, extravasation from the vessels,
formation of micrometastases, and growth of micrometastases into
macroscopic tumors
11. Metastasis
• Some variation in metastasis clearly relates to inherent differences in
the behavior of particular tumors
• However, tumor size and type cannot adequately explain the behavior
of individual cancers, and it is still open to question whether
metastasis is merely probabilistic (a matter of chance multiplied by
tumor cell number and time)
• OR reflects inherent differences in metastatic potential from tumor to
tumor (a deterministic model)
• The deterministic model proposes that metastasis is inevitable with
certain tumors because the tumor harbors cells with a specific
metastatic phenotype
12. Evasion of Immune Surveillance
• The specific factors that govern the outcome of interactions between
tumor cells and the host immune system are numerous
• Cancer cells express a variety of antigens that stimulate the host
immune system
• Despite the antigenicity of cancer cells, the immune response to
established tumors is ineffective, and in some instances may actually
promote cancer growth
• Defining mechanisms of immune evasion and “immunomanipulation”
by cancer cells has led to effective new immunotherapies that work
by reactivating latent host immune responses.
14. CARCINOGENIC AGENTS
• Carcinogenic agents inflict genetic damage, which lies at the heart of
carcinogenesis.
Three classes of carcinogenic agents have been identified:
(1) Chemicals,
(2) radiant energy,
(3) Microbial products.
19. CLINICAL ASPECTS
• Both malignant and benign tumors may cause problems because of:
(1) Location and impingement on adjacent structures,
(2) Hormone synthesis (paraneoplastic syndromes)
(3) Bleeding and infections
(4) Rupture or infarction,
(5) cachexia
21. Grading and Staging of Cancer
• when compared with grading, staging has proved to be of greater
clinical value
• Grading of a cancer is based on the degree of differentiation of the
tumor cells and, in some cancers, the number of mitoses and the
presence of certain architectural features
• The staging of solid cancers is based on the size of the primary lesion,
its extent of spread to regional lymph nodes, and the presence or
absence of bloodborne metastases
22. Tumor Markers
• Biochemical assays for tumor-associated enzymes, hormones, and
other tumor markers in the blood cannot be utilized for definitive
diagnosis of cancer;
• However, they are used with varying success as screening tests and
have utility in monitoring the response to therapy or detecting
disease recurrence
23. Molecular Diagnosis
• Because each T cell and B cell has unique antigen receptor gene
rearrangements, polymerase chain reaction (PCR)–based detection of
rearranged T-cell receptor or immunoglobulin genes allows
monoclonal (neoplastic) and polyclonal (reactive) proliferations to be
distinguished
• Certain genetic alterations are associated with a poor prognosis
• Another emerging use of molecular techniques is for detection of
minimal residual disease after treatment
• Diagnosis of hereditary predisposition to cancer.
Clinically, the “glucose-hunger” of tumors is used to visualize tumors via positron emission tomography (PET) scanning, in which patients are injected with 18F-fluorodeoxyglucose, a glucose derivative that is preferentially taken up into tumor cells (as well as normal, actively dividing tissues such as the bone marrow). Most tumors are PET-positive, and rapidly growing ones are markedly so
Aerobic glycolysis provides rapidly dividing tumor cells with metabolic intermediates that are needed for the synthesis of cellular components, whereas mitochondrial oxidative phosphorylation does not.
The reason growing cells rely on aerobic glycolysis becomes readily apparent when one considers that a growing cell has a strict biosynthetic requirement; it must duplicate all of its cellular components—DNA, RNA, proteins, lipid, and organelles—before it can divide and produce two daughter cells. While oxidative phosphorylation yields abundant ATP, it fails to produce any carbon moieties that can be used to build the cellular components needed for growth (proteins, lipids, and nucleic acids)
By contrast, in actively growing cells only a small fraction of the cellular glucose is shunted through the oxidative phosphorylation pathway, such that on average each molecule of glucose metabolized produces approximately four molecules of ATP
a major function of mitochondria in growing cells is not to generate ATP, but rather to carry out reactions that generate metabolic intermediates that can be shunted off and used as precursors in the synthesis of cellular building blocks
As might be guessed, metabolic reprogramming is produced by signaling cascades downstream of growth factor receptors, the very same pathways that are deregulated by mutations in oncogenes and tumors suppressor genes in cancers. Thus, whereas in rapidly dividing normal cells aerobic glycolysis ceases when the tissue is no longer growing, in cancer cells this reprogramming persists due to the action of oncogenes and the loss of tumor suppressor gene function. Some of the important points of cross-talk between pro–growth signaling factors and cellular metabolism are shown in Fig. 6.23 and include the following: • Growth factor receptor signaling. In addition to transmitting growth signals to the nucleus, signals from growth factor receptors also influence metabolism by upregulating glucose uptake and inhibiting the activity of pyruvate kinase, which catalyzes the last step in the glycolytic pathway, the conversion of phosphoenolpyruvate to pyruvate. This creates a damming effect that leads to the buildup of upstream glycolytic intermediates, which are siphoned off for synthesis of DNA, RNA, and protein. • RAS signaling. Signals downstream of RAS upregulate the activity of glucose transporters and multiple glycolytic enzymes, thus increasing glycolysis; promote shunting of mitochondrial intermediates to pathways leading to lipid biosynthesis; and stimulate factors that are required for protein synthesis. • MYC. As mentioned earlier, pro-growth pathways upregulate expression of the transcription factor MYC, which drives changes in gene expression that support anabolic metabolism and cell growth. Among the MYCregulated genes are those for several glycolytic enzymes and glutaminase, which is required for mitochondrial utilization of glutamine, a key source of carbon moieties needed for biosynthesis of cellular building blocks
Whether autophagy is always bad from the vantage point of the tumor, however, remains a matter of active investigation and debate. For example, under conditions of severe nutrient deprivation, tumor cells may use autophagy to become “dormant,” a state of metabolic hibernation that allows cells to survive hard times for long periods. Such cells are believed to be resistant to therapies that kill actively dividing cells, and could therefore be responsible for therapeutic failures. Thus, autophagy may be a tumor’s friend or foe depending on how the signaling pathways that regulate it are “wired” in a given tumor
apoptosis, or regulated cell death, refers to an orderly dismantling of cells into component pieces, which are then efficiently consumed by neighboring cells and professional phagocytes without stimulating inflammation
These stresses are enhanced manyfold when tumors are treated with chemotherapy or radiation therapy, which kill tumor cells by activating the intrinsic pathway of apoptosis. Thus, there is strong selective pressure, both before and during therapy, for cancer cells to develop resistance to intrinsic stresses that may induce apoptosis
Accordingly, evasion of apoptosis by cancer cells occurs mainly by way of acquired mutations and changes in gene expression that disable key components of the intrinsic pathway, or that reset the balance of regulatory factors so as to favor cell survival in the face of intrinsic stresses
Such an inappropriately activated repair system results in dicentric chromosomes that are pulled apart at anaphase, resulting in new double-stranded DNA breaks. The resulting genomic instability from the repeated bridge– fusion–breakage cycles eventually produces mitotic catastrophe, characterized by massive apoptosis. It follows that for tumors to acquire the ability to grow indefinitely, loss of growth restraints is not enough; both cellular senescence and mitotic catastrophe must also be avoided
In cells in which TP53 or RB mutations are disabled by mutations, the nonhomologous end-joining pathway is activated in a last-ditch effort to save the cell, joining the shortened ends of two chromosomes
If during crisis a cell manages to reactivate telomerase, the bridge–fusion–breakage cycles cease, and the cell is able to avoid death. However, during this period of genomic instability that precedes telomerase activation, numerous mutations could accumulate, helping the normal stem cells, is absent from or present at very low levels in most somatic cells. By contrast, telomere maintenance is seen in virtually all types of cancers. In 85% to 95% of cancers, this is due to upregulation of the enzyme telomerase. A few tumors use other mechanisms, termed alternative lengthening of telomeres, which depend on DNA recombination. Of interest, in a study of the progression from colonic adenoma to colonic adenocarcinoma, early lesions had a high degree of genomic instability with low telomerase expression, whereas malignant lesions had complex karyotypes with high levels of telomerase activity, consistent with a model of telomere-driven tumorigenesis in human cancer. Thus, it appears that unregulated proliferation in incipient tumors leads to telomere shortening, followed by chromosomal instability and the accumulation of mutations. If telomerase is then reactivated in these cells, telomeres are extended and these mutations become fixed, contributing to tumor growth.
Like normal tissues, tumors require delivery of oxygen and nutrients and removal of waste products; presumably the 1- to 2-mm zone represents the maximal distance across which oxygen, nutrients, and waste can diffuse to and from blood vessels
While the resulting tumor vasculature is effective at delivering nutrients and removing wastes, it is not entirely normal; the vessels are leaky and dilated, and have a haphazard pattern of connection, features that can be appreciated on angiograms
How do growing tumors develop a blood supply? The current paradigm is that angiogenesis is controlled by a balance between angiogenesis promoters and inhibitors; in angiogenic tumors this balance is skewed in favor of promoters
The local balance of angiogenic and anti-angiogenic factors is influenced by several factors: • Relative lack of oxygen due to hypoxia stabilizes HIF1α, an oxygen-sensitive transcription factor mentioned earlier, which then activates the transcription of proangiogenic cytokines such as VEGF. These factors create an angiogenic gradient that stimulates the proliferation of endothelial cells and guides the growth of new vessels toward the tumor. • Mutations involving tumor suppressors and oncogenes in cancers also tilt the balance in favor of angiogenesis. For example, p53 stimulates expression of antiangiogenic molecules, such as thrombospondin-1, and represses expression of proangiogenic molecules, such as VEGF. Thus, loss of p53 in tumor cells provides a more permissive environment for angiogenesis. • The transcription of VEGF also is influenced by signals from the RAS-MAP kinase pathway, and gain-offunction mutations in RAS or MYC upregulate the production of VEGF. Notably, elevated levels of VEGF can be detected in the serum and urine of a significant fraction of cancer patients
Predictably, this sequence of steps may be interrupted at any stage by either host-related or tumor-related factors. For the purpose of discussion, the metastatic cascade can be subdivided into two phases: (1) invasion of ECM and (2) vascular dissemination and homing of tumor cells
Invasion of Extracellular Matrix Human tissues are organized into a series of compartments separated from each other by two types of ECM: basement membranes and interstitial connective tissue (Chapter 1). Although organized differently, each type of ECM is composed of collagens, glycoproteins, and proteoglycans. Tumor cells must interact with the ECM at several stages in the metastatic cascade (see Fig. 6.27). A carcinoma first must breach the underlying basement membrane, then traverse the interstitial connective tissue, and ultimately gain access to the circulation by penetrating the vascular basement membrane. This process is repeated in reverse when tumor cell emboli extravasate at a distant site. Invasion of the ECM initiates the metastatic cascade and is an active process that can be resolved into several sequential steps (Fig. 6.28): • Loosening of intercellular connections between tumor cells
Local degradation of the basement membrane and interstitial connective tissue
Because of their invasive properties, tumor cells frequently escape their sites of origin and enter the circulation.
Several factors seem to limit the metastatic potential of circulating tumor cells. While in the circulation, tumor cells are vulnerable to destruction by host immune cells (discussed later), and the process of adhesion to normal vascular beds and invasion of normal distant tissues may be much more difficult than the escape of tumor cells from the cancer. Even following extravasation, tumor cells that have been selected for growth in the originating tissue may find it difficult to grow in a second site due to lack of critical stromal support or because of recognition and suppression by resident immune cells. Indeed, the concept of tumor dormancy, referring to the prolonged survival of micrometastases without progression, is well described in melanoma and in breast and prostate carcinoma
Despite these limiting factors, if neglected, virtually all malignant tumors will eventually produce macroscopic metastases. The site at which metastases appear is related to two factors: the anatomic location and vascular drainage of the primary tumor, and the tropism of particular tumors for specific tissues
for example, small cell carcinoma of the lung virtually always metastasizes to distant sites, whereas with some tumors, such as basal cell carcinoma, metastasis is the exception rather than the rule. In general, large tumors are more likely to metastasize than small tumors, presumably because (all other things being equal) large tumors will have been present in the patient for longer periods of time, providing additional chances for metastasis to occur
One possibility is that only rare tumor cells accumulate all of the mutations necessary for metastasis, and that this accounts for the inefficiency of the process. However, identification of metastasis-specific mutations and metastasis-specific patterns of gene expression has proven to be difficult. An alternative idea is that some tumors acquire all of the mutations needed for metastasis early in their development, and that these are the tumors that are fated to be “bad actors.” Metastasis, according to this view, is not dependent on the stochastic generation of metastatic subclones during tumor progression, but is an intrinsic property of the tumor that develops early on during carcinogenesis. These mechanisms are not mutually exclusive, and it could be that aggressive tumors acquire a metastasis-permissive gene expression pattern early in tumorigenesis, yet also require some additional random mutations to complete the metastatic phenotype. Nor can all blame be placed on tumor cells: as mentioned earlier, there is evidence that the makeup of the stroma, the presence of infiltrating immune cells, and the degree and quality of angiogenesis also influence metastasis
Evasion of Immune Surveillance
Long one of the “holy grails” of oncology, the promise of therapies that enable the host immune system to recognize and destroy cancer cells is finally coming to fruition, largely due to a clearer understanding of the mechanisms by which cancer cells evade the host response.
Tumor Antigens. As we have discussed, cancer is a disorder that is caused by driver mutations in oncogenes and tumor suppressor genes, which in most instances are acquired rather than inherited. In addition to pathogenic driver mutations, cancers, due to their inherent genetic instability, also accumulate passenger mutations. These may be particularly abundant in cancers that are caused by mutagenic exposures (e.g., sunlight, smoking). All of these varied mutations may generate new protein sequences (neoantigens) that the immune system has not seen and therefore is not tolerant of and can react to. In some instances, unmutated proteins expressed by tumor cells also can stimulate the host immune response. • One such antigen is tyrosinase, an enzyme involved in melanin biosynthesis that is expressed only in normal melanocytes and melanomas. It may be surprising that the immune system is able to respond to this normal self-antigen. The probable explanation is that tyrosinase is normally produced in such small amounts and in so few normal cells that it is not recognized by the immune system and fails to induce tolerance. • Another group of tumor antigens, the cancer-testis antigens, are encoded by genes that are silent in all adult tissues except germ cells in the testis—hence their name. Although the protein is present in the testis it is not expressed on the cell surface in a form that can be recognized by CD8+ T cells, because sperm do not express MHC class I molecules. Thus, for all practical purposes these antigens are tumor specific and are therefore capable of stimulating anti-tumor immune responses.
Immune Evasion by Cancers. Since the immune system is capable of recognizing and eliminating nascent cancers, it follows that tumors that reach clinically significant sizes must be composed of cells that are either invisible to the host immune system or that express factors that actively suppress host immunity. The term cancer immunoediting has been used to describe the ability of the immune system to promote the darwinian selection of the tumor subclones that are most able to avoid host immunity or even manipulate the immune system for their own malignant purposes
Genomic Instability as an Enabler of Malignancy The preceding section identified the eight defining features of malignancy, all of which appear to be produced by genetic alterations involving cancer genes. How do these mutations arise? Although humans are awash in environmental agents that are mutagenic (e.g., chemicals, radiation, sunlight), cancers are relatively rare outcomes of these encounters. This state of affairs results from the ability of normal cells to sense and repair DNA damage. The importance of DNA repair in maintaining the integrity of the genome is highlighted by several inherited disorders in which genes that encode proteins involved in DNA repair are defective. Individuals born with inherited defects in DNA repair genes are at greatly increased risk for the development of cancer. Defects in three types of DNA repair systems—mismatch repair, nucleotide excision repair, and recombination repair—are presented next. While these discussions focus on inherited syndromes, a point worthy of emphasis is that sporadic cancers often incur mutations in DNA repair genes as well; this in turn enables the accumulation of mutations in cancer genes that contribute directly to development of cancer
Chemical Carcinogens
Direct-acting agents require no metabolic conversion to become carcinogenic. They are typically weak carcinogens but are important because some of them are cancer chemotherapy drugs (e.g., alkylating agents) used in regimens that may cure certain types of cancer
The designation indirect-acting refers to chemicals that require metabolic conversion to an ultimate carcinogen. Some of the most potent indirect chemical carcinogens are polycyclic hydrocarbons that are created with burning of fossil fuels, plant, and animal material
Mechanisms of Action of Chemical Carcinogens Because malignant transformation results from mutations, it should come as no surprise that most chemical carcinogens are mutagenic. Indeed, all direct and ultimate carcinogens contain highly reactive electrophile groups that form chemical adducts with DNA, as well as with proteins and RNA. Any gene may be the target of chemical carcinogens, but understandably it is the mutation of important cancer genes, such as RAS and TP53, that is responsible for carcinogenesis. Indeed, specific chemical carcinogens, such as aflatoxin B1, produce characteristic mutations in TP53, such that detection of mutations within particular codons strongly points toward aflatoxin as the causative agent. Such specific “mutational signatures” also exist for cancers caused by UV light, tobacco smoke, and other environmental carcinogens and are proving to be useful tools in epidemiologic studies of carcinogenesis. Carcinogenicity of some chemicals is augmented by subsequent administration of promoters (e.g., phorbol esters, hormones, phenols, certain drugs), which are by themselves nontumorigenic. To be effective, repeated or sustained exposure to the promoter must follow the application of the mutagenic chemical, or initiator
Radiation Carcinogenesis Radiation, whatever its source (UV rays of sunlight, radiographs, nuclear fission, radionuclides), is an established carcinogen. Unprotected miners of radioactive elements have a 10-fold increased incidence of lung cancers. A follow-up study of survivors of the atomic bombs dropped on Hiroshima and Nagasaki disclosed a markedly increased incidence of leukemia after an average latent period of about 7 years, as well as increased mortality rates for thyroid, breast, colon, and lung carcinomas. The nuclear power accident at Chernobyl in the former Soviet Union continues to exact its toll in the form of high cancer incidence in the surrounding areas. More recently, it is feared that radiation release from a nuclear power plant in Japan damaged by a massive earthquake and tsunami will result in significantly increased cancer incidence in the surrounding geographic areas. Therapeutic irradiation of the head and neck can give rise to papillary thyroid cancers years later. The oncogenic properties of ionizing radiation are related to its mutagenic effects; it causes chromosome breakage, chromosomal rearrangements such as translocations and inversions, and, less frequently, point mutations. Biologically, doublestranded DNA breaks seem to be the most important form of DNA damage caused by radiation
Viral and Microbial Oncogenesis Many DNA and RNA viruses have proved to be oncogenic in animals as disparate as frogs and primates. Despite intense scrutiny, however, only a few viruses have been linked with human cancer. The following discussion focuses on human oncogenic viruses. Also discussed is the role of the bacterium Helicobacter pylori in gastric cancer. Oncogenic RNA Viruses Although the study of animal retroviruses has provided spectacular insights into the molecular basis of cancer, only one human retrovirus, human T-cell leukemia virus type 1 (HTLV-1), is firmly implicated in the pathogenesis of cancer in humans. HTLV-1 causes adult T-cell leukemia/lymphoma (ATLL), a tumor that is endemic in certain parts of Japan, the Caribbean basin, South America, and Africa, and found sporadically elsewhere, including the United States. Worldwide, it is estimated that 15 to 20 million people are infected with HTLV-1. Similar to the human immunodeficiency virus, which causes AIDS, HTLV-1 has tropism for CD4+ T cells, and hence this subset of T cells is the major target for neoplastic transformation. Human infection requires transmission of infected T cells via sexual intercourse, blood products, or breastfeeding. Leukemia develops in only 3% to 5% of the infected individuals, typically after a long latent period of 40 to 60 years. There is little doubt that HTLV-1 infection of T lymphocytes is necessary for leukemogenesis, but the molecular mechanisms of transformation are not certain. In contrast to several murine retroviruses, HTLV-1 does not contain an oncogene, and no consistent pattern of proviral integration next to a proto-oncogene has been discovered.
Several aspects of HTLV-1’s transforming activity are attributable to Tax, the protein product of the tax gene
Human Papillomavirus Scores of genetically distinct types of HPV have been identified. Some types (e.g., 1, 2, 4, and 7) cause benign squamous papillomas (warts) in humans (Chapters 18 and 24). Genital warts have low malignant potential and are also associated with low-risk HPVs, predominantly HPV-6 and HPV-11. By contrast, high-risk HPVs (e.g., types 16 and 18) cause several cancers, particularly squamous cell carcinoma of the cervix and anogenital region. In addition, at least 20% of oropharyngeal cancers, particularly those arising in the tonsils, are associated with high-risk HPVs. The oncogenic potential of HPV can be related to products of two early viral genes, E6 and E7 (Fig. 6.33), each of which has several activities that are pro-oncogenic. • Oncogenic activities of E6. The E6 protein binds to and mediates the degradation of p53, and also stimulates the expression of TERT, the catalytic subunit of telomerase, which you will recall contributes to the immortalization of cells. E6 from high-risk HPV types has a higher affinity for p53 than E6 from low-risk HPV types, a property that is likely to contribute to oncogenesis. • Oncogenic activities of E7. The E7 protein has effects that complement those of E6, all of which are centered on speeding cells through the G1-S cell cycle checkpoint. It binds to the RB protein and displaces the E2F transcription factors that are normally sequestered by RB, promoting progression through the cell cycle. As with E6 proteins and p53, E7 proteins from high-risk HPV types have a higher affinity for RB than do E7 proteins from low-risk HPV types. E7 also inactivates the CDK inhibitors p21 and p27, and binds and presumably activates cyclins E and A
high-risk HPVs encode oncogenic proteins that inactivate RB and p53, activate cyclin/ CDK complexes, and combat cellular senescence
Epstein-Barr Virus EBV, a member of the herpesvirus family, was the first virus linked to a human tumor, Burkitt lymphoma
Effects of Tumor on Host Location is crucial in both benign and malignant tumors. A small (1-cm) pituitary adenoma can compress and destroy the surrounding normal gland, giving rise to hypopituitarism. A 0.5-cm leiomyoma in the wall of the renal artery may encroach on the blood supply, leading to renal ischemia and hypertension. A comparably small carcinoma within the common bile duct may induce fatal biliary tract obstruction. Signs and symptoms related to hormone production are often seen in patients with benign and malignant neoplasms arising in endocrine glands. Adenomas and carcinomas arising in the beta cells of the pancreatic islets of Langerhans can produce hyperinsulinism, sometimes fatal
Cancer Cachexia Many cancer patients suffer progressive loss of body fat and lean body mass, accompanied by profound weakness, anorexia, and anemia—a condition referred to as cachexia. There is some correlation between the size and extent of spread of the cancer and the severity of the cachexia
Paraneoplastic Syndromes Symptom complexes that occur in patients with cancer and that cannot be readily explained by local or distant spread of the tumor or by the elaboration of hormones indigenous to the tissue of origin of the tumor are referred to as paraneoplastic syndromes
They appear in 10% to 15% of patients with cancer, and their clinical recognition is important for several reasons: • Such syndromes may represent the earliest manifestation of an occult neoplasm. • In affected patients, the pathologic changes may be associated with significant clinical illness and may even be lethal. • The symptom complex may mimic metastatic disease, thereby confounding treatment
The most common paraneoplastic syndromes are hypercalcemia, Cushing syndrome, and nonbacterial thrombotic endocarditis, and the neoplasms most often associated with these and other syndromes are lung and breast cancers and hematologic malignancie
Grading schemes have evolved for each type of malignancy, and generally range from two categories (low grade and high grade) to four categories. Criteria for the individual grades vary in different types of tumors and so are not detailed here, but all attempt, in essence, to judge the extent to which the tumor cells resemble or fail to resemble their normal counterparts
The major staging system currently in use is the American Joint Committee on Cancer Staging. This system uses a classification called the TNM system—T for primary tumor, N for regional lymph node involvement, and M for metastases. TNM staging varies for specific forms of cancer, but there are general principles
PSA, used to screen for prostatic adenocarcinoma, is one of the most frequently used tumor markers in clinical practice. Prostatic carcinoma can be suspected when elevated levels of PSA are found in the blood. However, PSA screening also highlights problems encountered with use of virtually every tumor marker. Although PSA levels often are elevated in cancer, PSA levels also may be elevated in benign prostatic hyperplasia (Chapter 18). Furthermore, there is no PSA level that ensures that a patient does not have prostate cancer. Thus, the PSA test suffers from both low sensitivity and low specificity, and its use as a screening tool has become quite controversial
The PSA assay is extremely valuable, however, for detecting residual disease or recurrence following treatment for prostate cancer. Other tumor markers used in clinical practice include carcinoembryonic antigen (CEA), which is elaborated by carcinomas of the colon, pancreas, stomach, and breast, and alpha fetoprotein (AFP), which is produced by hepatocellular carcinomas, yolk sac remnants in the gonads, and occasionally teratocarcinomas and embryonal cell carcinomas. Like PSA, CEA and AFP can be elevated in a variety of nonneoplastic conditions and thus also lack the specificity and sensitivity required for the early detection of cancers, but they may be useful in monitoring disease once the diagnosis is established. With successful resection of the tumor, these markers disappear from the serum; their reappearance almost always signifies recurrence
Many hematopoietic neoplasms, as well as a few solid tumors, are defined by particular translocations, so the diagnosis can be made by detection of such translocations. For example, fluorescence in situ hybridization (FISH) or PCR analysis (Chapter 7) can be used to detect translocations characteristic of Ewing sarcoma and several leukemias and lymphomas. PCR-based detection of BCR-ABL transcripts can confirm the diagnosis of chronic myeloid leukemia (Chapter 12). Finally, certain hematologic malignancies are now defined by the presence of point mutations in particular oncogenes. For example, as mentioned earlier, the diagnosis of another myeloid neoplasm called polycythemia vera requires the identification of specific mutations in JAK2, a gene that encodes a nonreceptor tyrosine kinase
Therapeutic decision-making. Therapies that directly target specific mutations are increasingly being developed, and thus detection of such mutations in a tumor can guide the development of targeted therapy, as discussed later. It is now becoming evident that certain targetable mutations transgress morphologic categories. One example involves a valine for glutamate substitution in amino acid 600 (V600E) of the serine/threonine kinase BRAF, which you will recall lies downstream of RAS in the growth factor signaling pathway. Melanomas with the V600E BRAF mutation respond well to BRAF inhibitors, whereas melanomas without this mutation show no response. Subsequently, it was realized that the same V600E mutation is also present in a subset of many other diverse cancers, including carcinomas of the colon and thyroid gland, most hairy cell leukemias, and many cases of Langerhans cell histiocytosis