Each of Koch's postulates represents a criterion that must be met before a disease can be positively linked with a

pathogen. In order to determine whether the criteria are met,tests are perfomed on laboratory animals and cultures
from healthy and diseased animals are compared . (Figure 1)
Disease and Implications for Improved Treatment of Human Disease
o Identification of causative factors in disease - to study molecular pathogenesis.
o Molecular pathogenesis takes into account the molecular alterations that occur in response to environmental
insults and other contributing factors, to produce pathology.
o By developing a deep understanding of molecular pathogenesis, we will uncover the pathways that
contribute to disease, either through loss-of-function or through gain-of-function.
o By understanding the involvement of specific genes, proteins, and pathways, we will be better equipped to
develop targeted therapies for specific diseases.
o Molecular pathogenesis research includes the study of host-pathogen interactions at the level of cellular and
molecular networks with application to the understanding of virulence factors, host resistance to pathogens,
and emerging (and resurgent) infectious disease agents.
o Molecular pathology - the study of disease at the molecular level. This includes molecules found in tissues,
organs, and even bodily fluids.
o The term "molecular diagnostics" is used to describe the medical diagnosis aspect of the field.

Pathogenesis definition
o Pathogenesis: The development of a disease and the chain of events leading to that disease.
o Types of pathogenesis include
1. microbial infection,
2. inflammation,
3. malignancy and
4. tissue breakdown.

Stages of Pathogenesis
To cause disease, a pathogen must successfully achieve four steps or stages of pathogenesis:
1. exposure (contact),
2. adhesion (colonization),
3. invasion, and
4. infection.

Understanding Molecular Pathogenesis

o Continued expansion of knowledge base with respect to underlying mechanisms of disease has resulted in
unprecedented patient management strategies.
o Identification of genetic variants in genes once associated with the diagnosis of a disease process is now
being reevaluated as it may impact new therapeutic options.
o three disease entities (Hepatitis C virus [HCV] infection, acute myeloid eukemia [AMLl, and cystic fibrosis
[CF] are described as examples of increased understanding of the pathology represented by these diseases
and how novel therapeutics are being introduced into clinical practice.

Understanding the Biology of the Disease

o A healthy person lives in harmony with the microbial flora that helps protect its host from invasion by
pathogens, usually defined as microorganisms that have the capacity to cause disease.
o The microbial flora is mostly bacteria and fungi and includes normal resident flora, which is present
consistently and which promptly reestablishes itself if disturbed, and transient flora, which may colonize the
host for hours to weeks but does not permanently establish itself.
o Organisms that are normal flora can occasionally cause disease, especially when defenses are disrupted.
o
o As the field of molecular pathology moves forward in the genomics age with big data and challenging
analytical questions about disease processes, bioinformatics is playing an increasingly important role.
o The interdisciplinary field of bioinformatics blends computer science and biostatistics with biomedical
sciences such as epidemiology, genetics, genomics, and proteomics.
 o In combination, these approaches facilitate the management, analysis, and interpretation of data from
biological experiments and observational studies.
o The goal of molecular pathology is to introduce some of the important concepts in bioinformatics that must
be considered when planning and executing a modern molecular pathology study.

Molecular Basis of Cardiovascular Disease

o A new era of innovative research is transforming the study of cardiovascular pathobiology from static
histopathology research to dynamic mechanistic cell and molecular biology investigation.
o The development of reliable cell culture methods to harvest, maintain, and study the cells of the
cardiovascular system now allows for the investigation of dynamic structure and function relationships at the
cellular and molecular levels.
o Stem/precursor/pluripotential populations of cells have been identified and isolated from both humans and
experimental animal models that are both renewable and differentiate along cardiovascular lineages to
regulate regeneration and repair. Bioactive molecules are being identified as diagnostic biomarkers and
therapeutic targets.

Bioactive molecules
o A type of chemical found in small amounts in plants and certain foods (such as fruits, vegetables, nuts, oils,
and whole grains).
o Bioactive compounds have actions in the body that may promote good health. They are being studied in the
prevention of cancer, heart disease, and other diseases. Examples of bioactive compounds include
lycopene, resveratrol, lignan, tannins, and indoles.

Molecular Basis of Hemostatic and Thrombotic Diseases

o The coagulation system, composed of cells and soluble protein elements, leads to hemostasis (physiologic
blood clotting) at the site of blood vessel injury.
o Thrombosis refers to the process of excessive clotting that results in adverse cardiovascular events,
including myocardial infarction, thrombotic stroke, and venous thromboembolism.
o Hemostasis is normally regulated by antithrombotic mechanisms that serve to prevent excess clot formation.
o Disorders of hemostasis or thrombosis can occur when components of the coagulation system are missing
or dysfunctional.
o Molecular Basis of Hemostatic and Thrombotic Diseases
o • Hemostatic defects may lead to bleeding via the following mechanisms:
o (1) deficient thrombin generation on the proper cellular surface due to deficiencies of factor VIII or IX
(hemophilia A and B) required for the propagation phase of thrombin generation, deficiencies of factors in
the final common pathway of thrombin generation (factors Il, V, and
o X), deficiency of factor XI (required for "over-drive" of coagulation), defect in fibrin polymerization via either
deficiencies or abnormalities of fibrinogen, or deficiency of Factor XIII (required for cross linking fibrin);

Molecular Basis of Hemostatic and Thrombotic Diseases

• Hemostatic defects may lead to bleeding via the following mechanisms:
1. defect in primary hemostasis due to Von Willebrand disease or platelet dysfunction; or
2. abnormal fibrinolysis.

Molecular Basis of Hemostatic and Thrombotic Diseases

• Defects in the anticoagulant system lead to thrombosis via the following mechanisms:
1. unopposed or excess generation of thrombin via antithrombin deficiency or prothrombin G20210A mutation
and
2. insufficient inactivation of procoagulant proteins via activated protein C resistance (including that due to the
factor V Leiden mutation) and deficiencies of protein C or protein S.

Molecular Basis of Lymphoid and Myeloid Diseases

o All types of mature blood cells are produced by differentiation of hematopoietic stem cells found in the bone
marrow.
o This process is controlled by transcription factors, which in turn are
moulications, and extraceluiar signals transmaied by celsurface
receptors.
o Mutation of genes encoding these hematopoietic transcription factors, microRNAs, epigenetic modifiers, or
receptors or deregulated expression) can initiate transformation of normal cells into leukemic cells, or cause
cell death and anemia.
o Diseases such as leukemia, lymphoma, and anemia are usually genetically complex, a large number of
ditterent mutations contribute to disease development, and most patients acquire more than one mutation.
This genetic complexity has resulted in proposed new treatments based on Individual patient leukemia
genomes and/or immunotherapy.

Molecular Basis of Diseases of Immunity

o The human immune system has evolved to protect against infection by microorganisms.
o Without a functioning immune system, humans cannot survive past the first few months of life.
o infectious diseases were the most common cause of death.
o The increase in life expectancy reflects progress in control of infectious diseases, including improved
hygiene, vaccines, and antimicrobial drugs.
o the improved control of infections may have come at the expense of increasing the risk for autoimmune and
allergic diseases.

Molecular Basis of Pulmonary Disease

o Pulmonary pathology includes a large spectrum of both neoplastic and nonneoplastic diseases that affect
the lung.
o Many of these diseases are the result of the unusual relationship of the lung with the outside world.
o Every breath that a human takes brings the outside world into the body in the form of infectious agents,
organic and inorganic particles, and noxious agents of many types.
o the lung has many defense mechanisms to protect itself from these insults, these protections are not
infallible and so lung pathology
o host cells and cellular products participate in the pathogenesis of the injury.
Molecular Basis of Pulmonary Disease
o Damage to the lung is particularly important given the role of the lung in the survival of the organism.
o Any impairment of lung function has widespread effects throughout the body, since all organs depend upon
the lungs for oxygen.
o Pulmonary pathology encompasses adverse changes in the lung tissues and the mechanisms through
which these occur.

Molecular Basis of Diseases of the Gastrointestinal Tract

o understanding of gastrointestinal disorders has continued to center on the molecular underpinning of
gastrointestinal neoplasia.
o First, the development of cancer in the setting of inflammatory conditions is well represented by the
association of Helicobacter pylori with gastric cancer and of inflammatory bowel diseases with colorectal
cancer.
o Second, the development of cancer in patients with hereditary predisposition syndromes has shed light not
only in the mechanisms of hereditary neoplasia, but has also led to major progress in the understanding of
the molecular basis of the more common forms of sporadic cancer.
o The molecular characterization of the steps of gastrointestinal neoplastic development and progression has
led to advances in disease diagnosis and treatment and has opened the opportunity for development of
more targeted approaches to cancer prevention, surveillance, and novel therapeutics.
Molecular Basis of Liver Disease
o Liver diseases are a cause of global morbidity and mortality.
o While the predominance of specific liver diseases varies with geographical location, the diversity of hepatic
diseases affecting the underdeveloped,
Itectious diseases of the liver to epasi and bestr-elated in esses.

o elucidation of basic mechanisms that lead from hepatic injury and inflammation to hepatic fibrosis and
cirrhosis.
o understanding of cellular and molecular aberrations in liver diseases such as
mairnant tumors of the inel, In the hope ofimproing diagnot, priognosic,
and therapeutic tools.
Molecular Basis of Diseases of the Exocrine Pancreas
o Pancreatitis is characterized as self-digestion of the pancreas by its own proteases.
o A premature activation of digestive enzymes within pancreatic acinar cells results in necrotic cell death and
the activation of the immune system. The serine protease trypsinogen is suggested to play a crucial role in
this process. Trypsinogen is activated by the lysosomal hydrolase cathepsin B within the acinar cell and
defines the onset of disease. This event is accompanied by a local and systemic immune response.
o The significant role of trypsinogen is underlined by genetic data; different mutations within PRSS1, the
cationic trypsinogen, or other genes that are related to the activation, degradation, or inhibition of trypsin are
associated with an increased risk of chronic pancreatitis.
Molecular Basis of Diseases of the Endocrine System
o endocrine disorders were caused by too much or too little hormone.
o the etiology of hormonal excess or deficiency was not known until the identification of gene mutations that
affect hormonal action, from hormone synthesis to receptor response, and the development of
hypothalamic-pituitary-target organ axis.
Molecular Basis of Gynecologic Diseases
o Gynecologic diseases in general are diseases that involved the female reproductive track.
o These diseases include benign and malignant tumors, pregnancy-related diseases, infection, and endocrine
diseases.
o Among them, malignant tumors are the most common cause of death.
o the causes of some of these diseases have been elucidated, for example, human papillomavirus infection
has been shown to be one of the major etiological factors associated with cervical cancer. Inactivation of the
BRCA1 tumor suppressor gene has been implicated in hereditary ovarian
o In spite of these findings, the molecular basis of most gynecologic diseases remains largely unknown.
BReast CAncer genes 1 and 2 (BRCA1/2)
o BRCA1 is a human tumor suppressor gene (also known as a caretaker gene) and is responsible for
repairing DNA. BRCA1 and BRCA2 are unrelated proteins, but both are normally expressed in the cells of
breast and other tissue, where they help repair damaged DNA, or destroy cells if DNA cannot be repaired.
o The BRCA1 gene provides instructions for making a protein that acts as a tumor suppressor. Tumor
suppressor proteins help prevent cells from growing and dividing too rapidly or in an uncontrolled way.
Molecular Basis of Kidney Disease
o The kidney is a complex organ populated by a variety of unique, specialized cells that function in a
coordinated fashion to maintain homeostasis in the body.
o Diseases affecting the kidney are numerous, and their clinical manifestations are dependent on specific
cellular, molecular, and immunological abnormalities.
o Current research has revealed much about the molecular pathology underlying diabetic nephropathy,
membranous nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, acute tubular
necrosis/acute kidney injury, and interstitial nephritis, among many others.
o The final common pathway of all progressive kidney diseases leading to renal failure is tubulointerstitial
fibrosis, characterized by the replacement of normal kidney with scar tissue. Inflammation, myofibroblast
activation, matrix accumulation, and tubular and vascular atrophy and dysfunction are all involved in this
fibrotic response.
Molecular Pathogenesis of Prostate Cancer
o The prostate is a male-specific hormone-responsive gland that is anatomically located in the retroperitoneal
space and is physically associated with the urethra and neck of the bladder.
o The anatomy of the prostate gland reflects four biologically distinct zones: (1) the peripheral zone, (2) the
central zone, (3) the transitional zone, and (4) the periurethral zone.
• epthelals reed ay a taye of columnar secretory cells, with abundaneidal
fibromuscular stroma separating individual glands.
o Androgens regulate the growth and survival of the cells composing the prostatic tissue, and elimination of
androgens (via castration) leads to atrophy of the prostate.
Various prostate pathologies tend to occur in specific anatomic regions of the gland (zones). For example, the
majority of hyperplastic proliferative lesions occur in the transitional zone, and the majority of prostate Molecular
Pathogenesis of Prostate Cancer
• The prostate is affected by three major forms of pathology:
1. inflammation (or prostatitis),
2. benign nodular hyperplasia (or benign prostatic hyperplasia (BPH)), and
3. malignant prostate cancer.
• Prestons or in tealse see of terre ent tierection chrone abe teria prostatitis)
and is often a granulomatous lesion.
o BPH occurs commonly among older men (>50 years old) and results from hyperplasia of prostate epithelial
and stromal cells, presenting as discrete nodules in the periurethral region.
o With progressive enlargement of these nodules, obstruction of the urethra can occur resulting in difficulty in
urination and an inability to efficiently empty the bladder.
o cancers occur in the peripheral zone.

Molecular Biology of Breast Cancer

o Breast cancer has been increasingly recognized as a heterogeneous disease with distinct subtypes being
identified with the advances of molecular techniques and diagnostics.
o subtyping mainly depended on immunohistochemical markers such as the estrogen receptor, the
progesterone receptor, and the human epidermal growth factor receptor 2 (HER2), novel subtypes within the
three historical subtypes have been defined using gene expression profiling and next-generation
sequencing.
o This new classification has both prognostic and predictive value not only in the advanced setting but also in
the treatment of early breast cancer.
o the discovery of genomic markers of sensitivity and resistance has led to the approval of multiple targeted
therapies.
o Biomarkers - refers to a broad subcategory of medical signs - that is, objective indications of medical state
observed from outside the patient - which can be measured accurately and reproducibly.
o Immune markers are proteins that determine our ability to resist harmful agents such as bacteria and other
foreign substances.
Because this natural process can also cause rejection of transplanted organs, it is important to study
immune function.

Histologic definitions for TIL

o Tumor infiltrating lymphocytes (TILs) consist of all lymphocytic cell populations that have invaded the tumor
tissue.
o TILs have been described in a number of solid tumors, including breast cancer, and are emerging as an
important biomarker in predicting the efficacy and outcome of treatment.
o tumor-infiltrating lymphocytes used to detect lymphocytes in tumor samples.

Molecular Basis of Skin Disease

o The skin is a stratified epithelium with an inner layer of proliferating cells that can also give rise to multiple
layers of terminally differentiating cells.
o It protects the body by providing a mechanical barrier against the external environment, a chemical barrier,
cutaneous immune surveillance, and myriad proteins acting as antimicrobial peptides or signaling host
responses through chemotactic, angiogenic, growth factor, and immunosuppressive activity. The structural
integrity of the skin depends on several proteins.
o Mutations in genes encoding these proteins disrupt skin architecture, giving rise to genetic skin diseases.
Mutations in hemidesmosome-related genes give rise to skin fragility syndromes called epidermolysis
bullosa, whereas aberration in desmosomal genes give rise to variable abnormalities in skin, hair, and heart.

Molecular Basis of Skin Disease

o common inflammatory skin dermatoses were revealed to be associated with genetic mutations, such as
atopic dermatitis and its association with mutations in filaggrin gene (FLG), coding for filaggrin.
o Several hemidesmosomal and desmosomal proteins may serve as target antigens for both inherited and
acquired vesiculobullous disorders. Skin cancers can also be associated with inherited and acquired
mutations.
o Understanding the molecular pathology of skin disease provides insight into the clinical features in affected
individuals and also allows for accurate diagnosis, improved genetic counseling, prenatal genetic diagnosis,
and can also be used to diagnose cutaneous infections with pathogens difficult to identify using standard
culture techniques, such as mycobacterial or human papilloma infections.
 o New molecular data also provide a platform to develop new drugs as well as drug repositioning to treat
genetic skin diseases. Thus, understanding the molecular pathology of skin diseases can have important
implications that benefit patients.
Molecular Basis of Diseases of the Nervous System
o The central nervous system (CNS) is composed of cellular components organized in a complex structure
that is unlike other organ systems.
o At the macroscopic level, the parenchyma of the CNS can be categorized into two structurally and
functionally unique components: gray and white matter.
o The CNS can be divided into a number of anatomic regions, each with specific neurologic or cognitive
functions.
o Disease or damage to these regions produces neurologic or cognitive deficits that correlate with the
anatomic location and extent of disease. There are several ways to divide these structures.
o The main divisions are the cerebrum, cerebellum, brainstem, and spinal cord.
o Developmental neuropathology encompasses a broad variety of cerebral malformations and functional
impairments caused by disturbances of brain development, manifesting during ages from the embryonic
period through adolescence and young adulthood.
Molecular Basis of Diseases of the Nervous System
o The neurologic and psychiatric manifestations of neurodevelopmental disorders range depend on the
affected neural systems and include such diverse manifestations as epilepsy, mental retardation, cerebral
palsy, breathing disorders, ataxia, autism, and schizophrenia.
o In terms of morbidity and mortality, the spectrum is extremely broad: the mildest neurodevelopmental
disorders can be asymptomatic, whereas the worst malformations often lead to intrauterine or neonatal
demise.
Molecular Assessment of Human Diseases in the Clinical Laboratory
• Genomics - major advances in nucleic acid sequence analysis and computing technology enabled the successful
completion of the Human Genome Project.
• This new knowledge at the genetic level has been followed at the transcriptomic
(RNA) and proteomic (protein) levels.
o These advances supported the development of targeted molecular diagnostics and therapeutics, facilitating
a more personalized approach to health care, reducing unnecessary treatments and improving health
outcomes.
o For example, infectious diseases and cancer are detected earlier and more accurately.
o Molecular testing is now an integral part of disease management and therapy and spans the entire spectrum
of applications that are performed on a routine basis in most hospital clinical laboratories.
Pharmacogenomics and Personalized Medicine in the Treatment of Human Diseases
o patients respond to therapeutic drugs differently, and much of this variation can be attributed to differences
in gene sequence or copy number, resulting in proteins with altered stability, cellular concentration,
metabolic activity, or signaling properties.
o The application of pharmacogenetics, the study of how inherited variants affect drug response, is expected
to reduce the number of adverse drug reactions by facilitating the selection of an appropriate drug and dose
more efficiently than using a trial-and-error approach.
o detection of somatic variants in cancer cells can help select an effective chemotherapeutic agent and
identify appropriate targeted therapies for the individual patient's unique tumor phenotype.
o Population health research
o We want to understand the causes and consequences of health and disease in populations.
o We also want to determine how good health and poor health are distributed through populations.
o Population health involves researchers from many different disciplines, such as epidemiologists,
demographers, health economists and sociologists.