178 research outputs found
Cell transformation in tumor-development: a result of accumulation of Misrepairs of DNA through many generations of cells
Development of a tumor is known to be a result of accumulation of DNA changes
in somatic cells. However, the processes of how DNA changes are produced and
how they accumulate in somatic cells are not clear. DNA changes include two
types: point DNA mutations and chromosome changes. However, point DNA mutations
(DNA mutations) are the main type of DNA changes that can remain and accumulate
in cells. Severe DNA injuries are the causes for DNA mutations. However,
Misrepair of DNA is an essential process for transforming a DNA injury into a
survivable and inheritable DNA mutation. In somatic cells, Misrepair of DNA is
the main source of DNA mutations. Since the surviving chance of a cell by
Misrepair of DNA is low, accumulation of DNA mutations can take place only
possibly in the cells that can proliferate. Tumors can only develop in the
tissues that are regenerable. The accumulation of Misrepairs of DNA needs to
proceed in many generations of cells, and cell transformation from a normal
cell into a tumor cell is a slow and long process. However, once a cell is
transformed especially when it is malignantly transformed, the deficiency of
DNA repair and the rapid cell proliferation will accelerate the accumulation of
DNA mutations. The process of accumulation of DNA mutations is actually the
process of aging of a genome DNA. Repeated cell injuries and repeated cell
regenerations are the two preconditions for tumor-development. For cancer
prevention, a moderate and flexible living style is advised.Comment: 14 pages, 3 figure
Premature aging as a consequence of Mis-construction of tissues and organs during body development
Hutchinson-Gilford Progeria syndrome, Werner syndrome, and Cockayne syndrome
are three genetic disorders, in which the children have premature aging
features. To understand the phenomenon of premature aging, the similarity of
aging features in these syndromes to that in normal aging is investigated.
Although these three syndromes have different genetic backgrounds, all the
patients have abnormal structures of tissues/organs like that in normal aging.
Therefore, the abnormality in tissue structure is the common point in premature
aging and normal aging. This abnormality links also a defective development and
a defective repair, the Misrepair. Defective development is a result of
Mis-construction of the structure of tissues and organs as consequence of
genetic mutations. Aging is a result of Mis-reconstructions, the Misrepairs,
for maintaining the structure of tissues/organs. Construction-reconstruction of
the structure of an organism is thus the coupling point of development and
aging. Mis- construction and Mis-reconstruction (Misrepair) are the essential
processes for the development of aging-like feathers. In conclusion, premature
aging is a result of Mis- construction of tissues and organs during body
development as consequence of genetic disorders.Comment: 10 pages, 1 figur
Misrepair mechanism in the development of atherosclerotic plaques
Atherosclerosis is a disease characterized by the development of
atherosclerotic plaques (APs) in arterial endothelium. The APs in part of an
arterial wall are inhomogeneous on size and on distribution. In order to
understand this in-homogeneity, the pathology of APs is analyzed by Misrepair
mechanism, a mechanism proposed in our Misrepair-accumulation aging theory. I.
In general, development of an AP is a result of repair of injured endothelium.
Because of infusion and deposition of lipids beneath endothelial cells, the
repair has to be achieved by altered remodeling of local endothelium. Such a
repair is a Misrepair. During repair, smooth muscular cells (SMCs) are
clustered and collagen fibers are produced to the lesion of endothelium for
reconstructing an anchoring structure for endothelial cells and for forming a
barrier to isolate the lipids. II. Altered remodeling (Misrepair) makes the
local part of endothelium have increased damage-sensitivity and reduced
repair-efficiency. Thus, this part of endothelium will have increased risk for
injuries, lipid-infusion, and Misrepairs. Focalized accumulation of Misrepairs
and focalized deposition of lipids result in development of a plaque. III. By a
viscous circle between lipid-infusion and endothelium-Misrepair, growing of an
AP is self-accelerating. Namely, once an AP develops, it grows in an increasing
rate with time and it does not stop growing. Within part of an arterial wall,
older APs grow faster than younger ones. The oldest and the biggest AP is the
most threatening one in narrowing local vessel lumen. Therefore, the
self-accelerated growing of an AP is a fatal factor in atherosclerosis. In
conclusion, development of APs is focalized and self-accelerating, because it
is a result of accumulation of Misrepairs of endothelium.Comment: 8 pages, 3 figure
Development of age spots as a result of accumulation of aged cells in aged skin
Age spots are the brown spots that develop in the skin but change in color
and shape with time. To understand the mechanism of development of age spots,
characteristics of age spots are analyzed by Misrepair mechanism, a mechanism
introduced in Misrepair-accumulation aging theory. An age spot is
pathologically a group of aggregated basal cells, which contain lipofuscin
bodies. Accumulation of lipofuscin bodies is a sign of aging of a cell.
Characteristics of age spots include: inhomogeneity in distribution, growing
flatly before becoming protruding, irregularity on shape, inhomogeneity on the
color and on the protruding degree of a spot, and softness of a protruding
spot. After analyzing these characteristics, we make a hypothesis on the
process of development of an age spot. A. Aging of a tissue is the basis for
development of age spots. B. A flat spot results from accumulation of
lipofuscin containing cells. When an aged cell remains, this cell can
accelerate the aging of its neighbor cells by increasing damage sensitivity and
reducing repair efficiency of the local tissue. By a viscous circle, more and
more neighbor cells become aged and they form a flat spot, which has an
irregular shape. C. A protruding spot develops when some of the cells in a flat
spot die and release lipofuscin bodies. For the survival of an organism, the un
degradable lipofuscin bodies have to be isolated by a capsule made by fibrotic
membrane, for maintaining the structural integrity of local epidermis.
Successive deaths of lipofuscin containing cells make the capsule include more
and more dead substances by layers of fibrotic membrane. In this way, the spot
"grows" in three-dimension, resulting in protruding of the spot. In conclusion,
development of an age spot is a result of accumulation of aged cells in aged
skin.Comment: 9 page
The high osmotic pressure in a lens fiber as a driving force for the development of senile cortical cataract
In lens cataract, the clouding change in lens leads to a decline of
transparency of part of the lens. There are three types of senile cataract:
cortical cataract, nuclear cataract, and posterior/anterior sub-capsular
cataract. The most common senile cataract is cortical cataract. For
understanding cortical cataract, the pathology and the causing factors in
cortical cataract are analyzed. The clouding change in senile cortical cataract
begins from the edge of the lens and develops progressively to lens centre. The
pathology of clouding change in cortical cataract is characterized by
disruption of some lens fibers, swelling of some other fibers, and deposition
of water between fibers. Based on the property of a lens fiber, we propose here
a hypothesis on the mechanism of development of senile cortical cataract. I.
Cortical cataract is triggered by disruption of a cortical lens fiber as a
result of injury. The disrupted fiber will release water and crystallin
proteins. II. Neighbor fibers can absorb this water due to high intracellular
osmotic pressure (IOP) and become swollen. Swelling makes a fiber be stiff and
have increased risk to disrupt when it is curved during the accommodation of
the lens. These fibers will release water again when they disrupt, and the
water will make more local fibers swelling. In this way, the local fibers
become swollen and then disrupt successively. III. The successive swellings and
disruptions of local fibers result in enlargement of a clouding change in lens.
Since the fibers on the outer part of lens cortex have higher risk to be
injured than that in the inner part, a clouding change starts from the edge of
the lens. In conclusion, the progressive development of senile cortical
cataract is a result of successive swellings and disruptions of local lens
fibers, and this is driven by the high IOP in a lens fiber.Comment: 8 pages, figure
Potential of longevity: hidden in structural complexity
In order to understand the phenomenon of longevity in biological world, the
relationship between the potential of longevity and the structural complexity
of an organism is analyzed. I. The potential of longevity is the maximum
lifespan of an organism if it lives in an ideal environment. The longevity of
an organism includes two parts: the time for development (development time) and
the time for structure-maintenance (maintenance time). II. The development time
of an organism depends on its structural complexity. The maintenance time is
related to two factors: the degree of damage-exposure and the potential of
functionality for structure-maintenance. The potential of functionality is
built in structural complexity. Since both of development time and maintenance
time are determined by structural complexity, the potential of longevity of an
organism is hidden in structural complexity. III. The individuals of different
species have different potentials of longevity because they have different
structural complexities. An animal has limited longevity because it has limited
structural complexity. Limited structural complexity and limited longevity are
essential for the survival of a species. IV. Despite having the same potential
of longevity, the individuals of a species can have different lifespans. The
lifespan of an individual is more related to the degree of damage-exposure,
which is determined by the living environment and the living habit of the
individual. In conclusion, the potential of longevity of an organism is hidden
in structural complexity, but the real lifespan of an organism is more related
to the living environment.Comment: 17 pages, 10 figure
Tissue fibrosis: a principal proof for the central role of Misrepair in aging
Tissue fibrosis is the phenomenon that a tissue has progressive deposition of
collagen fibers with age. Tissue fibrosis is associated with aging of most of
our organs, and it is the main pathology in arteriosclerosis, chronic
bronchitis/emphysema, and benign prostatic hyperplasia. The causes and
characteristics of fibrosis are analyzed with Misrepair mechanism, a mechanism
proposed in Misrepair-accumulation aging theory. Tissue fibrosis is known to be
a result of repairs of tissue by collagen fibers. A repair with collagen fibers
is a manner of "Misrepair". The collagen fibers are used for replacing dead
cells or disrupted extracellular matrixes (ECMs) including elastic fibers,
myofibers, and basement membrane. The progressive tissue fibrosis with age
manifests the essential role of Misrepair in aging, because it reveals three
facts: A. a process of Misrepair exists; B. Misrepairs are unavoidable; and C.
Misrepairs accumulate. As a result of accumulation of Misrepairs of tissue with
collagen fibers, tissue fibrosis is focalized and self-accelerating, appearing
as growing of spots of hyaline degeneration. Fibrosis results in stiffness or
atrophy of an organ and progressive failure of the organ. In arteriosclerosis,
the deposition of collagen fibers in arterial wall is for replacing disrupted
elastic fibers or myofibers, however results in hardness of the wall. Wrinkle
formation is part of skin fibrosis, and it may be a result of accumulation of
collagen fibers of different lengths. Senile hair-loss and hair-whitening are
probably consequence of dermal fibrosis. In conclusion, tissue fibrosis is a
result of accumulation of Misrepairs of tissue with collagen fibers, and the
phenomenon of fibrosis is a powerful proof for the central role of Misrepair in
aging.Comment: 13 pages, 4 figure
Pediatric lymphoma may develop by "one-step" cell transformation of a lymphoid cell
Lymphomas are a large group of neoplasms developed from lymphoid cells (LCs)
in lymph nodes (LNs) or lymphoid tissues (LTs). Some forms of lymphomas,
including Burkitt lymphoma (BL), ALK+ anaplastic large cell lymphoma
(ALK+-ALCL), and T-cell lymphoblastic lymphoma/leukemia (T-LBL), occur mainly
in children and teenagers. Hodgkin's lymphoma (HL) has a peak incidence at age
20s. To understand pediatric lymphoma, we have recently proposed two hypotheses
on the causes and the mechanism of cell transformation of a LC. Hypothesis A
is: repeated bone-remodeling during bone-growth and bone-repair may be a source
of cell injuries of marrow cells including hematopoietic stem cells (HSCs),
myeloid cells, and LCs, and thymic involution may be a source of damage to the
developing T-cells in thymus. Hypothesis B is: a LC may have three pathways on
transformation: a slow, a rapid, and an accelerated. In this paper, we discuss
pediatric lymphomas by this hypothesis. Having a peak incidence at young age,
BL, T-LBL, ALK+-ALCL, and HL develop more likely as a result of rapid
transformation of a LC. In BL, ALK+-ALCL, and HL, the cell transformations may
be triggered by severe viral infections. In T-LBL, the cell transformation may
be related to thymic involution. Occurring in both adults and children, diffuse
large B-cell lymphoma (DLBCL) may develop via slow or accelerated pathway. In
conclusion, pediatric lymphoma may develop as a result of "one-step" cell
transformation of a LC, and severe viral infections may be the main trigger for
the rapid transformation of a LC in a LN/LT.Comment: 28 pages, 2 figure
Three potential sources of cell injuries of lymphoid cells associated with developments of lymphoid leukemia and lymphoma
Lymphoid leukemia (LL) and lymphoma are blood cancers developed from lymphoid
cells (LCs). To understand the cause and the mechanism of cell transformation
of a LC, we studied the potential sources of cell injuries of LCs and analyzed
how DNA changes are generated and accumulate in LCs. I. The DNA changes that
contribute to cell transformation of a LC can be generated in the LCs in
marrow, thymus, lymph nodes (LNs), and/or lymphoid tissues (LTs). In LNs/LTs,
pathogen-infections may be the main cause for cell injuries of LCs. In marrow
cavity, repeated bone-remodeling during bone-growth and bone-repair, by
producing toxic substances, may be a source of damage to hematopoietic cells,
including hematopoietic stem cells (HSCs) and developing LCs. In thymus, thymic
involution and death of stromal cells may be a damaging factor for the
developing T-cells. II. Point DNA mutation (PDM) and chromosome change (CC) are
the two major types of DNA changes. CCs include numerical CCs (NCCs) and
structural CCs (SCCs). Generation of a PDM/SCC may be a result of Misrepair of
DNA on DNA breaks. Generation of NCC is rather a consequence of dysfunction of
cell division. III. Repeated cell injuries and cell proliferation drive the
accumulation of DNA changes in LCs and HSCs. However, long-term accumulation of
DNA changes occurs mainly in long-living stem cells including HSCs and memory
cells. In conclusion, the DNA changes in LCs are generated and accumulate as a
consequence of repeated cell injuries and repeated cell proliferation; and
three potential sources of cell injuries of LCs may be: repeated
bone-remodeling, long-term thymic involution, and repeated pathogen-infections.Comment: 29, pages, 4 figure
Development of pediatric myeloid leukemia may be related to the repeatedbone-remodeling during bone-growth
Acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) are two major
formsof leukemia developed from myeloid cells (MCs). To understand why AML and
CML occurin children, we analyzed the causes and the mechanism of cell
transformation of a MC. I. Forthe MCs in marrow cavity, repeated
bone-remodeling during bone-growth may be a source ofcell injuries. II. As a
type of blood cell, a MC may have higher survivability from DNAchanges and
require obtaining fewer cancerous properties for cell transformation than a
tissuecell. III. Point DNA mutations (PDMs) and chromosome changes (CCs) are
the two majortypes of DNA changes. CCs have three subtypes by effects on a
cell: great effect CCs(GECCs), mild-effect CCs (MECCs), and intermediate-effect
CCs (IECCs). A GECC affectsone or more genes and can alone trigger cell
transformation. PDMs/MECCs are mostly mildand can accumulate in cells. Some of
the PDMs/MECCs contribute to cell transformation. AnIECC affects one or more
genes and participates in cell transformation. IV. Based on II andIII, we
hypothesize that a MC may have two pathways on transformation: a slow and
anaccelerated. Slow pathway is driven by accumulation of PDMs/MECCs.
Accelerated pathwayis driven by accumulation of PDMs/MECCs/IECC(s). A
transformation via slow pathwayoccurs at old age; whereas that via accelerated
pathway occurs at any age. Thus, CML andpediatric AML may develop via
accelerated pathway, and adult AML may develop via bothpathways. In conclusion,
pediatric AML and CML may develop as a result of transformationof a MC via
accelerated pathway; and repeated bone-remodeling for bone-growth may be
atrigger for the transformation of a MC in a child.Comment: 30 pages, 5 figure
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