The present comparative review discusses conservation of early evolutionary, relic genetics in the genome of man, which determine two different mechanistic reductive division systems expressed by normal, human diploid...The present comparative review discusses conservation of early evolutionary, relic genetics in the genome of man, which determine two different mechanistic reductive division systems expressed by normal, human diploid cells. The divisions were orderly and segregated genomes reductively to near-diploid daughter cells, which showed gain of a proliferative advantage (GPA) over cells of origin. This fact of GPA expression is a fundamental requirement for initiation of tumorigenesis. The division systems were responses to a carcinogen-free induction system, consisting of short (1 - 3 days) exposures of young cells to nutritional deprivation of amino acid glutamine (AAD). In recovery growth (2 - 4 days) endo-tetra/ochtoploid cells and normal diploid metaphase cells demonstrated chromosomal reductive divisions to respectively heterozygous and homozygous altered daughter cells. Both division systems showed co-segregating whole complements, which for reduction of the diploid metaphases could only arise from gonomeric-based autonomous behavior of maternal and paternal (mat/pat) genomes. The timely associated appearance with these latter divisions was fast growing small-cells (1/2 volume-size reduced from normal diploidy), which became homozygous from haploid, genomic doubling. Both reductive divisions thus produced genome altered progeny cells with GPA, which was associated with pre-cancer-like cell-phenotypic changes. Since both “undesirable” reductive divisions expressed orderly division sequences, their genetic controls were assumed to be “old genetics”, evolutionarily conserved in the genome of man. Support for this idea was a search for evidential material in the evolutionary record from primeval time, when haploid organisms were established. The theory was that endopolyploid and gonomery-based reductive divisions relieved the early eukaryotic organisms from accidental, non-proliferative diploidy and polyploidy, bringing the organism back to vegetative haploid proliferation. Asexual cycles were common for maintenance of propagating haploid and diploid early unicellular eukaryotes. Reduction of accidental diploidy was referred to as “one-step meiosis” which meant gonomeric-based maternal and paternal genomic independent segregations. This interpretation was supported by exceptional chromosomal behaviors. However, multiple divisions expressing non-disjunction was the choice-explanation from evolutionists, which today is also suggested for the rarer LL-1 near haploid leukemia. These preserved non-mitotic mechanistic divisions systems are today witnessed in apomixes and parthenogenesis in many animal phyla. Thus, the indications are the modern genome of man harbors, relic-genetics from past “good” evolvements assuring “stable” proliferation of ancient, primitive eukaryotes, but with cancer-like effects for normal human cells.展开更多
In a series of publications, the hypothesis of a special-type of endo-polyploidy, marked by 4-chromatid chromosomes (diplochromosomes), in the initiation of tumorigenesis has been presented from in vitro experiments. ...In a series of publications, the hypothesis of a special-type of endo-polyploidy, marked by 4-chromatid chromosomes (diplochromosomes), in the initiation of tumorigenesis has been presented from in vitro experiments. This review uses cellular happenings in benign pre-neoplasia to substantiate this idea, which appears to be linked to the wound-healing process of injured tissue. Rarer association between a wound healing process and a cancer occurrence has long been known. The wound healing multi-program-system involved a phase of tetraploidy that showed diplochromosomes. The hypothesis is that the inflammatory phase may not always be sufficient in getting rid of dead and damaged cells (by apoptosis and autophagy), such that cells with genomic damage (DNA breakage) may survive by genomic repair associated with change to diplochromosomal tetraploidy. In vitro data have shown division of these cells to be an orderly, mechanistic two-step, meiotic-like system, resulting in only two types of progeny cells: 4n/4C/G1 and 2n/2C/G1 pseudo-diploid cells with hyperplastic-like growth-morphology. In vivo damage to tissues can be from many sources for example, physical, toxic environment or from a disease as in Barrett’s esophagus (BE) with acid reflux into the esophagus. For this condition, it is acknowledged that damage of the esophagus lining is a pre-condition to hyperplastic lesions of pre-neoplasia. These initial lesions were from “diploid” propagating cells and, 4n cells with G2 genomic content (no mitosis) accumulated in these lesions before a change to dysplasia. Cell cycle kinetics put these 4n cells in G1, which with S-phase entry would lead to asymmetric tetraploid mitoses, characteristic for dysplastic lesions. This change in hyperplasia to dysplasia is the root-essential condition for a potential progression of pre-neoplasia to cancer. In BE the hyperplastic lesion showed increasing gains of cells with inactivated p53 and p16[ink4a] genes, which destroyed the retinoblastoma (Rb) protein-control over S-phase entry from G1. Rb-protein is a key controller of cycling advancement from G1 (also for normal cells), and is frequently inactivated in tumor cells. Thus in BE, 4n/4C/G1 cells with mutated p53 and p16[ink4a] genes gained cycling ability to tetraploid aneuploid cell cycles, which constituted the change from hyperplasia to dysplastic lesions. In general, such lesions have high predictive value for a cancerous change. Proliferation rates of pre-neoplasia and progression have been shown to be increased by a component of the wound healing program.展开更多
The objective was to gain proof of genome damage-repair induced mitotic slippage process (MSP) to 4n-diplochromosome skewed division-system, earlier suggested to have “cancer-deciding” consequences. Our damage-model...The objective was to gain proof of genome damage-repair induced mitotic slippage process (MSP) to 4n-diplochromosome skewed division-system, earlier suggested to have “cancer-deciding” consequences. Our damage-model showed two succeeding phases: molecular mutations for initiation of fitness-gained cells, and large chromosomal changes to aneuploidy from inherited DNA-breakage-repair inaccuracies. The mutations were gained while DNA-repair and DNA-replication, co-existed in the route to tetraploidy, a phenomenon also expressed for some existing unicellular organisms. These organisms also showed genome reductive, amitotic, meioticlike division, and was the origin of human genome conserved, self-inflicted 90° reorientation of the 4n nucleus relative to the cytoskeleton axis. In the in vitro DNA-damage model, this remarkable 4n-event deciding “flat-upright” cell-growth characteristics showed several consequences, for example, cancer-important, E-cadherin-β-catenin cell-to-cell adherence destruction, which gave diploid progeny cells, mobility freedom from cell contact inhibition, likely in renewal tissues. This 4n-skewed division-system with inheritance in progeny cells for repeat occurrences as mentioned for flat-up-right growth patterns is similar to claimed concepts of metaplasia-EMT/MET embryogenesis events in cancer evolution. A scrutiny of this literature, proof-wise invalidated this embryological concept by tetraploid 8C cells occurring in MET events and, was noted for small cell occurrence, i.e., diploidy from 4n-8C reductive division, an also event for tumor relapse cells, derived from genome damaging therapy agents. Pre-cancer hyperplasia reported MSP, cadherincatenin destruction and 90° perpendicularity to basal cell membrane. The DNA-damage-repair model can weed-out therapy-agents triggering 4n-skewed division. Cancer-control, beginning-information, is likely from mutational identity of the 4n derived fitness-gained cells.展开更多
The objective herein was to connect the ontogeny process of diplochromosomal, amitotic, 4n-skewed division-system, to cytogenetic deficiency lesions in satellite, repetitive DNAs, especially in the chromosomal fragile...The objective herein was to connect the ontogeny process of diplochromosomal, amitotic, 4n-skewed division-system, to cytogenetic deficiency lesions in satellite, repetitive DNAs, especially in the chromosomal fragile sites, some 100 distributed over the genome. These latter studies had shown that chemical induced replication-stress led to un-replicated lesions in these fragile sites, which from inaccurate repair processes caused genomic instability. In the chain of events of the ontogeny process to the special tetraploidy, it was proposed that primary damaged human cells could undergo replication stress from repair-process present during cell replication, a suggestion verified by X-ray damaged cells producing the unstable fragile sites (see text). The cancer-importance for therapy is recognition of cell cycle change for the 4n derivative fitness-gained, diploid progeny cells. An open question is whether RB controlling G1 to S-period is mutated at this suggested tumorigenesis initiating phase, and if so, with what consequences for therapy. The fragile site studies further showed that repair of repetitive DNAs could produce two types of genomic changes: single gene mutations and CNVs, which were here shown to be chromosomally located on “borders” to repairing satellite lesions. This genomic placement was found to correspond to mutations identified in tumor sequencing (p53, Rb, MYC), favoring a bad luck location for their cancer “mutational nature”. The CNVs in cancers, are here seen as molecular expressions of long-known cytogenetic HSRs and DMs also with demonstrated origin from amplifications of single genes. Over-expression of oncogenes was hinted of being from duplications, but Drosophila genetics demonstrated the opposite, gene inactivation. The reduced eye-size from dominant, BAR-Ultra-Bar-eye phenotypes, was caused by duplications, inactivating the genetic system for eye-size. The finding of CNVs showing “evasion” of the immune system suggests, inactivation of immune-determining genetics. Since mutated genes on borders to satellite DNAs are a fact in hematological cancers, the 4n-skewed division-system is suggested to replace debated leukemogenesis with fitness-gain from molecular mutations. For these cancers the question is how normal bone marrow cells attain genomic damage for special tetraploidy, which was referred to studies of cells moving in artificial marrow-like substrate, needing serious attention.展开更多
The present study presents cytogenetics/cytology of haploidization in the origin of a new, fast growing diploid, small cell-type (F-dPCs). The sequence of events was haploid groupings of the chromosomes in normal, hum...The present study presents cytogenetics/cytology of haploidization in the origin of a new, fast growing diploid, small cell-type (F-dPCs). The sequence of events was haploid groupings of the chromosomes in normal, human metaphase cells, followed by genomic doubling to homozygousdiploidy. These events were responses to DNA replication stress fromamino acid glutamine deprivation. Importantly, these homozygous cells outgrew normal fibroblasts in 2 - 3 passages—they had gained proliferative advantage (GPA), presumably from loss (LOH) of tumor suppressor genes. They were morphologically changed cells with rounded nuclei that grew in a “streaming” growth pattern and with changed form and size of mitosis, similar to some hyperplasias. The grouping of the chromosomes in metaphase cells was asymmetric with a narrow range around the median (23) (no micro-nuclei), suggesting genetic control. The root-origin of haploidization was evidenced by maternal and paternal genomes occupying separate territories in metaphase cells, which assumedly permitted independent segregations of bichromatid chromosomes. In near-haploid ALL-L1 leukemia the loss of virtually, whole chromosomal complements was judged by SNP array analyses, as a primary event before genomic doubling to hyperdiploidy with LOH. From the present data such specific, non-random loss of chromosomes strongly suggested, a haploidization process capable of genomic doubling, as observed for the “birth” of the small, F-dPCs. This suggestion was supported by this type of leukemia being the L1-type, where L1 signifies small cells. The possibility now exists that a tumorigenic process can be initiated directly from diploid cells through haploid (near-haploid) distributed chromosomes in normal metaphase cells. This event followed by monosomic doublings to UPDs would lead to massive LOH and a return to para-diploidy, a frequent occurrence in many types of tumors. The present simple, cultural derivations of the extraordinary F-dPCs allow GPA-identification and experimental manipulations, perhaps relevant in a vaccine program.展开更多
The objective in this experimental article is to gain evidential proof of near-dead cells, (sick-cells in relapse tumor) responding with recovery growth from special 4n, multi-chromatid chromosomes. Note, near-dead &l...The objective in this experimental article is to gain evidential proof of near-dead cells, (sick-cells in relapse tumor) responding with recovery growth from special 4n, multi-chromatid chromosomes. Note, near-dead </span><i><span style="font-family:Verdana;">normal human cells</span></i><span style="font-family:Verdana;"> with such converted chromosome structure gave rise to proliferative, fitness-gained, diploid </span><i><span style="font-family:Verdana;">first cells</span></i><span style="font-family:Verdana;">,</span><i> </i><span style="font-family:Verdana;">which</span><i> </i><span style="font-family:Verdana;">further gave rise to three different cell shape changed, recovery growth patterns. Previously, two cell shape changes had been recovered from same type normal human cells, transiently exposed to amino acid glutamine deficient growth medium with recovery growths also associated with presence of the special 4n cells. The 4n cell-division had been concluded to be a meiotic-like two-step division system to the fitness-gained diploid cells in numerous experiments. The main characteristi</span><span style="font-family:Verdana;">cs of this division system, was firstly whole genomes without polar oriented bent centromeres moving apart followed by much rarer simple fission division to two or three diploid cells, selectable for first cell proliferatio</span><span style="font-family:Verdana;">n. In general these 4n cells showed metaphase type rosette figures moving apart not in the normal spindle associated mitotic shape with centromeres polar-pointing with sloping arms. This sequence of events induced by glutamine-deficiency, was earlier shown to cause DNA breakage in metabolic studies however, the near-death condition was only assumed from normal fibro-blastic cell-sheet shrinkage. This was rectified by an RNA virus (Coxakie-B3), which virology known is a highly cell killing virus (4+ CPE on their scale). This virus replicates only in replicating cells, which led to recovery growths with progressive phenotypic cell-shape changes (spindle, polygonal and roundness cells), each intervened by “total” cell destruction. These three different growth patterns </span><span style="font-family:Verdana;">had morphologies, indistinguishably from today’s cancer diagnostic morphologies. “Mitotic” analyses of beginning growths for the three phenotypes revealed the special rosette figure separations from special 4n and higher ploidy level cells, and also total absence of spindle type mitoses. Tumorigenesis-relevant </span><span style="font-family:Verdana;">was centromere-puffing with premature chromatid separation, and chromatin compaction, a mechanism, that was suggested to protect the genome from damage (text). We suggest that the multi-chromatid polyploid cells with their genome reductive division system, can be a tractable </span><i><span style="font-family:Verdana;">in vitro</span></i><span style="font-family:Verdana;"> model system for therapy information, when repeated from a cell-killing agent, producing virus-free recovery growths. Will it be enacted upon? Not likely with profit-greedy industrial Goliath in the helm of cancer research. But, a not for profit cancer organization, could change this appalling situation.展开更多
Official (NIH) cancer investigation is on identification of inherited cancer genes in you and me for early interventions, and for use of such knowledge in therapy. In this review the emphasis is on the unknown cancer ...Official (NIH) cancer investigation is on identification of inherited cancer genes in you and me for early interventions, and for use of such knowledge in therapy. In this review the emphasis is on the unknown cancer initiation, and on the question of a mechanism for inherited CIN (chromosomal instability). Evidence for fitness increased cells from the mitotic slippage process (in vivo/in vitro) originated from genome damaged diploid cells in G2/M, skipping mitosis to G1, which illegitimately permitted S-phase re-replication of the chromatid cohesed-2n cells to 4n-tetraploidy. During which, down-load of genome-wide cohesin occurred, producing 4-chromatid diplochromosomes, evolutionary conserved in repair of DNA. This type of 4n cells divided 2-step meiotic-like, leading to diploid aneuploid cells with increased fitness, and expression of gross chromosomal anomalies in proliferation. The diploid cohesed chromatids during re-replication would hinder replication of sticky heterochromatic regions, resulting in their under-replication, and known from Drosophila. The human chromosomes are longitudinally differentiated into satellite DNA regions, folic acid sensitive sites and the primary constriction (centromere);they are breakage sensitive regions and being heterochromatic. This strongly suggests, multiple, chromosomal regional under-replication-cites, translated to origin of slippage, S-CIN, a genome inherited destabilization mechanism. Logically, S-CIN would affect genes differentially depending on chromosome location, for example, the high frequency in cancers of mutated p53 on the small 17p-arm, which with centromere breakage would be preferentially lost in mitosis. This likely S-CIN mechanism in cancer evolution can be studied in vivo for APC mutated crypt cells with demonstrated mitotic slippage process.展开更多
In a series of publications a special, tetraploid diplochromosomal division system to only two types of progeny cells (4n/4C/G1 and 2n/4C para-diploid) has been suggested to initiate preneoplasia that can lead to a ca...In a series of publications a special, tetraploid diplochromosomal division system to only two types of progeny cells (4n/4C/G1 and 2n/4C para-diploid) has been suggested to initiate preneoplasia that can lead to a cancerous pathway. Colorectal and other preneoplasia are known with the pathogenic, histological phases of hyperplasia to arrested adenoma/nevi that can give rise to dysplasia with high risk for cancer development. The present theme is to find solutions to tumorigenic unsolved, biological problems (queries), explainable from the tetraploid 4n-system, which would support its operation in the cancerous pathway. Presently admitted, the mutational sequencing of the cancer genome (cancer chemistry) cannot discover so-called “dark matter”, which herein is considered to be the queries. The solutions from the 4n-system were largely supported by mutated APC-induced same type of tetraploidy from the mitotic slippage process. But importantly, these behaviors and consequences could be linked to the beginning of hyperplastic lesions and their development to the arrest-phase of preneoplasia (polyps/nevi). Function of HFSMs is mostly unknown, but for Barrett’s esophagus, HFSMs (p53, p16ink4a) caused inactivation of the Rb gene, leading to dysplasia with 4n, aneuploid, abnormal cell cycles. In vitro models of the 4n-system from normal human cells recapitulated preneoplasia-like histopathological changes. It was speculated that the “cancer-crucial” step to dysplasia could be therapy-vulnerable to CRISPR-caspase editing, and perhaps antibody treatment. Additionally, the 4n-system with spontaneous cell-behaviors together with preneoplasia molecular data promises construction of a more truthful cancer-paradigm than from sequencing data alone.展开更多
We have known since 1976 that cancer evolves clonally from one initiated<span style="font-family:;" "=""><span> normal human cell, the </span><i><span>first cell&...We have known since 1976 that cancer evolves clonally from one initiated<span style="font-family:;" "=""><span> normal human cell, the </span><i><span>first cell</span></i><span>. Today we see that this fact has been overshadowed from federal funding choice of the mutation theory (MT), which not yet has shown tumorigenesis-initiation in normal human cells. Our suggested, death signaled, stress model from time delayed S-period (replication slowness), causing repair instability from under-replicated lesions in repetitive DNAs, herein has the objective of revealing, significant literature support from a mini-review. We reasoned that early versus late S-period stress would </span><span>have different outcomes: early the slowness affecting mitotic slippage with</span> <span>diploid re-replication to 4n cells whereas late-S, with milder stress effect,</span><span> pro</span><span>ducing diploid cells. In cancer burden, near-half is diploid, but tetraploid</span><span> solid tumors have the attention. The initial 4n cells were special with orderly genomic reductive division to diploid first cells with measurable fitness-gain from hours-reduced total cell cycle time. Experimental data from Coxsakie-B3 virus infected normal fibroblasts, reiterated 4n cell production from </span><span>death-s</span><span>ignaled recovery-cells with progressive cell-phenotypic changes to polygon</span><span>al </span><span>and roundness cell-shapes, indistinguishable from diagnostic/prognostic </span><span>cancer </span><span>morphology. The 4n cells showed a self-inflicted 90</span></span><span style="font-family:;" "=""><span><span style="color:#4F4F4F;white-space:normal;background-color:#FFFFFF;"><span style="color:#4F4F4F;white-space:normal;background-color:#FFFFFF;">°</span></span></span><span> turn of the 4n nucleus</span></span><span style="font-family:;" "=""> <span>before division, affecting a perpendicular orientation of the fitness-gained</span><span> first cells relative to neighboring cells. In an illustrated cell cycle drawing with early and late S-period stress, it became clear that coding genes on borders of repair unstable satellite, repetitive DNA regions, could become mutated. We found these mutations to be tumor SMGs (significantly mutated genes). Evidential material was presented for loss of function genetics driving tumorigenesis to a parasitic lifestyle.</span></span>展开更多
Cancers in young children in early growing age was a short PBS (KQED) report (11/21/2014), but without informational source, which prompted a Google search. Sports-associated injuries with medical healing treatments c...Cancers in young children in early growing age was a short PBS (KQED) report (11/21/2014), but without informational source, which prompted a Google search. Sports-associated injuries with medical healing treatments concluded that there were no association between these body traumas and cancer development. But there are other activities from young children, such as “dare-devil” skateboard and bicycling meter-high jumping with potential high energy falls, to serious broken-bone injuries. Falls of children are among the most common causes of US emergency response. The question is why bodily injury is associated with cancer-development? An answer to this question was exemplified by osteosarcoma in young children, which suggested that injury to growing points of bone and surrounding soft tissue cells would elicit a repair process (wound healing process) producing polyploidy with diplochromosomes. The non-mitotic reductive division of such 4-chromatid chromosomes has been shown?in vitro?to produce pathological cancer-like phenotypes, including gain of a proliferative advantage.展开更多
<p> <span><span style="font-family:;" "=""><span>Normal cells must become cancer-enabling before anything else occurs, according to latest literature. The goal in this ...<p> <span><span style="font-family:;" "=""><span>Normal cells must become cancer-enabling before anything else occurs, according to latest literature. The goal in this mini-review is to demonstrate special tetraploidy in the enabling process. This we have shown from genomic damage, DDR (DNA Damage Response) activity with skip of mitosis leading to diploid G2 cells at the G1 border in need of chromatin repair for continued cell cycling to the special tetraploid division system. In several studies</span><span> </span><span>specific methylation transferase genes were activated in normal human cells in tissue fields</span><span>, </span><span>containing different cell growth stages of the cancerous process. Histology studies, in addition to molecular chemistry for identification of oncogenic mutational change</span></span></span><span><span><span>,</span></span></span><span><span><span> w</span></span></span><span><span><span>ere</span></span></span><span><span><span style="font-family:;" "=""><span> a welcome change (see below). In a study on melanoma origin, DDR also showed arrested diploid cells regaining cycling from methylation transferase activity with causation of 2n melanocytes transforming to 4n melanoblasts, giving rise to epigenetic tumorigenesis enabled First Cells. Such First Cells were from Barrett’s esophagus shown to have inherited the unique division system from 4n diplochromosomal cells, first described in mouse ascites cancer cells (below). We discovered that the large nucleus prior to chromosomal division turned 90<span style="color:#4F4F4F;white-space:normal;background-color:#FFFFFF;">°</span> relative to the cytoskeleton axis, and divided genome reductive to diploid, First Cells, in a perpendicular </span><span>orientation to the surrounding normal cells they had originated from. This unique division system was herein shown to occur at metastasis stage, imply</span><span>ing activity throughout the cancerous evolution. Another study showed 4-chromatid tetraploidy in development to B-cell lymphoma, and that such cancer cells also proliferated with participation of this unusual division system. Such participation has long been known from Bloom’s inherited syndrome with repair chiasmas between the four chromatids, also an </span><i><span>in vitro</span></i><span> observation by us. Our cytogenetic approach also revealed that they believed mitotic division in cancer cells is wrong because such cell divisions were found to be from an adaptation between amitosis and mitosis, called amitotic</span></span></span></span><span><span><span>-</span></span></span><span><span><span style="font-family:;" "=""><span>mitosis. Amitosis means division without centrosomes, which has long been known from oral cancer cells, in that MOTCs (microtubule orga</span><span>nizing center) were lacking centrioles. This observation calls for re-introduction </span><span>of karyotype and cell division studies in cancer cell proliferation. It has high probability of contributing novel approaches to cancer control from screening of drugs against the amitotic-mitotic division apparatus.</span></span></span></span><span><span><span style="font-family:;" "=""> </span></span></span> </p> <span></span><span></span> <p> <span></span> </p>展开更多
文摘The present comparative review discusses conservation of early evolutionary, relic genetics in the genome of man, which determine two different mechanistic reductive division systems expressed by normal, human diploid cells. The divisions were orderly and segregated genomes reductively to near-diploid daughter cells, which showed gain of a proliferative advantage (GPA) over cells of origin. This fact of GPA expression is a fundamental requirement for initiation of tumorigenesis. The division systems were responses to a carcinogen-free induction system, consisting of short (1 - 3 days) exposures of young cells to nutritional deprivation of amino acid glutamine (AAD). In recovery growth (2 - 4 days) endo-tetra/ochtoploid cells and normal diploid metaphase cells demonstrated chromosomal reductive divisions to respectively heterozygous and homozygous altered daughter cells. Both division systems showed co-segregating whole complements, which for reduction of the diploid metaphases could only arise from gonomeric-based autonomous behavior of maternal and paternal (mat/pat) genomes. The timely associated appearance with these latter divisions was fast growing small-cells (1/2 volume-size reduced from normal diploidy), which became homozygous from haploid, genomic doubling. Both reductive divisions thus produced genome altered progeny cells with GPA, which was associated with pre-cancer-like cell-phenotypic changes. Since both “undesirable” reductive divisions expressed orderly division sequences, their genetic controls were assumed to be “old genetics”, evolutionarily conserved in the genome of man. Support for this idea was a search for evidential material in the evolutionary record from primeval time, when haploid organisms were established. The theory was that endopolyploid and gonomery-based reductive divisions relieved the early eukaryotic organisms from accidental, non-proliferative diploidy and polyploidy, bringing the organism back to vegetative haploid proliferation. Asexual cycles were common for maintenance of propagating haploid and diploid early unicellular eukaryotes. Reduction of accidental diploidy was referred to as “one-step meiosis” which meant gonomeric-based maternal and paternal genomic independent segregations. This interpretation was supported by exceptional chromosomal behaviors. However, multiple divisions expressing non-disjunction was the choice-explanation from evolutionists, which today is also suggested for the rarer LL-1 near haploid leukemia. These preserved non-mitotic mechanistic divisions systems are today witnessed in apomixes and parthenogenesis in many animal phyla. Thus, the indications are the modern genome of man harbors, relic-genetics from past “good” evolvements assuring “stable” proliferation of ancient, primitive eukaryotes, but with cancer-like effects for normal human cells.
文摘In a series of publications, the hypothesis of a special-type of endo-polyploidy, marked by 4-chromatid chromosomes (diplochromosomes), in the initiation of tumorigenesis has been presented from in vitro experiments. This review uses cellular happenings in benign pre-neoplasia to substantiate this idea, which appears to be linked to the wound-healing process of injured tissue. Rarer association between a wound healing process and a cancer occurrence has long been known. The wound healing multi-program-system involved a phase of tetraploidy that showed diplochromosomes. The hypothesis is that the inflammatory phase may not always be sufficient in getting rid of dead and damaged cells (by apoptosis and autophagy), such that cells with genomic damage (DNA breakage) may survive by genomic repair associated with change to diplochromosomal tetraploidy. In vitro data have shown division of these cells to be an orderly, mechanistic two-step, meiotic-like system, resulting in only two types of progeny cells: 4n/4C/G1 and 2n/2C/G1 pseudo-diploid cells with hyperplastic-like growth-morphology. In vivo damage to tissues can be from many sources for example, physical, toxic environment or from a disease as in Barrett’s esophagus (BE) with acid reflux into the esophagus. For this condition, it is acknowledged that damage of the esophagus lining is a pre-condition to hyperplastic lesions of pre-neoplasia. These initial lesions were from “diploid” propagating cells and, 4n cells with G2 genomic content (no mitosis) accumulated in these lesions before a change to dysplasia. Cell cycle kinetics put these 4n cells in G1, which with S-phase entry would lead to asymmetric tetraploid mitoses, characteristic for dysplastic lesions. This change in hyperplasia to dysplasia is the root-essential condition for a potential progression of pre-neoplasia to cancer. In BE the hyperplastic lesion showed increasing gains of cells with inactivated p53 and p16[ink4a] genes, which destroyed the retinoblastoma (Rb) protein-control over S-phase entry from G1. Rb-protein is a key controller of cycling advancement from G1 (also for normal cells), and is frequently inactivated in tumor cells. Thus in BE, 4n/4C/G1 cells with mutated p53 and p16[ink4a] genes gained cycling ability to tetraploid aneuploid cell cycles, which constituted the change from hyperplasia to dysplastic lesions. In general, such lesions have high predictive value for a cancerous change. Proliferation rates of pre-neoplasia and progression have been shown to be increased by a component of the wound healing program.
文摘The objective was to gain proof of genome damage-repair induced mitotic slippage process (MSP) to 4n-diplochromosome skewed division-system, earlier suggested to have “cancer-deciding” consequences. Our damage-model showed two succeeding phases: molecular mutations for initiation of fitness-gained cells, and large chromosomal changes to aneuploidy from inherited DNA-breakage-repair inaccuracies. The mutations were gained while DNA-repair and DNA-replication, co-existed in the route to tetraploidy, a phenomenon also expressed for some existing unicellular organisms. These organisms also showed genome reductive, amitotic, meioticlike division, and was the origin of human genome conserved, self-inflicted 90° reorientation of the 4n nucleus relative to the cytoskeleton axis. In the in vitro DNA-damage model, this remarkable 4n-event deciding “flat-upright” cell-growth characteristics showed several consequences, for example, cancer-important, E-cadherin-β-catenin cell-to-cell adherence destruction, which gave diploid progeny cells, mobility freedom from cell contact inhibition, likely in renewal tissues. This 4n-skewed division-system with inheritance in progeny cells for repeat occurrences as mentioned for flat-up-right growth patterns is similar to claimed concepts of metaplasia-EMT/MET embryogenesis events in cancer evolution. A scrutiny of this literature, proof-wise invalidated this embryological concept by tetraploid 8C cells occurring in MET events and, was noted for small cell occurrence, i.e., diploidy from 4n-8C reductive division, an also event for tumor relapse cells, derived from genome damaging therapy agents. Pre-cancer hyperplasia reported MSP, cadherincatenin destruction and 90° perpendicularity to basal cell membrane. The DNA-damage-repair model can weed-out therapy-agents triggering 4n-skewed division. Cancer-control, beginning-information, is likely from mutational identity of the 4n derived fitness-gained cells.
文摘The objective herein was to connect the ontogeny process of diplochromosomal, amitotic, 4n-skewed division-system, to cytogenetic deficiency lesions in satellite, repetitive DNAs, especially in the chromosomal fragile sites, some 100 distributed over the genome. These latter studies had shown that chemical induced replication-stress led to un-replicated lesions in these fragile sites, which from inaccurate repair processes caused genomic instability. In the chain of events of the ontogeny process to the special tetraploidy, it was proposed that primary damaged human cells could undergo replication stress from repair-process present during cell replication, a suggestion verified by X-ray damaged cells producing the unstable fragile sites (see text). The cancer-importance for therapy is recognition of cell cycle change for the 4n derivative fitness-gained, diploid progeny cells. An open question is whether RB controlling G1 to S-period is mutated at this suggested tumorigenesis initiating phase, and if so, with what consequences for therapy. The fragile site studies further showed that repair of repetitive DNAs could produce two types of genomic changes: single gene mutations and CNVs, which were here shown to be chromosomally located on “borders” to repairing satellite lesions. This genomic placement was found to correspond to mutations identified in tumor sequencing (p53, Rb, MYC), favoring a bad luck location for their cancer “mutational nature”. The CNVs in cancers, are here seen as molecular expressions of long-known cytogenetic HSRs and DMs also with demonstrated origin from amplifications of single genes. Over-expression of oncogenes was hinted of being from duplications, but Drosophila genetics demonstrated the opposite, gene inactivation. The reduced eye-size from dominant, BAR-Ultra-Bar-eye phenotypes, was caused by duplications, inactivating the genetic system for eye-size. The finding of CNVs showing “evasion” of the immune system suggests, inactivation of immune-determining genetics. Since mutated genes on borders to satellite DNAs are a fact in hematological cancers, the 4n-skewed division-system is suggested to replace debated leukemogenesis with fitness-gain from molecular mutations. For these cancers the question is how normal bone marrow cells attain genomic damage for special tetraploidy, which was referred to studies of cells moving in artificial marrow-like substrate, needing serious attention.
文摘The present study presents cytogenetics/cytology of haploidization in the origin of a new, fast growing diploid, small cell-type (F-dPCs). The sequence of events was haploid groupings of the chromosomes in normal, human metaphase cells, followed by genomic doubling to homozygousdiploidy. These events were responses to DNA replication stress fromamino acid glutamine deprivation. Importantly, these homozygous cells outgrew normal fibroblasts in 2 - 3 passages—they had gained proliferative advantage (GPA), presumably from loss (LOH) of tumor suppressor genes. They were morphologically changed cells with rounded nuclei that grew in a “streaming” growth pattern and with changed form and size of mitosis, similar to some hyperplasias. The grouping of the chromosomes in metaphase cells was asymmetric with a narrow range around the median (23) (no micro-nuclei), suggesting genetic control. The root-origin of haploidization was evidenced by maternal and paternal genomes occupying separate territories in metaphase cells, which assumedly permitted independent segregations of bichromatid chromosomes. In near-haploid ALL-L1 leukemia the loss of virtually, whole chromosomal complements was judged by SNP array analyses, as a primary event before genomic doubling to hyperdiploidy with LOH. From the present data such specific, non-random loss of chromosomes strongly suggested, a haploidization process capable of genomic doubling, as observed for the “birth” of the small, F-dPCs. This suggestion was supported by this type of leukemia being the L1-type, where L1 signifies small cells. The possibility now exists that a tumorigenic process can be initiated directly from diploid cells through haploid (near-haploid) distributed chromosomes in normal metaphase cells. This event followed by monosomic doublings to UPDs would lead to massive LOH and a return to para-diploidy, a frequent occurrence in many types of tumors. The present simple, cultural derivations of the extraordinary F-dPCs allow GPA-identification and experimental manipulations, perhaps relevant in a vaccine program.
文摘The objective in this experimental article is to gain evidential proof of near-dead cells, (sick-cells in relapse tumor) responding with recovery growth from special 4n, multi-chromatid chromosomes. Note, near-dead </span><i><span style="font-family:Verdana;">normal human cells</span></i><span style="font-family:Verdana;"> with such converted chromosome structure gave rise to proliferative, fitness-gained, diploid </span><i><span style="font-family:Verdana;">first cells</span></i><span style="font-family:Verdana;">,</span><i> </i><span style="font-family:Verdana;">which</span><i> </i><span style="font-family:Verdana;">further gave rise to three different cell shape changed, recovery growth patterns. Previously, two cell shape changes had been recovered from same type normal human cells, transiently exposed to amino acid glutamine deficient growth medium with recovery growths also associated with presence of the special 4n cells. The 4n cell-division had been concluded to be a meiotic-like two-step division system to the fitness-gained diploid cells in numerous experiments. The main characteristi</span><span style="font-family:Verdana;">cs of this division system, was firstly whole genomes without polar oriented bent centromeres moving apart followed by much rarer simple fission division to two or three diploid cells, selectable for first cell proliferatio</span><span style="font-family:Verdana;">n. In general these 4n cells showed metaphase type rosette figures moving apart not in the normal spindle associated mitotic shape with centromeres polar-pointing with sloping arms. This sequence of events induced by glutamine-deficiency, was earlier shown to cause DNA breakage in metabolic studies however, the near-death condition was only assumed from normal fibro-blastic cell-sheet shrinkage. This was rectified by an RNA virus (Coxakie-B3), which virology known is a highly cell killing virus (4+ CPE on their scale). This virus replicates only in replicating cells, which led to recovery growths with progressive phenotypic cell-shape changes (spindle, polygonal and roundness cells), each intervened by “total” cell destruction. These three different growth patterns </span><span style="font-family:Verdana;">had morphologies, indistinguishably from today’s cancer diagnostic morphologies. “Mitotic” analyses of beginning growths for the three phenotypes revealed the special rosette figure separations from special 4n and higher ploidy level cells, and also total absence of spindle type mitoses. Tumorigenesis-relevant </span><span style="font-family:Verdana;">was centromere-puffing with premature chromatid separation, and chromatin compaction, a mechanism, that was suggested to protect the genome from damage (text). We suggest that the multi-chromatid polyploid cells with their genome reductive division system, can be a tractable </span><i><span style="font-family:Verdana;">in vitro</span></i><span style="font-family:Verdana;"> model system for therapy information, when repeated from a cell-killing agent, producing virus-free recovery growths. Will it be enacted upon? Not likely with profit-greedy industrial Goliath in the helm of cancer research. But, a not for profit cancer organization, could change this appalling situation.
文摘Official (NIH) cancer investigation is on identification of inherited cancer genes in you and me for early interventions, and for use of such knowledge in therapy. In this review the emphasis is on the unknown cancer initiation, and on the question of a mechanism for inherited CIN (chromosomal instability). Evidence for fitness increased cells from the mitotic slippage process (in vivo/in vitro) originated from genome damaged diploid cells in G2/M, skipping mitosis to G1, which illegitimately permitted S-phase re-replication of the chromatid cohesed-2n cells to 4n-tetraploidy. During which, down-load of genome-wide cohesin occurred, producing 4-chromatid diplochromosomes, evolutionary conserved in repair of DNA. This type of 4n cells divided 2-step meiotic-like, leading to diploid aneuploid cells with increased fitness, and expression of gross chromosomal anomalies in proliferation. The diploid cohesed chromatids during re-replication would hinder replication of sticky heterochromatic regions, resulting in their under-replication, and known from Drosophila. The human chromosomes are longitudinally differentiated into satellite DNA regions, folic acid sensitive sites and the primary constriction (centromere);they are breakage sensitive regions and being heterochromatic. This strongly suggests, multiple, chromosomal regional under-replication-cites, translated to origin of slippage, S-CIN, a genome inherited destabilization mechanism. Logically, S-CIN would affect genes differentially depending on chromosome location, for example, the high frequency in cancers of mutated p53 on the small 17p-arm, which with centromere breakage would be preferentially lost in mitosis. This likely S-CIN mechanism in cancer evolution can be studied in vivo for APC mutated crypt cells with demonstrated mitotic slippage process.
文摘In a series of publications a special, tetraploid diplochromosomal division system to only two types of progeny cells (4n/4C/G1 and 2n/4C para-diploid) has been suggested to initiate preneoplasia that can lead to a cancerous pathway. Colorectal and other preneoplasia are known with the pathogenic, histological phases of hyperplasia to arrested adenoma/nevi that can give rise to dysplasia with high risk for cancer development. The present theme is to find solutions to tumorigenic unsolved, biological problems (queries), explainable from the tetraploid 4n-system, which would support its operation in the cancerous pathway. Presently admitted, the mutational sequencing of the cancer genome (cancer chemistry) cannot discover so-called “dark matter”, which herein is considered to be the queries. The solutions from the 4n-system were largely supported by mutated APC-induced same type of tetraploidy from the mitotic slippage process. But importantly, these behaviors and consequences could be linked to the beginning of hyperplastic lesions and their development to the arrest-phase of preneoplasia (polyps/nevi). Function of HFSMs is mostly unknown, but for Barrett’s esophagus, HFSMs (p53, p16ink4a) caused inactivation of the Rb gene, leading to dysplasia with 4n, aneuploid, abnormal cell cycles. In vitro models of the 4n-system from normal human cells recapitulated preneoplasia-like histopathological changes. It was speculated that the “cancer-crucial” step to dysplasia could be therapy-vulnerable to CRISPR-caspase editing, and perhaps antibody treatment. Additionally, the 4n-system with spontaneous cell-behaviors together with preneoplasia molecular data promises construction of a more truthful cancer-paradigm than from sequencing data alone.
文摘We have known since 1976 that cancer evolves clonally from one initiated<span style="font-family:;" "=""><span> normal human cell, the </span><i><span>first cell</span></i><span>. Today we see that this fact has been overshadowed from federal funding choice of the mutation theory (MT), which not yet has shown tumorigenesis-initiation in normal human cells. Our suggested, death signaled, stress model from time delayed S-period (replication slowness), causing repair instability from under-replicated lesions in repetitive DNAs, herein has the objective of revealing, significant literature support from a mini-review. We reasoned that early versus late S-period stress would </span><span>have different outcomes: early the slowness affecting mitotic slippage with</span> <span>diploid re-replication to 4n cells whereas late-S, with milder stress effect,</span><span> pro</span><span>ducing diploid cells. In cancer burden, near-half is diploid, but tetraploid</span><span> solid tumors have the attention. The initial 4n cells were special with orderly genomic reductive division to diploid first cells with measurable fitness-gain from hours-reduced total cell cycle time. Experimental data from Coxsakie-B3 virus infected normal fibroblasts, reiterated 4n cell production from </span><span>death-s</span><span>ignaled recovery-cells with progressive cell-phenotypic changes to polygon</span><span>al </span><span>and roundness cell-shapes, indistinguishable from diagnostic/prognostic </span><span>cancer </span><span>morphology. The 4n cells showed a self-inflicted 90</span></span><span style="font-family:;" "=""><span><span style="color:#4F4F4F;white-space:normal;background-color:#FFFFFF;"><span style="color:#4F4F4F;white-space:normal;background-color:#FFFFFF;">°</span></span></span><span> turn of the 4n nucleus</span></span><span style="font-family:;" "=""> <span>before division, affecting a perpendicular orientation of the fitness-gained</span><span> first cells relative to neighboring cells. In an illustrated cell cycle drawing with early and late S-period stress, it became clear that coding genes on borders of repair unstable satellite, repetitive DNA regions, could become mutated. We found these mutations to be tumor SMGs (significantly mutated genes). Evidential material was presented for loss of function genetics driving tumorigenesis to a parasitic lifestyle.</span></span>
文摘Cancers in young children in early growing age was a short PBS (KQED) report (11/21/2014), but without informational source, which prompted a Google search. Sports-associated injuries with medical healing treatments concluded that there were no association between these body traumas and cancer development. But there are other activities from young children, such as “dare-devil” skateboard and bicycling meter-high jumping with potential high energy falls, to serious broken-bone injuries. Falls of children are among the most common causes of US emergency response. The question is why bodily injury is associated with cancer-development? An answer to this question was exemplified by osteosarcoma in young children, which suggested that injury to growing points of bone and surrounding soft tissue cells would elicit a repair process (wound healing process) producing polyploidy with diplochromosomes. The non-mitotic reductive division of such 4-chromatid chromosomes has been shown?in vitro?to produce pathological cancer-like phenotypes, including gain of a proliferative advantage.
文摘<p> <span><span style="font-family:;" "=""><span>Normal cells must become cancer-enabling before anything else occurs, according to latest literature. The goal in this mini-review is to demonstrate special tetraploidy in the enabling process. This we have shown from genomic damage, DDR (DNA Damage Response) activity with skip of mitosis leading to diploid G2 cells at the G1 border in need of chromatin repair for continued cell cycling to the special tetraploid division system. In several studies</span><span> </span><span>specific methylation transferase genes were activated in normal human cells in tissue fields</span><span>, </span><span>containing different cell growth stages of the cancerous process. Histology studies, in addition to molecular chemistry for identification of oncogenic mutational change</span></span></span><span><span><span>,</span></span></span><span><span><span> w</span></span></span><span><span><span>ere</span></span></span><span><span><span style="font-family:;" "=""><span> a welcome change (see below). In a study on melanoma origin, DDR also showed arrested diploid cells regaining cycling from methylation transferase activity with causation of 2n melanocytes transforming to 4n melanoblasts, giving rise to epigenetic tumorigenesis enabled First Cells. Such First Cells were from Barrett’s esophagus shown to have inherited the unique division system from 4n diplochromosomal cells, first described in mouse ascites cancer cells (below). We discovered that the large nucleus prior to chromosomal division turned 90<span style="color:#4F4F4F;white-space:normal;background-color:#FFFFFF;">°</span> relative to the cytoskeleton axis, and divided genome reductive to diploid, First Cells, in a perpendicular </span><span>orientation to the surrounding normal cells they had originated from. This unique division system was herein shown to occur at metastasis stage, imply</span><span>ing activity throughout the cancerous evolution. Another study showed 4-chromatid tetraploidy in development to B-cell lymphoma, and that such cancer cells also proliferated with participation of this unusual division system. Such participation has long been known from Bloom’s inherited syndrome with repair chiasmas between the four chromatids, also an </span><i><span>in vitro</span></i><span> observation by us. Our cytogenetic approach also revealed that they believed mitotic division in cancer cells is wrong because such cell divisions were found to be from an adaptation between amitosis and mitosis, called amitotic</span></span></span></span><span><span><span>-</span></span></span><span><span><span style="font-family:;" "=""><span>mitosis. Amitosis means division without centrosomes, which has long been known from oral cancer cells, in that MOTCs (microtubule orga</span><span>nizing center) were lacking centrioles. This observation calls for re-introduction </span><span>of karyotype and cell division studies in cancer cell proliferation. It has high probability of contributing novel approaches to cancer control from screening of drugs against the amitotic-mitotic division apparatus.</span></span></span></span><span><span><span style="font-family:;" "=""> </span></span></span> </p> <span></span><span></span> <p> <span></span> </p>
