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From Gene Mutations to Breast Cancer.

Localized Tissue-Microcirculatory Unit Abnormalities in individuals at  risk for cancer.

Biophysical-Semeiotic morphological analysis of vasomotion in both physiology and pathology.



In the war against cancers, we must possibly find a “clinical” tool that helps “all” doctors in bed side recognizing, in apparently healthy, genetical errors, causing hyperinsulinemia-insulinresistance, melatonine as well as endogenous oppioids deficiency, metabolic disorders, prevalence of stress axis, a.s.o., which, in turn, can aggravate chromosomal aberrations as those observed in cancer cells.

 In fact, our target can be reached hopefully if “all” doctors are able to ascertain, or at least suspect, clinically in otherwise healthy people gene mutations, oncogenesis is based on, possibly long time before cancer on-set.

As a working hypothesis, I thought previously (at the end of 1970) that all gene mutations, of whatever nature, are necessarily accompanied with similar microvascular modification, both structural and functional,  of the local microcirculatory bed in subjects involved by abnormalities of pschyco-neuro-endocrinel-immune system, i.e. by oncological terrain (See: “Oncological Terrain” in my site, HONCode ID, N. 233736,

 As a matter of fact, both genetical and environmental factors can induce contemporaneously parenchymal and microvascular cell alterations, according to the well-known concept of Tischedorf’s “Angiobiotopie”. For instance, a family of molecules called cyclins was descovered. It is through changes in the production of cyclins during the cell cycle that the activities of the genes controlling it are themselves regulated. All these events (control, regulation a.s.o.), however, can happen only by means of changes in local microcirculation, i.e., in supplying information-material-energy to cells, which need to repair their damaged n-DNA.

 Now, thanks to Biophysical Semeiotics (See the above cited-site), we can fortunately evaluate clinically both structure and function of the microcirculatory bed, in a precise manner and in all biological system (2-5).

Based on 45-year-long "clinical" experience, I think that the decline in cancer rates all over the world could be more intense if scientists will consider and discuss the possibility that the "Oncological Terrain", based on Congenital Acidosic Enzyme-Metabolic Histangiopathy, a mitochondrial functional cytopatology, almost always eredited by mother, really exists.

In other words, as regards oncogenesis, we must consider not only n-DNA abnormalities, but also alterations of m-DNA.

As a matter of fact, e.g., not all smokers, on the one hand, are involved by pulmonary cancer, as well as not all people with chronic hepatitis, on the other hand, will die of hepatocarcinoma. Moreover, in some families malignancies occur more frequently than in others.

 Actually, as I described in the above-mentioned papers, there are other irrefutable as well as unavoidable causes that accounts for the reason of existence of the oncological “real” risk, i.e. oncological terrain, and consequently, Congenital Acidosic Enzyme-Metabolic Histangiopathy, i.e. m-DNA abnormalities.

At this point, the first question is the following:

"What does characterize oncological terrain from the "clinical" and microcirculatory point of view?".

In fact, in order to perform efficacious cancer primary prevention on very large scale, it is unavoidable that the modifications occurring in the biological controll system could be easily, promptly, and “quantitatively” ascertained and properly evaluated at the bed-side, i.e., with the aid of a “clinical” method, by the use of a sthetoscope, and certainly without application of sophysticated but expensive semeiotics, that may not be applyed in all individuals, that is, on largest scale, because only a few doctors can utilize them.

If it is possible to answer this first question, a second one immediately follows:

 "The oncological terrain which certanly can be worsened by the negative intervention of environmental factors, is also in some way, at least partially, reversible?".

It is urgent and necessary to know if the oncological terrain can be reversed, i.e., if it can totally or, at least, greatly disappear, with the aid of drugs and/or diet, ethymologically speaking, which exert a favourable influence on the characteristic modifications of the psycho-neuro-endocrine-immunological system, that  just represent the “oncological terrain”.

 My answers to these questions are readable in my above-cited site (5).

The war against cancer will be fortunately won if all doctor are able to recognize, with the aid of a stethoscope, individuals apparently healthy but positive for “oncological terrain”, particularly intense in a well defined tissue region, who have to undergo immediately to proper diet, ethymologically speaking, and therapy with histangioprotective drugs, in some cases.

At this point, however, it is unavoidable to investigate and possibly clarify the relation between gene mutations, including m-DNA alterations, microcirculatory abnormalities, oncological terrain, and oncogenesis (Fig.1).


Fig. 1

Gene mutations  cause local tissue-microvascular unit abnormalities,direcltly and/or indirectly, e.g. AVA and DEB structural and functional alterations, blood-flow centralization, tissue acidosis, a.s.o., which in turn, but exclusively in presence of oncological terrain, based on Congenital Acidosis Enzyme-Metabolic Histangiopathy, can bring about oncogenesis.


From Gene Mutations to Breast Cancer.

             Cancer results, notoriously, from the accumulation of mutations in genes (n-DNA) that regulate cellular proliferation and these mutations can occur early in the process of malignant transformation or later, during progression to an invasive carcinoma. The inheritance of mutated allele is commonly followed by the loss of the second allele from a somatic cell, leading to the inactivation of a tumor-suppressor gene and triggering malignant transformation.

Genes important to the development of cancer regulate diverse cellular pathways, including the progression of cells through the cell cycle, resistance to programmed cell death (apoptosis), and the response to signals that direct cellular differentiation. Moreover, the inactivation of genes that contribute to the stability of the genome itself can favor the acquisition of errors in other genes that regulate proliferation. The importance of this latter pathway in the development of breast cancer is highlighted by two recent studies linking the function of the BRCAl gene, implicated in the genetic predisposition to breast and ovarian cancer, with that of the A1M gene, which in its mutant form causes the genomic instability in ataxia-telangiectasia (6, 7)

 Errors in n-DNA that arise during normal replication of the molecule (nucleotide mismatches) or that are induced by ionizing radiation or genotoxic drugs can cause mutations in coding sequences or breaks in double-stranded chromosomal DNA. If the nucleotide mismatch is not repaired before a round of DNA replication occurs, that mutation is transmitted to daughter cells. A mitotic catastrophe can be caused by  an unrepaired break in double-stranded DNA when the cell attempts to segregate broken chromosomes. Studies of yeast have identifìed genes that sense damaged DNA and cause the arrest of the cell cycle, which allows time for the molecular defect to be repaired. These genes operate at several specific "checkpoints" in the cell cycle as a means of ensuring genomic integrity before DNA is synthesized. The most critical checkpoint gene yet identifìed that is related to cancer in humans is the tumour-suppressor p53, not essential for cell viability, but critical for monitoring damage to DNA.

Inactivation of p53 is an early step in the development of many kinds of tumors. Patients with the Li-Fraumeni syndrome usually carry one mutant  germ-line p53 allele and are at risk for the development of sarcomas, leukemia, and cancers of the breast, brain, and adrenal glands. In rare cases of the Li-Fraumeni patients do not have a germ-line p53 mutation, but they may have a mutation in CHK2, a gene encoding a protein kinase that directly activates p53 protein by adding a phosphate group to it (7 8). The Li-Fraumeni syndrome is rare, but in over half of all sporadic cases of cancer, p53 is inactivated at some point during the progression of the disease. In cases of cancer without p53 mutations there are frequently alterations in two other genes - MDM2 and pl4ARF -that regulate the expresion of p53.

The sensing of breaks in DNA and the activation of p53 require ATM. This gene encodes a kinase that activates both CHK2 and p53 in response to damaged DNA.

Children with ataxia-telangiectasia have inactivating mutations in both ATM alleles and have immunodeficiency, cerebellar abnormalities, and a predisposition to cancer, primarily lymphomas. Their cells fail to activate p53 in response to damaged DNA, demonstrate genomic instability, and are extremely sensitive to genotoxic agents. A similar disorder, the Nijmegen breakage syndrome, is caused by homozygous inactivation of the NBS gene. The NBS protein appears to be directly involved in the repair of breaks in double-stranded DNA. The recent observation that NBS is activated by ATM after DNA is damaged identifies a cellular pathway that can account for the similar clinical consequences of mutations in these two genes.(10, 11)

 Into this pathway of response to damaged DNA enters the BRCAl gene. Mutations in one germ-line allele of BRCAl are responsible, according to some authors, but not to others, for approximately half of all cases of familial breast cancer. The normal function of the BRCAl protein remains elusive, but important information has emerged from the identification of other proteins that interact with it. The discovery that both ATM and CHK2 can add phosphate groups to the BRCAl protein after n-DNA is damaged (6, 11) and that the phosphorylated BRCAl is relocalized within the nucleus suggests that it, too, may participate in the response to damaged n-DNA. ATM can also phosphorylate a BRCAl cofactor, CtlP, that regulates gene transcription (7) and there are indications that BRCAl protein is part of a complex that includes NBS and other DNA-repair proteins (13). The current data suggest that BRCAl is critical for the repair of double-stranded breaks in chromosomes. These new insights raise important questions about the genetic events that lead to breast cancer. Why should breast epithelial cells be more susceptible than other types of cells to the consequences of the genomic instability caused by loss of function of the BRCAl gene? And why should breast cancer develop in carriers of a mutant germ-line BRCAl allele after the somatic loss of the second BRCAl allele, whereas BRCAl is rarely if ever inactivated in patients with sporadic breast cancers? No answers to these questions have yet emerged, but the susceptibility of breast tissue to DNA damage may reflect the repeated cycles of estrogen-driven cellular proliferation that occur normally in this tissue. As for why the inactivation of BRCAl occurs only in cases of familial breast cancer, it is possible that inheritance of one mutant BRCAl germ-line allele increases the likelihood that a breast epithelial cell will lose the second allele before the occurrence of the estrogen-driven proliferation associated with puberty.

Mutations in BRCAl and BRCA2 have been associated with an increase in the lifetime risk of breast cancer by a factor of more than 20, but these highly penetrant mutant alleles are relatively rare in the general population. In contrast, 1% of the population carries an inactive ATM allele. Some studies have suggested that such relatively common alleles are associated with a moderate increase in the risk of breast cancer, although the magnitude of this increase is debated (14, 15). Completion of the human-genome project and other advances are likely to uncover additional common variations within a host of novel genes implicated in the response to n-DNA damage. Defining the possible adverse or even protective contribution of these genetic variations to the development of breast cancer and marshaling this information to improve clinical care will be the challenge.

In addition, authors demonstrated recently that in carriers of BRCA1 mutations, the overall increased risk of cancer at sites other than breast and ovary is small and is observed in women but generally not in men. BRCA1 mutations may confer increased risks of other abdominal cancers in women and increased risks of pancreatic cancer in men and women (36).


Localized Tissue-Microcirculatory Unit Abnormalities in individuals at  risk for cancer.

At this point, continuing present discussion, analyzing breast cancer as example, I will illustrate briefly localized tissue-microcirculatory unit inherited abnormalities, i.e., in the precise site of risk for malignancy and obviously in the area of cancer itself, after discussing the biological significance of microcirculatory deterministic chaos (For further information, see

Chaos, a mathematical concept, has been described as "deterministic randomness", meaning that a chaotic system is deterministic, but so complicated that looks random. Chaos theory tells us it is impossible to predict the long term behaviour of very complex systems, because all the conditions are not known with precision at any time and uncertanty increases with time (16) .

 It is well known that electrocardiograms, for example, of healthy hearts constantly vary, however slightly, in an unpredictable way. But in dying patient the intervals between beats (R-R) become practically identical and electrical signals predictably cyclic (17).

We described in previous papers, for the first time clinically, spleen (18), liver (19), kidney (20) and pancreas (20) chaotic oscillations, partly due to Autonomic Nervous System activity.

More precisely speaking, organ and tissue oscillations are related to their local microvessels chaotic activity, i.e. the complexity of the dynamism of the firsts corresponds exactly to that of the second. In addition, the physiologically functioning organ presents complex, chaotic oscillations, constrained to a “strange attractor” in the phase space (See later on).

On the contrary, in a diseased organ there are cyclic, periodic, regular, identical, predictable and low oscillations without highest spikes (HS).

 In conclusion, the microcirculatory bed and consequently the related organ as biological dynamic system loses complexity, it loses its adaptative capacity and ability to responde (16). Interestingly, biophysical-semeiotic evaluation of the complexity degree is very important as regards prevention, diagnosis and therapeutic monitoring.

As mentioned above, the chaotic size fluctuations of kidney, pancreas, liver, spleen, aorta, heart (obviously, regardless systo-diastolic movements), a.s.o. are due to their congestion and decongestion (6 cicles per minute) as clinical and experimental evidence suggests.

In facts, organs chaotic oscillations are strictly analogous and synchronous with related microvessels fluctuations, presenting really identical behaviour .

Consequently, we are allowed to state that chaotic behaviour of local nutritional capillaries and venules brings about volume randome changing of the related organs, mentioned above. Therefore, it is easy and reliable to assess in a precise manner oscillations of about all organs and tissues by means of the evaluation of corresponding microvessels fluctuations.

In other words, besides kidney, pancreas, heart, spleen, liver, a.s.o., chaotic oscillations assessment, it is practical, usefull and reliable to evaluate the "oscillations" of important tissues, organs and glands, such as bone-marrow, prostate, lungs, gall-bladder, breast, urinary-bladder, stomach-duodenum, a.s.o. (18, 20, 21), evaluating vasomotility and vasomotion of related microcirculatory bed.

As regards bone marrow and breast, for example, digital pressure upon the middle line of breast-bone (and/or hyliac crests) and mammary gland, respectively, in healthy, brings about choledocic "arteriolar", "venular" reflexes as well as upper (=small arteries and arterioles, according to Hammersen) and lower ureteral reflex (= nutritional capillaries), which fluctuate in a chaotic manner, as mentioned above. Interestingly, moreover, AP values of marrow- and mamma-oxygenation and CoQlO levels (34) are in perfect relation with fractal dimension of chaotic choledocic and ureteral fluctuations.

 At this point, it appears relevant to outline that during acute disorder, flogistic in nature, local periodic microvascular oscillations (choledocic and/or upper and low ureteral reflexes) show the most intense degree, almost equal to that of the highest spikes (HS), demonstrating clearly the real biological nature of oscillating complexity, namely the adaptative capacity and ability to responde.

In fact, during phlogistic process, the interstitial oedema increases both vasomotility and vasomotion, as experimental evidence demonstrates (= occlusive digital pressure upon superficial lymphatic vessels) (22). In other words, chaos theory has stimulated some important technical developments in the way we can analyze and interpret medical and other time series data (23).

As regards the above-mentioned "strange attractors" of chaotic dynamic systems, a key concept is "fractal dimension", very different from the topological one, as demonstrates the generation of Koch's curve (24), which, as the name implies, was developed for fractals, but the practical applications of which has emerged as a byproduct of attempts to prove that certain systems have strange, chaotic, fractal at-tractors, by analyzing time evolution data (23).

When brain wave data, e.g., in rats are "re-constructed", the attractor for a healthy rat is computed to have a "dimension" of about 5,9 while that for the same rat in epileptic seizure has a dimension of only 2,5 (25). The suggestion is that the "dimension" correlates with the flexibility and adaptability of the organisms: the larger number implies a chaotic system with well developed flexible response to stimuli, whereas the low value associated with the seizure can be regarded as evidence of suppression or malfunction of a number of key elements of the rat's physiology.

A somewhat similar argument can be applied to biophysical-semeiotic data, as regards, e.g., pancreatic oscillations in case of classical or "variant" Reaven's syndrome in diabetic evolution (26) as well as in diabetes mellitus (22). It must also be remembered that fractal dimension (fD) and system complexity are directly correlated.


From the above remarks, there is chaos in the microvascular system (See my site 

In facts, intensity of choledocic and low ureteral reflexes is really different in the healthy subjects, as the reflex oscillation is concerned, varying from 0,5 to 1,5 cm, from biophysical semeiotic stand-point, so that the ratio HS/minimal fluctuations is 3/1. The oscillations become less chaotic when an organ is evolving to a pathological state and finally all oscillations are identical and regular in diseased organs: f D decreases from 3,81  (NN = 3,81) to 1.

Analogously, we observe deterministic chaos in the duration of single cycle; the lenght of normal period is 10,5 sec in an average, ranging from 9 to 12 sec. In hyperfunctioning organs, e.g. in case of a trivial flu, as bone marrow is concerned for example, oscillation intensity is like HS and cycle duration results restricted to 9-11 sec. On the other hand, in diseased organ the duration is fixed at 10 sec. and intensity is 0,5 cm.

The clinical evidence corroborates biophysical semeiotic theory of the existence of chaos in microcirculatory bed because there is a perfect concordance between chaos and biophysical semeiotic parameters. Our clinical biophysical semeiotic data corroborate actually those of other A. (27, 28), about random, chaotic activity in the “vasomotion”, due to the great number of different in-put in the smooth muscle cells. In diseased organ it is possible that a lot of in-puts decrease and/or disappear and a mechanism becomes dominant. Consequently the tissue present rhythmic “vasomotion” (25, 29), as demonstrated in our tachograms (See later on).

In case of "pathological" oedema, a lot of stimuli, which bring about a random, chaotic “vasomotion”, apparently are eliminated, causing a regular “vasomotion” (25, 29), as we observed in a long, well established experience. On the contrary, in a jatrogenic oedema, i.e. during digital lymphatic or venous vessels obstruction, after 2 sec vasomotility increases, showing exclusively HS and, therafter, also vasomotion becomes very intense.

From the above remarks, the vasomotion clearly depends from vasomotility and the two phenomena are really different in nature (22, 30).

Due to a lot of in-puts small arteries and arterioles constrict and dilate autonomously (6 cycles per minute, from biophysical semeiotic stand-point), as arteriolar choledocic reflex demonstrates, because of numerous arteriolar pace-makers. This arteriolar vasomotility, based on sphygmicity, aimes at maintaining a physiological “vasomotion” and consequently flow-motion, so that O2 and metabolites tissue supply persists normal under different conditions. Therefore, vascular tone and vasomotility of healthy people are in perfect relation to tissue request.

 In an organ or tissue, in other words, arteriolar activity and diameter are generally correlated to a certain extence. Under physiological conditions, arteriolar tone enhancing brings about increasing of blood pressure. In such case, due to secondary hypoxia, the blood pressure should subsequently increase (30). On the contrary, the increased vasomotility, due to enhanced tone, permits to maintaining a regular flow-motion and fuell supplying, although high blood pressure as well as hematocryt, avoiding a vicious circle.

From a physiological point of view, vasomotility and vasomotion provide to:


1) efficacious and economic tissue blood distribution;

2) reducing peripheral vascular resistence;

3) under some circumstances, permits interstitial fluid to be absorbed (28, 31).


Interestingly, Biophysical Semeiotics allows the doctor to observe clinical and experimental evidence, which enlights the relation between vasomotility and vasomotion: digital pressure upon radial arteries induces down-wards in succession arteriolar dilation with increased vasomotility ® enhancing of vasomotion ® occlusion (disactivation) of AVA, functionally speaking, so that O2 and metabolites supply to tissues persists in normal ranges to certain extence of digital pressure.

From the above remarks, one can understand that, in case of essential hypertension, e.g., the used drug results really efficacious exclusively in the case fractal dimension of resistence microvessels returnes to physiological values, beside the normalization of blood pressure.

At this point I illustrate an interesting aspect of vasomotion, wich allows readers to understand the primary role played by microcircle abnormalities in the oncogenesis.

Biophysical-Semeiotic morphological analysis of vasomotion in both physiology and pathology.

From the practical point of view it is sufficient and reliable to evaluate periods as well as intensity of low ureteral reflex oscillation (= vasomotion), as described above, for example during mean digital pressure, applied upon the middle third of biceps muscle, compressing it between thumb and other fingers, of a supine individual, psychophysically relaxed. The muscle pressure allows doctor to examine resistance microvessels dynamics and flowmotion of nutritional capillaries.

However, the original morphological analysis of vasomotion, i.e the precise evaluation of low ureteral reflex oscillations, reveals interestingly the actual condition of related tissue-micro vascular-units, in whatever tissue, in a synergetic model. In order to realize this analysis is unavoidable to transfer upon Cartesian coordinates intensity (ordinate, cm) and duration (abscisse, sec.) of three successive fluctuations of low ureteral reflex, observed for example in the above-mentioned situation, during biceps muscle microvascular units stimulation. In healthy subject we observe a characteristic diagram (Fig. 1).



Fig. 1


Interestingly, in 3 sec (ascending line: AL) it is reached the highest intensity (NN = 0,5-1,5 cm); the "plateau" line (PL) lasts physiologically 3 sec, then in 1 sec (descending line: DL) the line returns to basal value (i.e. abscisse), where persists for 2-5 sec, varying the periods from 9 to 12 seconds under physiological condition.

On the contrary, in pathological situations, e.g. essential hypertension, the diagram results interestingly modified (Fig.2): AL as well as DL are normal, 3 sec. and 1 sec respectively; intensity is approxi-mately 0,5 cm, in a "predictable" manner; the physiological highest waves, i.e. highest spikes of 1.5 cm intensity (HS), are absent.




In the figure are referred, in geometrical manner, the physiological microcirculation of biceps muscle (oben) and that of an hypertensive patient.



 Finally, in case of hyperfunctioning tissue, e.g. the bone-marrow during infective disorders of whatever nature, digital pressure upon the middle line of breast bone, brings about low ureteral reflex oscillations, characterized by PL of 5 or more sec, intensity as well as periods practically identical each other (Fig. 3). Intensity and PL of every oscillation are directly correlated: more high the intensity, more prolonged appears PL and consequently more efficacious is the flow-motion of related nutritional capillaries.



Fig. 3

Vasomotion of hyperfunctioning tissue-microvascular unit(e.g. bone marrow).


This clinical evidence underlines the inner consistence of Biophysical Semeiotics.

 In addition, superimposing the parameters of three subsequent oscillations of low ureteral reflex, in accordance with the lenght of single period, we realize really interesting figures. In healthy people the obtained area shows a "strange" shape, like a "strange" attractor (Fig. 4: fractal dimension (fD) >3 (22), that corresponds to the space occupied by a fractal structure.




Fig. 4

Strange attractor: healthy subject.


On the contrary, under pathological condition, e.g. essential hypertension as far as biceps muscle microcirculatory bed is concerned, the area obtained in this manner appears quite small, resembling an attractor at fixed point (Fig. 5).




Fig. 5

Fixed point attractor: hypertensive patient


Finally, the area corresponding to hyperfunctioning microcirculatory units results the largest one, due exclusively to its large Euclidean perimeter; its shape, however, resembles clearly a deformed circle, corresponding to a “closed loop” attractor (Fig. 6) (32, 33).



Fig. 6

Closed loop attractor in hyperfunctioning bone-marrow.


From the above remarks it results that morphological analysis of vasomotion, by means of Biophysical Semeiotics, in physiological as well as in pathological conditions, represents an original, reliable and usefull tool in both clinics and research, as allows us to state a long, well established experience.


We can now turn to our argument, saying that in the precise site of  real risk for breast cancer, “light” digital pressure causes upper (= vasomotility) and lower (vasomotion) ureteral reflexes, which show the characteristic type II, dissociated microcirculatory activation: at rest, upper ureteral reflex oscillations last 7-8 sec. (NN = 6 sec.), in relation to the seriousness of underlying risk, while lower ureteral reflex fluctuates for 6 sec., i.e. normally, (or less than normally, in particularly serious cases), although related vasomotility is increased (Fig. 7).

Consequently, doctor can recognize the precise site as well as “quantify” the real risk for breast  and other cancer, thanks the modified microcirculatory activity, which appears more clearly altered under stress tests, as boxer’s test, apnea test, Restano’s manoeuvre, insulin secretion acute pick test, a.s.o. (See Glossary in the above-cited site).


Fig. 7

The figure shows,  in  geometrical manner, the characteristic oscillations  of upper (vasomotility) and lower (vasomotion) ureteral reflexes, during small stimulation of the trigger-points, precisely  related to diseased tissular area, in case of type II, dissociated, microcirculatory activation. Doctor can  observe as well as quantify  them, of course, generally in individual, apparently healthy, but really  involved by oncological terrain and  at real risk for cancer, different in intensity,  in whatever biological system.



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Last update: March 18, 2018