Zsuzsanna Suba - Academia.edu (original) (raw)
Papers by Zsuzsanna Suba
review, 2024
Important tumor biomarkers, therapeutic targets, and mechanisms of tumorigenesis were discovered ... more Important tumor biomarkers, therapeutic targets, and mechanisms of tumorigenesis were discovered in animal models. Mouse models of malignant gliomas were represented by transplantable, chemicallyinduced, and genetically-engineered cells. The aim of the study was to investigate the morphological, molecular, and immunological characteristics of two original glioblastoma (GB) strains, M2 and M6. These are new, chemically-induced, transplantable tissue models of malignant diffuse mouse glioma. Tissues from M2 GB and M6 GB were transplanted into immunocompetent C57BL/6 mice. The clinical manifestations of M2 GB and M6 GB growth in mice include motility disorders, cachexia, and priapism. Morphologically, M2 GB and M6 GB are characterized by diffuse proliferation, cellular and nuclear polymorphism, high mitotic activity, and pathological forms of mitosis due to the aggressive nature of these tumors. Flow cytometry showed that CD3+ T lymphocytes (~32%) and F4/80+ macrophages (~28-50%) highly infiltrated both tumors. M2 GB had higher levels of F4/80+ macrophages than M6 GB.
Cancers, 2024
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
article, 2013
Correlations between estrogen signaling and human morbidity seems to be very unclear and difficul... more Correlations between estrogen signaling and human morbidity seems to be very unclear and difficult topic. Nowadays, the opinions of scientists have been partially changed regarding "estrogen induced diseases", but the overwhelming literary data are still contradictory. Physiological estrogen levels in healthy premenopausal women supply protection against insulin resistance, hypertension, cardiovascular diseases and malignancies as compared with men of the same age. However, after menopause a decreased ovarian estrogen synthesis will rapidly deteriorate the glucose sensitivity and increases the prevalence of life threatening diseases. New findings on the functions of tissular estrogen receptors (ERs) indicate that estradiol plays important role in the maintenance of glucose homeostasis and energy expenditure. Diverse disorders associated with insulin resistance are usually well treatable by estradiol substitution both in pre-and postmenopausal women as well as in animal experiments. ERs seem to have balanced interplay in the maintenance of adaptation to the momentarily changing intra and extracellular stimuli. This equilibrium may be shattered in case of a defective estrogen supply or by the derangement of ER signaling pathways. Understanding the crosstalk and interplay between ERs illuminates the fact that there is no good or bad ER isoform, but they construe a complex system so as to achieve an ideal internal milieu. Considering the regulatory effects of ERs on food intake, insulin secretion, glucose uptake and metabolic processes, estrogen administration may be a therapeutic avenue to repair insulin sensitivity in patients with dysmetabolism and diabetes mellitus.
Background In tumors, somatic mutagenesis presumably drives DNA damage response (DDR) via altered... more Background In tumors, somatic mutagenesis presumably drives DNA damage response (DDR) via altered regulatory pathways increasing genomic instability and proliferative activity. These considerations led to the standard therapeutic strategy against cancer: the disruption of mutation activated DNA repair pathways of tumors. Purpose Justifying that cancer cells are not enemies to be killed, but rather they are ill human cells having the remnants of physiologic regulatory pathways. Results 1. Genomic instability and cancer development may be originated from the flaw of estrogen signal rather than excessive estrogen signaling. 2. Healthy cells with genomic instability exhibit somatic mutations helping DNA restitution. 3. Somatic mutations in tumor cells aim the restoration of DNA damage rather than further genomic derangement. 4. In tumors, estrogen signal drives the pathways of DNA stabilization leading to apoptotic death. 5. In the peritumoral cellular infiltration, the genomic damage of tumor induces inflammatory cytokine secretion and increased estrogen synthesis. In the inflammatory cells, increased growth factor receptor (GFR) signal confers unliganded activation of estrogen receptors (ERs). 6. In tumor cells responsive to genotoxic therapy, constitutive mutations help the upregulation of estrogen signal and consequential apoptosis. In tumors non responsive to genotoxic therapy, the possibilities for ER activation via either liganded or unliganded pathway, are exhausted leading to farther genomic instability and unrestrained proliferation. Conclusion Understanding the real character and behavior of human tumors at molecular level suggests that we should learn the genome repairing methods of tumors and follow them by supportive therapy rather than provoking additional genomic damages.
Oncology Reviews, 2023
This work presents the history of the recognition of principal regulatory capacities of estrogen ... more This work presents the history of the recognition of principal regulatory capacities of estrogen hormones having been mistakenly regarded as breast cancer promoting agents for more than 120 years. Comprehensive analysis of the results of clinical, epidemiological, immunological and molecular studies justified that endogenous estrogens are the principal regulators of embryonic development, survival and reproduction via orchestrating appropriate expression and even edition of all genes in mammalians. Medical use of chemically modified synthetic estrogens caused toxic complications; thromboembolic events and increased cancer risk in female organs as they proved to be endocrine disruptors deregulating estrogen receptors (ERs) rather than their activators. Synthetic estrogen treatment exhibits ambiguous correlations with cancer risk at different sites, which may be attributed to an inhibition of the unliganded activation of estrogen receptors (ERs) coupled with compensatory liganded activation. The principle of estrogen induced breast cancer led to the introduction of antiestrogen therapies against this tumor; inhibition of the liganded activation of estrogen receptors and aromatase enzyme activity. The initial enthusiasm turned into disappointment as the majority of breast cancers proved to be primarily resistant to antiestrogens. In addition, nearly all patients showing earlier good tumor responses to endocrine therapy, later experienced secondary resistance leading to metastatic disease and fatal outcome. Studying the molecular events in tumors responsive and unresponsive to antiestrogen therapy, it was illuminated that a complete inhibition of liganded ER activation stimulates the growth of cancers, while a successful compensatory upregulation of estrogen signal may achieve DNA restoration, tumor regression and patient’s survival. Recognition of the principal role of endogenous estrogens in gene expression, gene edition and DNA repair, estrogen treatment and stimulation of ER expression in patients may bring about a great turn in medical practice.
Oncology Reviews, 2023
This work presents the history of the recognition of principal regulatory capacities of estrogen ... more This work presents the history of the recognition of principal regulatory capacities of estrogen hormones having been mistakenly regarded as breast cancer promoting agents for more than 120 years. Comprehensive analysis of the results of clinical, epidemiological, immunological and molecular studies justified that endogenous estrogens are the principal regulators of embryonic development, survival and reproduction via orchestrating appropriate expression and even edition of all genes in mammalians. Medical use of chemically modified synthetic estrogens caused toxic complications; thromboembolic events and increased cancer risk in female organs as they proved to be endocrine disruptors deregulating estrogen receptors (ERs) rather than their activators. Synthetic estrogen treatment exhibits ambiguous correlations with cancer risk at different sites, which may be attributed to an inhibition of the unliganded activation of estrogen receptors (ERs) coupled with compensatory liganded activation. The principle of estrogen induced breast cancer led to the introduction of antiestrogen therapies against this tumor; inhibition of the liganded activation of estrogen receptors and aromatase enzyme activity. The initial enthusiasm turned into disappointment as the majority of breast cancers proved to be primarily resistant to antiestrogens. In addition, nearly all patients showing earlier good tumor responses to endocrine therapy, later experienced secondary resistance leading to metastatic disease and fatal outcome. Studying the molecular events in tumors responsive and unresponsive to antiestrogen therapy, it was illuminated that a complete inhibition of liganded ER activation stimulates the growth of cancers, while a successful compensatory upregulation of estrogen signal may achieve DNA restoration, tumor regression and patient’s survival. Recognition of the principal role of endogenous estrogens in gene expression, gene edition and DNA repair, estrogen treatment and stimulation of ER expression in patients may bring about a great turn in medical practice.
Journal of Craniofacial Surgery, 2004
Numerous possibilities are available for the reconstruction of facial bone defects. The materials... more Numerous possibilities are available for the reconstruction of facial bone defects. The materials used to fill such defects must satisfy various requirements. One of the most important is that they must undergo transformation into autologous bone tissue in the process of remodeling. A report is given of the long-term results of augmentations of large bone defects performed with different bone-substitute materials in two patients. In one case, augmentation was carried out with beta-tricalcium phosphate after the removal of a fibromyxoma. In the second case, three large cystic lesions in the mandible of a patient with Gorlin-Goltz syndrome were filled with beta-tricalcium phosphate, with a mixture of beta-tricalcium phosphate and platelet concentrate, or with hydroxyapatite of algal origin. The process of ossification was checked at 6-month intervals by means of clinical, radiologic (orthopantomograms and two-dimensional and three-dimensional computer tomograms), and histologic methods. At 1 year after the intervention, the site of the augmentation was in all cases occupied by hard tissue of good quality. With the given imaging procedures, it was difficult to distinguish between the original bone and the region filled with bone-substitute material. The three-dimensional computer tomogram images indicated that the contours and quality of the new bone corresponded with the physiologic and anatomical conditions. The histologic examinations show the remodeling of the bone-substitute materials. The bone-substitute materials applied in these cases fully satisfied the demands of transformation into bone (remodeling). The speed of remodeling seemed to be the fastest when the mixture of beta-tricalcium phosphate and platelet concentrate was used.
Fogorvosi szemle, 2006
Malignant melanoma occurs only rarely as a primary tumour in the oral cavity, with an incidence o... more Malignant melanoma occurs only rarely as a primary tumour in the oral cavity, with an incidence of 1-2 percent. Oral melanomas are predominantly to be found in the hard and soft palate, and less often in the gingiva and mandible. Mucosal malignant melanomas are much more aggressive than those situated in the skin. In two-thirds of the cases the route of formation of the metastases is lymphogenic, and haematogenic in the remainder. The typical sites of the distant metastases are the skin, the lungs, the brain, the liver, and the bones. Metastatic malignant melanoma in the oral cavity, a rarity in the literature, is associated with a very poor prognosis. This paper reports on two cases in which an isolated distant metastasis developed in the oral cavity.
Orvosi Hetilap, Jun 23, 2002
When the maxilla is edentulous and the alveolar process is extensively absorbed, a dental root ca... more When the maxilla is edentulous and the alveolar process is extensively absorbed, a dental root can be implanted only after the implantation of bone or a bone-substitute. Only in this way can the subjective and objective negative features associated with a removable prosthesis be avoided. Many forms of bone-substitutes are known. Freely taken bone from the patient generally serves as the gold standard for the classification of bone-substitutes. The aim of our work was to compare two materials (the patient's own bone and beta-tricalcium phosphate) in the same patient. Ten patients were selected who for some reason did not want or could not wear a removable prosthesis. The maxilla was so atrophied that bone or bone-substitute implantation was necessary before the dental root could be implanted. The maxilla had to be elevated from inside (sinus elevation) and thickened from outside (onlay-plasty). Bone was taken in the usual manner from the hipbone. For the internal elevation, such ...
Fogorvosi szemle, 2004
Healing of extraction wounds was examined in an animal experiment model on Beagle dogs. After bil... more Healing of extraction wounds was examined in an animal experiment model on Beagle dogs. After bilateral extraction of the premolars of 12 dogs the alveoli were filled up with a combination of beta-tricalcium phosphate (Cerasorb) graft and platelet rich plasma (PRP) on the experimental side, and with Cerasorb alone on the control side. Biopsy specimens were taken from the regenerating bone at 6, 12 and 24 weeks after surgery for histological study. Results of the histologic and histomorphometric examinations revealed that after 6 weeks the newly formed bone was significantly denser on the experimental side. After 12 weeks this difference became moderate, and after 24 weeks the bone forming activity was nearly equal on the two sides. These results suggest that local administration of Cerasorb and PRP results in more intense bone regeneration, especially in the early phase.
Fogorvosi szemle, 2006
Graft insertion can effectively enhance the regeneration of debilitated bone. The effects of an a... more Graft insertion can effectively enhance the regeneration of debilitated bone. The effects of an alloplastic bone-replacing material, beta-tricalcium phosphate (Cerasorb), and of autogenous bone graft were compared. In 17 edentulous patients, the maxillary sinus floor was extremely atrophied to such an extent that implant placement was impossible. The Schneiderian membrane was surgically elevated bilaterally by insertion of Cerasorb (experimental side) and autogenous bone graft (control side). After surgery, the recovery was followed clinically and radiologically. After 6 months, 68 bone cylinders were excised from the grafted areas and implants were inserted into their places. The bone samples were embedded into resin, and the osteointegration of the grafts was studied histologically. Trabecular bone volume (TBV) and trabecular bone pattern factor (TBPf) were quantified by histomorphometry. Cerasorb proved to be an effective bone-replacing material with osteoconductivity; it was cap...
Orvosi hetilap, 2005
INTRODUCTION The metabolic syndrome develops on the basis of peripheral insulin resistance. It is... more INTRODUCTION The metabolic syndrome develops on the basis of peripheral insulin resistance. It is a continuously progressing metabolic disorder, which concludes finally into serious diseases. Type-2 diabetes, cardiovascular disease and--according to the recent literature--malignancies are the most important consequences. A well-known fact, that metabolic disorders; such as diabetes and obesity, can deeply influence the structure and function of the salivary glands. Considering these data, the question arises; is there any correlation among insulin resistance, type-2 diabetes and salivary gland tumors? AIMS A retrospective epidemiological examination was performed to analyze the correlations between salivary gland tumors and insulin resistance states (type-2 diabetes and metabolic syndrome). METHODS Data of 438 patients were analyzed in the Maxillofacial Surgery Clinic of the Semmelweis University. In 224 cases salivary gland tumors were surgically removed. In 214 control cases, bone...
article, 2007
Alcohol and tobacco are considered as major risk factors for oral cancer (OC). In the developed c... more Alcohol and tobacco are considered as major risk factors for oral cancer (OC). In the developed countries reduction of alcohol and tobacco consumption has achieved favorable decreasing trends in OC morbidity and mortality over the last decades. At the same time the earlier very high male-female OC ratio showed a declining tendency all over the world. This trend used to be simply interpreted by the increasing exposure to tobacco and alcohol among women. However, literary data support an enhanced prevalence of women among non-smoker non-drinker OC cases. These findings focused the attention for further underlying mechanisms in the initiation of OC, such as metabolic and hormonal disorders. Insulin resistant states (metabolic syndrome and type-2 diabetes) are sources of many human diseases. Reactive hyperinsulinemia, increased production of insulin-like growth factors, hyperglycemia and its serious consequences are all proven cancer promoters. Decreased blood perfusion of the tissues c...
PURPOSE The effects of 2 graft materials, beta-tricalcium phosphate (Cerasorb) alone and a combin... more PURPOSE The effects of 2 graft materials, beta-tricalcium phosphate (Cerasorb) alone and a combination of Cerasorb and platelet-rich plasma (PRP), on the bone regeneration process were evaluated in the canine mandible. MATERIALS AND METHODS The mandibular premolars of 12 beagle dogs were surgically removed. The extraction sockets were filled with Cerasorb on the control side and a mixture of Cerasorb and PRP on the test side. Bilateral biopsy samples were taken from the graft insertion sites at 6, 12, and 24 weeks after surgery. Sections were prepared from the undecalcified resin-embedded samples. RESULTS Six weeks after grafting, the proliferation of cellular osteogenic mesenchyma was more abundant in the test group. The histomorphometric data revealed a significantly higher percentage of bone area in the test group (45.9%) than in the control group (30.8%) (P < .05). Twelve weeks after grafting, the test group still had some advantage over the control group in terms of bone reg...
Pineal hormone melatonin is the mediator of physiological adaptation to external light, and to th... more Pineal hormone melatonin is the mediator of physiological adaptation to external light, and to the day and night rhythms of activity and rest. It seems to be a natural hormone to facilitate sleep as melatonin secretion is physiologically increased in darkness at night being associated with decreased hormonal and metabolic activities. Immigrants from low cancer incidence regions to northern high-incidence areas might exhibit similarly higher or excessive cancer risk as compared with the inhabitants of their adoptive country. Additional cancer risk may be conferred by incongruence between their dark pigmentation and the poor light exposure of foreign environment. Many studies established the racial/ethnic disparities in the risk and biology of female breast cancer in United States between African-American and Caucasian women. Mammary tumors in black women are diagnosed at earlier age, and are associated with higher rate of mortality as compared with cancers of white cases. Poor light ...
Obesity is preferentially associated with female cancers, which correlation is consistent for end... more Obesity is preferentially associated with female cancers, which correlation is consistent for endometrial, breast and ovarian malignancies. Increased risk for the cancers of female organ triad in obese women supports the presumption that high body weight may confer cancer risk through female hormonal mechanisms. In the 80s and 90s of the past century the carcinogenic capacity of female sexual steroid hormones had become a prevailing concept under the name of ―estrogen hypothesis‖. Several authors presumed that high estrogen levels unopposed by progestin continuously stimulate estrogen receptors, which may be a mechanism of gynecologic and breast cancer initiation. As endometrial cancer cases exhibited even decreased total and bioavailable estradiol levels, it has been proposed that low progesterone, rather than increased estrogen level may be the crucial determinant of cancer risk. This presumption construed the concept of ―unopposed normal estrogen level‖ attributed to defective pr...
article, 2012
North-America and northern European countries exhibit the highest incidence rate of breast cancer... more North-America and northern European countries exhibit the highest incidence rate of breast cancer, whereas women in southern regions are relatively protected. Immigrants from low cancer incidence regions to high-incidence areas might exhibit similarly higher or excessive cancer risk as compared with the inhabitants of their adoptive country. Additional cancer risk may be conferred by incongruence between their biological characteristics and foreign environment. Many studies established the racial/ethnic disparities in the risk and nature of female breast cancer in United States between African-American and Caucasian women. Mammary tumors in black women are diagnosed at earlier age, and are associated with higher rate of mortality as compared with cancers of white cases. Results of studies on these ethnic/racial differences in breast cancer incidence suggest that excessive pigmentation of dark skinned women results in a relative light-deficiency. Poor light exposure may explain the deleterious metabolic and hormonal alterations; such as insulinresistance, deficiencies of estrogen, thyroxin and vitamin-D conferring excessive cancer risk. The more northern the location of an adoptive country the higher the cancer risk for dark skinned immigrants. Recognition of the deleterious systemic effects of darkness and excessive melatonin synthesis enables cancer protection treatment for people living in lightdeficient environment. Recent patents provide new methods for the prevention of hormonal and metabolic abnormities.
INTRODUCTION Autogenous bone graft insertion can effectively enhance the regeneration of the debi... more INTRODUCTION Autogenous bone graft insertion can effectively enhance the regeneration of the debilitated bone. However, bone graft can be harvested only by a second surgery, which is inconvenient for the patient and raises the possibility of many complications. AIMS The effect of an alloplastic bone-replacing material, beta-tricalcium phosphate and that of the autogenous bone graft were compared. The studies were performed on patients deriving from four European centers. METHODS In 20 edentulous patients, the alveolar ridge was extremely atrophied, so fixation of the denture was impossible. The base of the maxillary sinus was surgically elevated bilaterally by insertion of Cerasorb (beta-tricalcium phosphate) (experimental side) and by autogenous bone graft (control side). After surgery the recovery was controlled clinically and radiologically. After 6 months bone cylinders were excised from the grafted areas and implants were inserted into their place. 80 bone samples were embedded...
Hindawi, 2020
Cancer cells are embarrassed human cells exhibiting the remnants of same mechanisms for DNA stabi... more Cancer cells are embarrassed human cells exhibiting the remnants of same mechanisms for DNA stabilization like patients have in their healthy cells. Antiestrogens target the liganded activation of ERs, which is the principal means of genomic regulation in both patients and their tumors. e artificial blockade of liganded ER activation is an emergency situation promoting strong compensatory actions even in cancer cells. When tumor cells are capable of an appropriate upregulation of ER signaling resulting in DNA repair, a tumor response may be detected. In contrast, when ER signaling is completely inhibited, tumor cells show unrestrained proliferation, and tumor growth may be observed. e laboratory investigations of genomic mechanisms in antiestrogen-responsive and antiestrogen-unresponsive tumor cells have considerably enhanced our knowledge regarding the principal regulatory capacity of estrogen signaling. In antiestrogen-responsive tumor cells, a compensatory increased expression and liganded activation of estrogen receptors (ERs) result in an apoptotic death. Conversely, in antiestrogen resistant tumors exhibiting a complete blockade of liganded ER activation, a compensatory effort for unliganded ER activation is characteristic, conferred by the increased expression and activity of growth factor receptors. However, even extreme unliganded ER activation is incapable of DNA restoration when the liganded ER activation is completely blocked. Researchers mistakenly suspect even today that in tumors growing under antiestrogen treatment, the increased unliganded activation of estrogen receptor via activating mutations is an aggressive survival technique, whilst it is a compensatory effort against the blockade of liganded ER activation. e capacity of liganded ERs for genome modification in emergency states provides possibilities for estrogen/ER use in medical practice including cancer cure.
Obesity and its comorbidities exhibit a gender-related dimorphism. Obese males tend to accrue mor... more Obesity and its comorbidities exhibit a gender-related dimorphism. Obese males tend to accrue more visceral fat leading to abdominal adiposity, which shows a strong correlation with serious obesity-associated comorbidities, cardiovascular diseases, and cancers. In contrast, obese females accumulate excessive fatty tissue predominantly subcutaneously, enjoying strong protection from the obesity-related diseases. Considering the gender-related differences in the epidemiology of obesity and obesity-related diseases, the health advantage of obese women as compared with obese men may be attributed to their stronger estrogen signaling and an increased activation of estrogen-regulated genes. The recently clarified intracrine, paracrine, and endocrine functions of adipose tissue illuminate that concentrations of estrogens and the suitable expression and activity of their receptors strongly define the regulatory functions in both men and women. The causal factor of obesity is deficient estrogen signaling; however, there is no direct correlation between obesity and cancer risk. All environmental and genetic cancer risk factors are in correlation with defective estrogen signaling; however, they may or may not be associated with the development of obesity. In contrast, the defect of estrogen signaling is in strong direct correlation with insulin resistance as estrogen regulates all steps of glucose uptake. In central obesity, the increased secretion of cytokines and the associated low-grade inflammation are not causal factors of developing insulin resistance, but rather, they are compensatory processes for the activation of aromatase synthesis and estrogen production. Similarly, the increased synthesis of growth factors and the abundant expression of growth factor receptors are not efforts for initiating an unrestrained cell proliferation, but rather, they provide pathways for an increased unliganded activation of estrogen receptors. In conclusion, a causal therapy against obesity and obesity-related diseases aims to improve estrogen signaling in both men and women.
review, 2024
Important tumor biomarkers, therapeutic targets, and mechanisms of tumorigenesis were discovered ... more Important tumor biomarkers, therapeutic targets, and mechanisms of tumorigenesis were discovered in animal models. Mouse models of malignant gliomas were represented by transplantable, chemicallyinduced, and genetically-engineered cells. The aim of the study was to investigate the morphological, molecular, and immunological characteristics of two original glioblastoma (GB) strains, M2 and M6. These are new, chemically-induced, transplantable tissue models of malignant diffuse mouse glioma. Tissues from M2 GB and M6 GB were transplanted into immunocompetent C57BL/6 mice. The clinical manifestations of M2 GB and M6 GB growth in mice include motility disorders, cachexia, and priapism. Morphologically, M2 GB and M6 GB are characterized by diffuse proliferation, cellular and nuclear polymorphism, high mitotic activity, and pathological forms of mitosis due to the aggressive nature of these tumors. Flow cytometry showed that CD3+ T lymphocytes (~32%) and F4/80+ macrophages (~28-50%) highly infiltrated both tumors. M2 GB had higher levels of F4/80+ macrophages than M6 GB.
Cancers, 2024
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
article, 2013
Correlations between estrogen signaling and human morbidity seems to be very unclear and difficul... more Correlations between estrogen signaling and human morbidity seems to be very unclear and difficult topic. Nowadays, the opinions of scientists have been partially changed regarding "estrogen induced diseases", but the overwhelming literary data are still contradictory. Physiological estrogen levels in healthy premenopausal women supply protection against insulin resistance, hypertension, cardiovascular diseases and malignancies as compared with men of the same age. However, after menopause a decreased ovarian estrogen synthesis will rapidly deteriorate the glucose sensitivity and increases the prevalence of life threatening diseases. New findings on the functions of tissular estrogen receptors (ERs) indicate that estradiol plays important role in the maintenance of glucose homeostasis and energy expenditure. Diverse disorders associated with insulin resistance are usually well treatable by estradiol substitution both in pre-and postmenopausal women as well as in animal experiments. ERs seem to have balanced interplay in the maintenance of adaptation to the momentarily changing intra and extracellular stimuli. This equilibrium may be shattered in case of a defective estrogen supply or by the derangement of ER signaling pathways. Understanding the crosstalk and interplay between ERs illuminates the fact that there is no good or bad ER isoform, but they construe a complex system so as to achieve an ideal internal milieu. Considering the regulatory effects of ERs on food intake, insulin secretion, glucose uptake and metabolic processes, estrogen administration may be a therapeutic avenue to repair insulin sensitivity in patients with dysmetabolism and diabetes mellitus.
Background In tumors, somatic mutagenesis presumably drives DNA damage response (DDR) via altered... more Background In tumors, somatic mutagenesis presumably drives DNA damage response (DDR) via altered regulatory pathways increasing genomic instability and proliferative activity. These considerations led to the standard therapeutic strategy against cancer: the disruption of mutation activated DNA repair pathways of tumors. Purpose Justifying that cancer cells are not enemies to be killed, but rather they are ill human cells having the remnants of physiologic regulatory pathways. Results 1. Genomic instability and cancer development may be originated from the flaw of estrogen signal rather than excessive estrogen signaling. 2. Healthy cells with genomic instability exhibit somatic mutations helping DNA restitution. 3. Somatic mutations in tumor cells aim the restoration of DNA damage rather than further genomic derangement. 4. In tumors, estrogen signal drives the pathways of DNA stabilization leading to apoptotic death. 5. In the peritumoral cellular infiltration, the genomic damage of tumor induces inflammatory cytokine secretion and increased estrogen synthesis. In the inflammatory cells, increased growth factor receptor (GFR) signal confers unliganded activation of estrogen receptors (ERs). 6. In tumor cells responsive to genotoxic therapy, constitutive mutations help the upregulation of estrogen signal and consequential apoptosis. In tumors non responsive to genotoxic therapy, the possibilities for ER activation via either liganded or unliganded pathway, are exhausted leading to farther genomic instability and unrestrained proliferation. Conclusion Understanding the real character and behavior of human tumors at molecular level suggests that we should learn the genome repairing methods of tumors and follow them by supportive therapy rather than provoking additional genomic damages.
Oncology Reviews, 2023
This work presents the history of the recognition of principal regulatory capacities of estrogen ... more This work presents the history of the recognition of principal regulatory capacities of estrogen hormones having been mistakenly regarded as breast cancer promoting agents for more than 120 years. Comprehensive analysis of the results of clinical, epidemiological, immunological and molecular studies justified that endogenous estrogens are the principal regulators of embryonic development, survival and reproduction via orchestrating appropriate expression and even edition of all genes in mammalians. Medical use of chemically modified synthetic estrogens caused toxic complications; thromboembolic events and increased cancer risk in female organs as they proved to be endocrine disruptors deregulating estrogen receptors (ERs) rather than their activators. Synthetic estrogen treatment exhibits ambiguous correlations with cancer risk at different sites, which may be attributed to an inhibition of the unliganded activation of estrogen receptors (ERs) coupled with compensatory liganded activation. The principle of estrogen induced breast cancer led to the introduction of antiestrogen therapies against this tumor; inhibition of the liganded activation of estrogen receptors and aromatase enzyme activity. The initial enthusiasm turned into disappointment as the majority of breast cancers proved to be primarily resistant to antiestrogens. In addition, nearly all patients showing earlier good tumor responses to endocrine therapy, later experienced secondary resistance leading to metastatic disease and fatal outcome. Studying the molecular events in tumors responsive and unresponsive to antiestrogen therapy, it was illuminated that a complete inhibition of liganded ER activation stimulates the growth of cancers, while a successful compensatory upregulation of estrogen signal may achieve DNA restoration, tumor regression and patient’s survival. Recognition of the principal role of endogenous estrogens in gene expression, gene edition and DNA repair, estrogen treatment and stimulation of ER expression in patients may bring about a great turn in medical practice.
Oncology Reviews, 2023
This work presents the history of the recognition of principal regulatory capacities of estrogen ... more This work presents the history of the recognition of principal regulatory capacities of estrogen hormones having been mistakenly regarded as breast cancer promoting agents for more than 120 years. Comprehensive analysis of the results of clinical, epidemiological, immunological and molecular studies justified that endogenous estrogens are the principal regulators of embryonic development, survival and reproduction via orchestrating appropriate expression and even edition of all genes in mammalians. Medical use of chemically modified synthetic estrogens caused toxic complications; thromboembolic events and increased cancer risk in female organs as they proved to be endocrine disruptors deregulating estrogen receptors (ERs) rather than their activators. Synthetic estrogen treatment exhibits ambiguous correlations with cancer risk at different sites, which may be attributed to an inhibition of the unliganded activation of estrogen receptors (ERs) coupled with compensatory liganded activation. The principle of estrogen induced breast cancer led to the introduction of antiestrogen therapies against this tumor; inhibition of the liganded activation of estrogen receptors and aromatase enzyme activity. The initial enthusiasm turned into disappointment as the majority of breast cancers proved to be primarily resistant to antiestrogens. In addition, nearly all patients showing earlier good tumor responses to endocrine therapy, later experienced secondary resistance leading to metastatic disease and fatal outcome. Studying the molecular events in tumors responsive and unresponsive to antiestrogen therapy, it was illuminated that a complete inhibition of liganded ER activation stimulates the growth of cancers, while a successful compensatory upregulation of estrogen signal may achieve DNA restoration, tumor regression and patient’s survival. Recognition of the principal role of endogenous estrogens in gene expression, gene edition and DNA repair, estrogen treatment and stimulation of ER expression in patients may bring about a great turn in medical practice.
Journal of Craniofacial Surgery, 2004
Numerous possibilities are available for the reconstruction of facial bone defects. The materials... more Numerous possibilities are available for the reconstruction of facial bone defects. The materials used to fill such defects must satisfy various requirements. One of the most important is that they must undergo transformation into autologous bone tissue in the process of remodeling. A report is given of the long-term results of augmentations of large bone defects performed with different bone-substitute materials in two patients. In one case, augmentation was carried out with beta-tricalcium phosphate after the removal of a fibromyxoma. In the second case, three large cystic lesions in the mandible of a patient with Gorlin-Goltz syndrome were filled with beta-tricalcium phosphate, with a mixture of beta-tricalcium phosphate and platelet concentrate, or with hydroxyapatite of algal origin. The process of ossification was checked at 6-month intervals by means of clinical, radiologic (orthopantomograms and two-dimensional and three-dimensional computer tomograms), and histologic methods. At 1 year after the intervention, the site of the augmentation was in all cases occupied by hard tissue of good quality. With the given imaging procedures, it was difficult to distinguish between the original bone and the region filled with bone-substitute material. The three-dimensional computer tomogram images indicated that the contours and quality of the new bone corresponded with the physiologic and anatomical conditions. The histologic examinations show the remodeling of the bone-substitute materials. The bone-substitute materials applied in these cases fully satisfied the demands of transformation into bone (remodeling). The speed of remodeling seemed to be the fastest when the mixture of beta-tricalcium phosphate and platelet concentrate was used.
Fogorvosi szemle, 2006
Malignant melanoma occurs only rarely as a primary tumour in the oral cavity, with an incidence o... more Malignant melanoma occurs only rarely as a primary tumour in the oral cavity, with an incidence of 1-2 percent. Oral melanomas are predominantly to be found in the hard and soft palate, and less often in the gingiva and mandible. Mucosal malignant melanomas are much more aggressive than those situated in the skin. In two-thirds of the cases the route of formation of the metastases is lymphogenic, and haematogenic in the remainder. The typical sites of the distant metastases are the skin, the lungs, the brain, the liver, and the bones. Metastatic malignant melanoma in the oral cavity, a rarity in the literature, is associated with a very poor prognosis. This paper reports on two cases in which an isolated distant metastasis developed in the oral cavity.
Orvosi Hetilap, Jun 23, 2002
When the maxilla is edentulous and the alveolar process is extensively absorbed, a dental root ca... more When the maxilla is edentulous and the alveolar process is extensively absorbed, a dental root can be implanted only after the implantation of bone or a bone-substitute. Only in this way can the subjective and objective negative features associated with a removable prosthesis be avoided. Many forms of bone-substitutes are known. Freely taken bone from the patient generally serves as the gold standard for the classification of bone-substitutes. The aim of our work was to compare two materials (the patient's own bone and beta-tricalcium phosphate) in the same patient. Ten patients were selected who for some reason did not want or could not wear a removable prosthesis. The maxilla was so atrophied that bone or bone-substitute implantation was necessary before the dental root could be implanted. The maxilla had to be elevated from inside (sinus elevation) and thickened from outside (onlay-plasty). Bone was taken in the usual manner from the hipbone. For the internal elevation, such ...
Fogorvosi szemle, 2004
Healing of extraction wounds was examined in an animal experiment model on Beagle dogs. After bil... more Healing of extraction wounds was examined in an animal experiment model on Beagle dogs. After bilateral extraction of the premolars of 12 dogs the alveoli were filled up with a combination of beta-tricalcium phosphate (Cerasorb) graft and platelet rich plasma (PRP) on the experimental side, and with Cerasorb alone on the control side. Biopsy specimens were taken from the regenerating bone at 6, 12 and 24 weeks after surgery for histological study. Results of the histologic and histomorphometric examinations revealed that after 6 weeks the newly formed bone was significantly denser on the experimental side. After 12 weeks this difference became moderate, and after 24 weeks the bone forming activity was nearly equal on the two sides. These results suggest that local administration of Cerasorb and PRP results in more intense bone regeneration, especially in the early phase.
Fogorvosi szemle, 2006
Graft insertion can effectively enhance the regeneration of debilitated bone. The effects of an a... more Graft insertion can effectively enhance the regeneration of debilitated bone. The effects of an alloplastic bone-replacing material, beta-tricalcium phosphate (Cerasorb), and of autogenous bone graft were compared. In 17 edentulous patients, the maxillary sinus floor was extremely atrophied to such an extent that implant placement was impossible. The Schneiderian membrane was surgically elevated bilaterally by insertion of Cerasorb (experimental side) and autogenous bone graft (control side). After surgery, the recovery was followed clinically and radiologically. After 6 months, 68 bone cylinders were excised from the grafted areas and implants were inserted into their places. The bone samples were embedded into resin, and the osteointegration of the grafts was studied histologically. Trabecular bone volume (TBV) and trabecular bone pattern factor (TBPf) were quantified by histomorphometry. Cerasorb proved to be an effective bone-replacing material with osteoconductivity; it was cap...
Orvosi hetilap, 2005
INTRODUCTION The metabolic syndrome develops on the basis of peripheral insulin resistance. It is... more INTRODUCTION The metabolic syndrome develops on the basis of peripheral insulin resistance. It is a continuously progressing metabolic disorder, which concludes finally into serious diseases. Type-2 diabetes, cardiovascular disease and--according to the recent literature--malignancies are the most important consequences. A well-known fact, that metabolic disorders; such as diabetes and obesity, can deeply influence the structure and function of the salivary glands. Considering these data, the question arises; is there any correlation among insulin resistance, type-2 diabetes and salivary gland tumors? AIMS A retrospective epidemiological examination was performed to analyze the correlations between salivary gland tumors and insulin resistance states (type-2 diabetes and metabolic syndrome). METHODS Data of 438 patients were analyzed in the Maxillofacial Surgery Clinic of the Semmelweis University. In 224 cases salivary gland tumors were surgically removed. In 214 control cases, bone...
article, 2007
Alcohol and tobacco are considered as major risk factors for oral cancer (OC). In the developed c... more Alcohol and tobacco are considered as major risk factors for oral cancer (OC). In the developed countries reduction of alcohol and tobacco consumption has achieved favorable decreasing trends in OC morbidity and mortality over the last decades. At the same time the earlier very high male-female OC ratio showed a declining tendency all over the world. This trend used to be simply interpreted by the increasing exposure to tobacco and alcohol among women. However, literary data support an enhanced prevalence of women among non-smoker non-drinker OC cases. These findings focused the attention for further underlying mechanisms in the initiation of OC, such as metabolic and hormonal disorders. Insulin resistant states (metabolic syndrome and type-2 diabetes) are sources of many human diseases. Reactive hyperinsulinemia, increased production of insulin-like growth factors, hyperglycemia and its serious consequences are all proven cancer promoters. Decreased blood perfusion of the tissues c...
PURPOSE The effects of 2 graft materials, beta-tricalcium phosphate (Cerasorb) alone and a combin... more PURPOSE The effects of 2 graft materials, beta-tricalcium phosphate (Cerasorb) alone and a combination of Cerasorb and platelet-rich plasma (PRP), on the bone regeneration process were evaluated in the canine mandible. MATERIALS AND METHODS The mandibular premolars of 12 beagle dogs were surgically removed. The extraction sockets were filled with Cerasorb on the control side and a mixture of Cerasorb and PRP on the test side. Bilateral biopsy samples were taken from the graft insertion sites at 6, 12, and 24 weeks after surgery. Sections were prepared from the undecalcified resin-embedded samples. RESULTS Six weeks after grafting, the proliferation of cellular osteogenic mesenchyma was more abundant in the test group. The histomorphometric data revealed a significantly higher percentage of bone area in the test group (45.9%) than in the control group (30.8%) (P < .05). Twelve weeks after grafting, the test group still had some advantage over the control group in terms of bone reg...
Pineal hormone melatonin is the mediator of physiological adaptation to external light, and to th... more Pineal hormone melatonin is the mediator of physiological adaptation to external light, and to the day and night rhythms of activity and rest. It seems to be a natural hormone to facilitate sleep as melatonin secretion is physiologically increased in darkness at night being associated with decreased hormonal and metabolic activities. Immigrants from low cancer incidence regions to northern high-incidence areas might exhibit similarly higher or excessive cancer risk as compared with the inhabitants of their adoptive country. Additional cancer risk may be conferred by incongruence between their dark pigmentation and the poor light exposure of foreign environment. Many studies established the racial/ethnic disparities in the risk and biology of female breast cancer in United States between African-American and Caucasian women. Mammary tumors in black women are diagnosed at earlier age, and are associated with higher rate of mortality as compared with cancers of white cases. Poor light ...
Obesity is preferentially associated with female cancers, which correlation is consistent for end... more Obesity is preferentially associated with female cancers, which correlation is consistent for endometrial, breast and ovarian malignancies. Increased risk for the cancers of female organ triad in obese women supports the presumption that high body weight may confer cancer risk through female hormonal mechanisms. In the 80s and 90s of the past century the carcinogenic capacity of female sexual steroid hormones had become a prevailing concept under the name of ―estrogen hypothesis‖. Several authors presumed that high estrogen levels unopposed by progestin continuously stimulate estrogen receptors, which may be a mechanism of gynecologic and breast cancer initiation. As endometrial cancer cases exhibited even decreased total and bioavailable estradiol levels, it has been proposed that low progesterone, rather than increased estrogen level may be the crucial determinant of cancer risk. This presumption construed the concept of ―unopposed normal estrogen level‖ attributed to defective pr...
article, 2012
North-America and northern European countries exhibit the highest incidence rate of breast cancer... more North-America and northern European countries exhibit the highest incidence rate of breast cancer, whereas women in southern regions are relatively protected. Immigrants from low cancer incidence regions to high-incidence areas might exhibit similarly higher or excessive cancer risk as compared with the inhabitants of their adoptive country. Additional cancer risk may be conferred by incongruence between their biological characteristics and foreign environment. Many studies established the racial/ethnic disparities in the risk and nature of female breast cancer in United States between African-American and Caucasian women. Mammary tumors in black women are diagnosed at earlier age, and are associated with higher rate of mortality as compared with cancers of white cases. Results of studies on these ethnic/racial differences in breast cancer incidence suggest that excessive pigmentation of dark skinned women results in a relative light-deficiency. Poor light exposure may explain the deleterious metabolic and hormonal alterations; such as insulinresistance, deficiencies of estrogen, thyroxin and vitamin-D conferring excessive cancer risk. The more northern the location of an adoptive country the higher the cancer risk for dark skinned immigrants. Recognition of the deleterious systemic effects of darkness and excessive melatonin synthesis enables cancer protection treatment for people living in lightdeficient environment. Recent patents provide new methods for the prevention of hormonal and metabolic abnormities.
INTRODUCTION Autogenous bone graft insertion can effectively enhance the regeneration of the debi... more INTRODUCTION Autogenous bone graft insertion can effectively enhance the regeneration of the debilitated bone. However, bone graft can be harvested only by a second surgery, which is inconvenient for the patient and raises the possibility of many complications. AIMS The effect of an alloplastic bone-replacing material, beta-tricalcium phosphate and that of the autogenous bone graft were compared. The studies were performed on patients deriving from four European centers. METHODS In 20 edentulous patients, the alveolar ridge was extremely atrophied, so fixation of the denture was impossible. The base of the maxillary sinus was surgically elevated bilaterally by insertion of Cerasorb (beta-tricalcium phosphate) (experimental side) and by autogenous bone graft (control side). After surgery the recovery was controlled clinically and radiologically. After 6 months bone cylinders were excised from the grafted areas and implants were inserted into their place. 80 bone samples were embedded...
Hindawi, 2020
Cancer cells are embarrassed human cells exhibiting the remnants of same mechanisms for DNA stabi... more Cancer cells are embarrassed human cells exhibiting the remnants of same mechanisms for DNA stabilization like patients have in their healthy cells. Antiestrogens target the liganded activation of ERs, which is the principal means of genomic regulation in both patients and their tumors. e artificial blockade of liganded ER activation is an emergency situation promoting strong compensatory actions even in cancer cells. When tumor cells are capable of an appropriate upregulation of ER signaling resulting in DNA repair, a tumor response may be detected. In contrast, when ER signaling is completely inhibited, tumor cells show unrestrained proliferation, and tumor growth may be observed. e laboratory investigations of genomic mechanisms in antiestrogen-responsive and antiestrogen-unresponsive tumor cells have considerably enhanced our knowledge regarding the principal regulatory capacity of estrogen signaling. In antiestrogen-responsive tumor cells, a compensatory increased expression and liganded activation of estrogen receptors (ERs) result in an apoptotic death. Conversely, in antiestrogen resistant tumors exhibiting a complete blockade of liganded ER activation, a compensatory effort for unliganded ER activation is characteristic, conferred by the increased expression and activity of growth factor receptors. However, even extreme unliganded ER activation is incapable of DNA restoration when the liganded ER activation is completely blocked. Researchers mistakenly suspect even today that in tumors growing under antiestrogen treatment, the increased unliganded activation of estrogen receptor via activating mutations is an aggressive survival technique, whilst it is a compensatory effort against the blockade of liganded ER activation. e capacity of liganded ERs for genome modification in emergency states provides possibilities for estrogen/ER use in medical practice including cancer cure.
Obesity and its comorbidities exhibit a gender-related dimorphism. Obese males tend to accrue mor... more Obesity and its comorbidities exhibit a gender-related dimorphism. Obese males tend to accrue more visceral fat leading to abdominal adiposity, which shows a strong correlation with serious obesity-associated comorbidities, cardiovascular diseases, and cancers. In contrast, obese females accumulate excessive fatty tissue predominantly subcutaneously, enjoying strong protection from the obesity-related diseases. Considering the gender-related differences in the epidemiology of obesity and obesity-related diseases, the health advantage of obese women as compared with obese men may be attributed to their stronger estrogen signaling and an increased activation of estrogen-regulated genes. The recently clarified intracrine, paracrine, and endocrine functions of adipose tissue illuminate that concentrations of estrogens and the suitable expression and activity of their receptors strongly define the regulatory functions in both men and women. The causal factor of obesity is deficient estrogen signaling; however, there is no direct correlation between obesity and cancer risk. All environmental and genetic cancer risk factors are in correlation with defective estrogen signaling; however, they may or may not be associated with the development of obesity. In contrast, the defect of estrogen signaling is in strong direct correlation with insulin resistance as estrogen regulates all steps of glucose uptake. In central obesity, the increased secretion of cytokines and the associated low-grade inflammation are not causal factors of developing insulin resistance, but rather, they are compensatory processes for the activation of aromatase synthesis and estrogen production. Similarly, the increased synthesis of growth factors and the abundant expression of growth factor receptors are not efforts for initiating an unrestrained cell proliferation, but rather, they provide pathways for an increased unliganded activation of estrogen receptors. In conclusion, a causal therapy against obesity and obesity-related diseases aims to improve estrogen signaling in both men and women.
book chapter, 2019
In the early 1940's, the US Food and Drug Administration (FDA) approved marketing of synthetic es... more In the early 1940's, the US Food and Drug Administration (FDA) approved marketing of synthetic estrogens; non steroidal Diethylstilbestrol (DES) and Ethinylestradiol (EE) as well as Conjugated Equine Estrogens (CEEs) for medical purposes. High Dose Estrogen (HDE) therapy using DES and EE was introduced into the treatment of advanced breast cancer in postmenopausal women. Oral contraceptives (OCs) comprising EE were developed in the early 1960s and EE became a standard component of near all combined forms of contraceptive pills. Use of exclusively synthetic estrogens for both HDE therapy of breast cancer and contraception ensured a possibility for clear evaluations of the risks and benefits of synthetic hormone use. HDE therapy for breast cancer induced serious toxicity affecting near all organs, suggesting a genome-wide disturbance in cellular mechanisms. OCs comprising low doses of EE which may induce arterial and venous thromboembolic events and show ambiguous correlations with cancer risk at different sites by means of altered regulation of Estrogen Receptors [ERs]. In contrast, for menopausal Hormone Replacement Therapy [HRT] both synthetic and natural estrogens extracted from biological samples were prescribed. Among postmenopausal women, the use of estrogens with different origin and even their combinations with synthetic progestins resulted in a chaos of quite controversial clinical experiences concerning the risks for arterial and venous thromboembolism and for cancers of breasts and endometrium. Analysis of the effects of specific HRT types in postmenopausal women justified that horse urine derived CEE without synthetic progestin is a highly beneficial formula against breast cancer, coronary heart disease and bone loss. The presented study reveals that an 80 year period of synthetic hormone prescription may be blamed for the misbelief that ERs exposed to elevated endogenous estrogen concentrations may be deregulated and drive cancer promoting changes. In tumors constitutively upregulating ER alpha expression, recent patents disclose amplifying ESR1 mutations.
Springer, 2022
Abstract Although our understanding of breast cancer development has been shown a remarkable incr... more Abstract
Although our understanding of breast cancer development has been shown a remarkable increase in the past 50 years, the disease is a serious public health problem and poses major challenges even today. In 1896, estrogen withdrawal by oophorectomy resulted in a transient tumor regression in the minority of premenopausal breast cancer cases. From that time onward, a direct correlation between serum estrogen concentration and tumor growth has been erroneously supposed and estrogen withdrawal gained great popularity among specialists of breast cancer care. Development of chemically modified synthetic estrogens and progestins and their use in menopausal hormone therapy (MHT) resulted in controversial risks and benefits concerning women’s health and further supported the belief of estrogen-induced breast cancer. The ambiguous correlations between MHT and breast cancer risk revealed that synthetic hormones are not bioidentical, but rather they are endocrine disruptors deregulating the work of genomic machinery. Identification of estrogen receptors (ERs) as transcription factors in targeted tissues was a milestone in cancer research promoting immense development in human genetics and in understanding the regulation of the whole genomic machinery. Estrogen activation of ERs was mistakenly regarded as a fuel for breast cancer initiation and growth, and an increased ER positivity in tumors was erroneously evaluated as aggressive survival technique. By contrast, elevated ER expression of tumors showed direct correlation with high differentiation and good prognosis of the disease. In addition, the overexpression of human epidermal growth factor receptor (HER-2) in breast tumors is erroneously regarded as a direct activator of cell proliferation. Conversely, in tumors, growth factor receptors serve the regulation of ERs via unliganded pathway helping DNA restoration and apoptotic death. Breast cancer cells need medical help for their self-directed upregulation of estrogen signal and DNA repair rather than further deterioration of their genomic mechanisms. The principle of estrogen-induced breast cancer led to the introduction of antiestrogen therapies against this tumor and inhibition of the liganded activation of estrogen receptors and aromatase enzyme activity. The initial enthusiasm turned into disappointment as the majority of breast cancers proved to be primarily resistant to antiestrogens. Later, near all patients showing earlier good tumor responses experienced secondary resistance to endocrine therapy leading to metastatic disease and fatal outcome. Molecular events in tumors, responsive and unresponsive to antiestrogen therapy, illuminated that a successful inhibition of liganded ER activation stimulates, while a strong compensatory upregulation of estrogen signal inhibits the growth of tumor and helps patient’s survival. Recognition of the principal role of endogenous estrogens in gene expression, gene edition, and DNA repair reveals that estrogen treatment and upregulation of ER expression may bring about a great turn in breast cancer care.