Zinc: The Wonder Drug for the Treatment of Carcinomas.

Evidence is evolving that support the relationship that all carcinomas exhibit the following important relationships: The malignant cells exhibit a significant decreased zinc compared to the normal cells. The higher zinc levels that exist in the normal cells are cytotoxic in the malignant cells. The decrease in zinc is due to the down regulation of the ZIP-family zinc uptake transporter. These cells are as "ZIP-deficient/decreased zinc" malignancies. This provides a target for a chemotherapy that can restore the high zinc levels that will manifest cytotoxic effects in the malignant cells. In order to achieve this, a vehicle that facilitates the uptake and accumulation of zinc in the ZIP-deficient cells is required. The zinc ionophore, clioquinol, exhibits the properties that will provide these requirements. This is demonstrated by the treatment of a patient with 3% Clioquinol Cream, which successfully suppressed the progression of androgen-dependent prostate cancer. This treatment should also be efficacious for pancreatic cancer, liver cancer, breast cancer, thyroid cancer, kidney cancer, stomach cancer, gall bladder cancer, and lung cancer; which are carcinomas that exhibit decreased zinc. Thus, it is appropriate to describe that "Zinc is the wonder drug for the treatment of carcinomas".

The Suppression of Prolactin is required for the Treatment of Advanced Prostate Cancer.

Androgen-independent advanced prostate cancer is a terminal malignancy that generally results in death within five years. Its cause has been unknown, and a treatment did not exist. Prevailing views have mistakenly implicated impaired androgen receptor activity in the development of androgen-independent malignancy; which has deterred the existence of an effective treatment. Instead, recent reports have provided evidence that prolactin promotes the development and progression of androgen-independent malignancy; which follows androgen ablation treatment for androgen-dependent prostate cancer. That relationship dictates that a treatment for advanced prostate cancer should suppress the concentration plasma prolactin. This has been achieved with cabergoline (dopamine agonist; Dostinex) treatment of a patient that resulted in 88% decreased plasma prolactin, and terminated the malignancy. That likely represents the first effective treatment for advanced prostate cancer. It remains to establish if this treatment will be successful for other patients with advanced prostate cancer.

A Novel Patient Case Report to Show the Successful Termination of Untreatable Androgen-independent Prostate Cancer: Treatment with Cabergoline (Dopamine agonist).

INTRODUCTION: Testosterone promotes the initial development of androgen-dependent prostate cancer. This is the basis for androgen ablation treatment, which attenuates, but does not terminate, the malignancy. Instead, it leads to prolactin-dependent malignancy; in which patient death generally occurs within 5 years. This report describes the novel treatment of a patient; which terminated androgen-independent prostate cancer. RESULTS: Patient "XY" was diagnosed with prostate malignancy and metastases. He received hormonal androgen ablation treatment, chemotherapy, and radiation treatment. He developed androgen-independent prostate cancer; with expected death in 2-3 years. He was treated with cabergoline (dopamine agonist) treatment, which decreased the plasma prolactin 88%; by inhibiting the pituitary production of prolactin. The subsequent PET scan (positron emission tomography) revealed the absence of malignancy; and the CTC (circulating tumor cells) decreased from count=5.4 to count=0. DISCUSSION: The cause of androgen-independent malignancy has been unknown, and an effective chemotherapy did not exist. The activities of normal and malignant prostate cells are regulated primarily by testosterone. When testosterone availability diminishes; prolactin regulation is manifested. This is represented when androgen ablation results in the development of prolactin-dependent malignancy. An effective chemotherapy would be targeted to eliminate the plasma prolactin-manifestation of the androgen-independent malignancy. CONCLUSIONS: This report of a novel chemotherapy for androgen-independent malignancy corroborates our understanding of the implications of prolactin in its development and treatment. There are about 165,000 cases/year with 25,000 deaths/year in the U.S.; and 1.0 million cases/year with 260,000 deaths/year worldwide. Those patients with androgen-independent prostate cancer can now employ this cabergoline treatment to prevent or terminate this deadly type of prostate cancer.

A Proposed Efficacious Treatment with Clioquinol (Zinc Ionophore) and Cabergoline (Prolactin Dopamine Agonist) for the Treatment of Terminal Androgen-independent Prostate Cancer. Why and How?

All cases of prostate cancer exhibit the hallmark condition of marked decrease in zinc in malignancy compared to the high zinc levels in the normal and benign prostate. There exists no reported corroborated case of prostate cancer in which malignancy exhibits the high zinc levels that exist in the normal prostate acinar epithelium. The decrease in zinc is achieved by the downregulation of ZIP1 zinc transporter, which prevents the uptake and accumulation of cytotoxic zinc levels. Thus, prostate cancer is a "ZIP1-deficient" malignancy. Testosterone and prolactin are the major hormones that similarly regulate the growth, proliferation, metabolism, and functional activities of the acinar epithelial cells in the peripheral zone (the site of development and progression of malignancy). Testosterone regulation provides the basis for androgen ablation treatment of advanced prostate cancer, which leads to the development of terminal androgen-independent malignancy. Androgen-independent malignancy progresses under the influence of prolactin. These relationships provide the basis for the prevention and treatment of advanced prostate cancer. Clioquinol (zinc ionophore; 5-chloro-7-iodoquinolin-8-ol) is employed to facilitate zinc transport and accumulation in the ZIP1-deficient malignant cells and induce cytotoxic effects. Cabergoline (dopamine agonist) is employed to decrease prolactin production and its role in the progression of androgen-independent malignancy. We propose a clioquinol/cabergoline treatment regimen that will be efficacious for aborting terminal advanced prostate cancer. FDA policies permit this treatment regimen to be employed for these patients.

Energy Dispersive X-Ray Fluorescence Zn/Fe Ratiometric Determination of Zinc Levels in Expressed Prostatic Fluid: A Direct, Non-Invasive and Highly Accurate Screening for Prostate Cancer.

Prostate specific antigen (PSA) does not provide the reliability that is required for the accurate urology screening of prostate cancer (PCa). Consequently, there has been a major focus and search for a simple, rapid, direct, preferably non-invasive, and highly accurate biomarker and procedure for the urology screening for prostate cancer. Virtually all PCa cases exhibit a marked decrease in zinc in prostate tissue and in prostatic fluid. This is a hallmark "signature" clinical characteristic for all prostate cancers, which provides the clinical basis for zinc screening of PCa. Energy dispersive x-ray fluorescence (EDXRF) of zinc levels in expressed prostatic fluid (EPF) provides > 90% accuracy for the identification of prostate cancer vs normal/benign prostate. An energy dispersive x-ray fluorescence (EDXRF) Zn/Fe ratiometric analysis of expressed prostatic fluid (EPF) can provide > 90% accuracy for the identification of prostate cancer vs normal/benign prostate. This will be achieved by direct EDXRF analysis of a "drop" of EPF directly deposited on a filter paper disc during the urology digital rectal examination of the subject. Interfering and confounding conditions that besiege PSA do not exist in the EDXRF Zn/Fe radiometric analyses. This report reviews the basis for zinc analysis for PCA, provides the supporting evidence that EDXRF Zn/Fe ratiometric analysis of EPF will provide a simple, rapid, direct, non-invasive, and highly accurate biomarker and procedure for the urology screening for prostate cancer.

Testosterone, prolactin, and oncogenic regulation of the prostate gland. A new concept: Testosterone-independent malignancy is the development of prolactin-dependent malignancy!

Hormone-independent malignancy is a major issue of morbidity and deaths that confronts prostate cancer. Despite decades of research, the oncogenic and hormonal implications in the development and progression of prostate malignancy remain mostly speculative. This is largely due to the absence and/or lack of consideration by contemporary clinicians and biomedical investigators regarding the established implications of the co-regulation of testosterone and prolactin in the development, maintenance, metabolism and functions of the prostate gland. Especially relevant is the major metabolic function of production of high levels of citrate by the peripheral zone acinar epithelial cells. Citrate production, along with growth and proliferation by these cells, is regulated by co-existing testosterone and prolactin signaling pathways; and by the oncogenic down-regulation of ZIP1 transporter/zinc/citrate in the development of malignancy. These relationships had not been considered in the issues of hormonedependent malignancy. This review provides the relevant background that has established the dual role of testosterone and prolactin regulation of the prostate gland; which is essential to address the implications in the oncogenic development and progression of hormone-dependent malignancy. The oncogenic factor along with testosterone-dependent and prolactin-dependent relationships leads to the plausible concept that androgen ablation for the treatment of testosteronedependent malignancy results in the development of prolactindependent malignancy; which is testosterone-independent malignancy. Consequently, both testosterone ablation and prolactin ablation are required to prevent and/or abort terminal hormonedependent prostate cancer.

The implications of the hypocitricemic response to surgery and the role of liver function and hepatocyte metabolism: An important, but neglected, clinical relationship.

Reported studies more than forty years ago established that all surgery patients exhibit a marked postoperative hypocitricemia within one day following surgery and persists for seven days and longer. Animals also exhibit the postoperative hypocitricemia. The hypocitricemia results from increased liver clearance of plasma citrate, in which the hepatocytes become capable of transporting and utilizing citrate from plasma. This represents a physiologic/metabolic response during the patient recovery from surgery. The extensive hypocitricemia in response to surgery is not manifested by known citricemic hormones, but is initiated via an unidentified putative endocrine hypocitricemic hormone. In addition to the importance relating to surgery patients, the surgical hypocitricemic effects, along with the liver and hepatic cell effects, will impact virtually all human and animal clinical and experimental studies that include surgical intervention; including the conclusions and translational clinical implications. Unfortunately, the hypocitricemic response to surgery has been ignored for the past forty years, and most contemporary clinicians and biomedical investigators are not aware of this clinical relationship. The intent of this review is to inform members of the medical community of the established hypocitricemic response to surgery and the important role of liver clearance and hepatocyte metabolism of plasma citrate; which, hopefully, will generate interest and research that should be integrated into contemporary issues that involve surgical intervention.

Poor Science; Poorly Trained Scientists; Poor Policies: Major Deterrents to the War on Cancer.

Although the availability of funding has been described as the major limitation on advances in cancer, the progress in the war on cancer has been deterred mainly by poor science, poorly trained scientists, and poor NIH policies. This is the result of NIH policies of its extreme focus on molecular biology (genomics, molecular genetics, molecular biology) identification of the molecular factors and pathways; which are required for the acceptability of treatment and preventive protocols. As such, this has influenced virtually all agencies that provide grants for medical research to adopt the NIH policies. This has impacted the funding of the research as well as the focus of the training of scientists. Directors of NCI Dr. Varmus (also Nobel Prize awardee) and Dr. Zerhouni had addressed this issue; and they rejected the necessity of molecular biology studies and information. NIH should return to the holistic physiological/pathophysiological approach to studies of cancer issues. This would provide the best approach for winning the war on cancer.

Decreased zinc in the development and progression of malignancy: an important common relationship and potential for prevention and treatment of carcinomas.

INTRODUCTION: Efficacious chemotherapy does not exist for treatment or prevention of prostate, liver, and pancreatic carcinomas, and some other cancers that exhibit decreased zinc in malignancy. Zinc treatment offers a potential solution; but its support has been deterred by adverse bias. Areas covered: 1. The clinical and experimental evidence for the common ZIP transporter/Zn down regulation in these cancers. 2. The evidence for a zinc approach to prevent and/or treat these carcinomas. 3. The issues that introduce bias against support for the zinc approach. Expert opinion: ZIP/Zn downregulation is a clinically established common event in prostate, hepatocellular and pancreatic cancers. 2. Compelling evidence supports the plausibility that a zinc treatment regimen will prevent development of malignancy and termination of progressing malignancy in these cancers; and likely other carcinomas that exhibit decreased zinc. 3. Scientifically-unfounded issues that oppose this ZIP/Zn relationship have introduced bias against support for research and funding of a zinc treatment approach. 4. The clinically-established and supporting experimental evidence provide the scientific credibility that should dictate the support for research and funding of a zinc approach for the treatment and possible prevention of these cancers. 5. This is in the best interest of the medical community and the public-at-large.

A comprehensive review of the role of zinc in normal prostate function and metabolism; and its implications in prostate cancer.

The human prostate gland contains extremely high zinc levels; which is due to the specialized zinc-accumulating acinar epithelial of the peripheral zone. These cells evolved for their unique capability to produce and secrete extremely levels of citrate, which is achieved by the high cellular zinc level effects on the cell metabolism. This review highlights the specific functional and metabolic alterations that result from the accumulation of the high zinc levels, especially its effects on mitochondrial citrate metabolism and terminal oxidation. The implications of zinc in the development and progression of prostate cancer are described, which is the most consistent hallmark characteristic of prostate cancer. The requirement for decreased zinc resulting from down regulation of ZIP1 to prevent zinc cytotoxicity in the malignant cells is described as an essential early event in prostate oncogenesis. This provides the basis for the concept that an agent (such as the zinc ionophore, clioquinol) that facilitates zinc uptake and accumulation in ZIP1-deficient prostate tumors cells will markedly inhibit tumor growth. In the current absence of an efficacious chemotherapy for advanced prostate cancer, and for prevention of early development of malignancy; a zinc treatment regimen is a plausible approach that should be pursued.

In situ clinical evidence that zinc levels are decreased in breast invasive ductal carcinoma.

PURPOSE: Altered zinc levels in malignant cells versus their normal cells have important implications in the development and progression of several cancers. Prostate, pancreatic, and hepatocellular carcinomas exhibit consistent marked zinc decrease in situ in the malignant cells, and other cancers (such as kidney, lung, and thyroid) also exhibit decreased tissue zinc levels. However, zinc levels are increased in breast cancer tissue compared to breast normal tissue, and the contemporary dominant view is that zinc is increased in invasive ductal carcinoma. This has important implications regarding the role and effects of zinc in breast malignancy compared to other cancers, which caused us to initiate this study to either confirm or challenge the contemporary view of an increased zinc level in the invasive ductal malignant cells. METHODS: We employed dithizone staining of breast tissue sections and tissue cores to determine the relative in situ cellular zinc levels specifically in the invasive ductal malignant cells as compared to normal ductal epithelium. This approach had not been employed in any of the reported breast studies. RESULTS: The results revealed that the zinc levels are consistently and markedly decreased in the ductal malignant cells as compared with higher prominent zinc levels in the normal ductal epithelium. Decreased zinc is evident in Grade 1 well-differentiated malignancy and in Grade 2 and Grade 3 carcinomas. Among the twenty-five cancer cases in this study, none exhibited increased zinc in the invasive ductal carcinoma compared to the zinc level in the normal ductal epithelium. CONCLUSIONS: The decreased zinc levels in breast invasive ductal carcinoma is consistent with prostate, pancreatic, and liver carcinomas in which the decrease in zinc is a required event in the development of malignancy to prevent cytotoxicity that would result from the higher zinc levels in the normal cells. This new understanding requires a redirection in elucidating the mechanisms and factors regarding the regulation of zinc in breast cancer, its potential translational applications as possible biomarkers, and for treatment of breast invasive ductal carcinoma.

Zinc Ionophore (Clioquinol) Inhibition of Human ZIP1-Deficient Prostate Tumor Growth in the Mouse Ectopic Xenograft Model: A Zinc Approach for the Efficacious Treatment of Prostate Cancer.

Prostate cancer remains the second leading cause of cancer deaths in males. This is mainly due to the absence of an available efficacious chemotherapy despite decades of research in pursuit of effective treatment approaches. A plausible target for the treatment is the established clinical relationship that the zinc levels in the malignant cells are markedly decreased compared to the normal epithelium in virtually all cases of prostate cancer, and at all stages malignancy. The decrease in zinc results from the downregulation of the functional zinc uptake transporter, ZIP1; which occurs during early development of prostate malignancy. This is an essential requirement for the development of malignancy to prevent the cytotoxic/tumor-suppressor effects of increased zinc on the premalignant and malignant cells. Thus prostate cancer is a ZIP1-deficient malignancy. This relationship provides the basis for a treatment regimen that will facilitate the uptake and accumulation of zinc into the premalignant and malignant cells. In this report we employed a zinc ionophore (clioquinol) approach in the treatment of mice with human ZIP1-deficient prostate tumors (ectopic xenograft model). Clioquinol treatment resulted in 85%inhibition of tumor growth due to the cytotoxic effects of zinc. Coupled with additional results from earlier studies, the compelling evidence provides a plausible approach for the effective treatment of human prostate cancer; including primary site malignancy, hormone-resistant cancer, and metastasis. Additionally, this approach might be effective in preventing the development of malignancy in individuals suspected of presenting with early development of malignancy. Clinical trials are now required in leading to the potential for an efficacious zinc-treatment approach, which is urgently needed for the treatment of prostate cancer.

Plasma Citrate Homeostasis: How It Is Regulated; And Its Physiological and Clinical Implications. An Important, But Neglected, Relationship in Medicine.

The homeostatic maintenance of a normal plasma citrate concentration is an important factor in humans and in animals; and is required for many normal physiological activities. Dysregulation of normal plasma citrate presents pathophysiological hypocitricemic or hypercitricemic conditions. This can lead to clinical consequences in many areas of medicine; such as impaired blood clotting, altered acid/base status, impaired neuromuscular/cardiac activities, hypocitraturia and stone formation, bone disorders with loss of bone strength and increased fractures, hypocitricemia of surgical stress. These important implications of citrate relationships have been largely ignored by the contemporary clinical and biomedical community; to the extent that it is not even described in most current textbooks and review papers. This review describes the physiological, endocrine, and metabolic relationships in the normal regulation and maintenance of plasma citrate; and presents some important clinical consequences of its dysfunctional maintenance. The importance of bone, kidney and liver activities in the maintenance of normal plasma citrate is described along with the citricemic roles of parathyroid hormone, calcitonin and vitamin D. These factors and relationships are presented as the contemporary understanding of the integrated regulation of plasma citrate as the basis for its clinical importance in medicine. The exclusion of these citrate relationships leads to misunderstanding and misrepresentation of physiological and clinical conditions in many issues in medicine and paramedicine areas. The intent of this review is to revive the interest and support for research to address the many unknown and speculative issues of plasma citrate regulation and its important clinical implications. This is in the best interest of the medical community and the public-at-large.

In vitro BMP2 stimulation of osteoblast citrate production in concert with mineralized bone nodule formation.

BACKGROUND: That citrate is a major indispensible component of bone in humans and in all osteovertebrates has been known for about seventy-five years. Yet, its role and importance in the structure and function of bone and bone formation have remained unknown. However, recent studies have identified that citrate is a major and essential component of the apatite/collagen structure of bone; and that the biomechanical properties of bone (e.g., stability, strength, resistance to fracture) depend on the appropriate incorporation of citrate in the structure of bone. The osteoblasts have recently been identified as citrate-producing cells that provide the citrate that is incorporated in the apatite/collagen structure during osteogenesis. Little is known regarding the factors and mechanisms involved in the regulation of citrate that is incorporated along with mineralization during the process of bone formation. Because of the importance of BMP2 in the initiation of osteogenesis and the development of the osteoblasts, it is essential to determine its possible implication in the development of the citrate-producing capability of the osteoblasts (i.e., "citration") during the formation of mineralized bone nodules. METHODS: The goal of this study was to determine if BMP2 promotes the development of citrate-producing osteoblasts for increased citrate incorporation in the formation of mineralized bone nodules. The study employed MC3T3 mesenchyme stem cell osteogenic differentiation in the presence and absence of BMP2. RESULTS: The results showed that BMP2 treatment increased the osteogenic development of mineralized bone nodules. In addition, BMP2 increased osteoblast citrate production and incorporation in the mineralized bone nodule. This was accompanied by increased ZIP1 transporter, which is an essential genetic/metabolic event for citrate-producing cells. CONCLUSIONS: The results demonstrate, for the first time, that BMP2 facilitates the osteoblast "citration" process in concert with mineralization during bone formation; and provide confirmation of the important role of osteoblasts as specialized citrate-producing cells in the process of bone formation. However, it is essential to determine if these in vitro effects will occur in vivo in BMP2-implant induction of bone formation. "Citration" is essential for osteoinductive bone to represent the chemical, structural, and biomechanical properties of "normal" bone.

Evidence that Human Prostate Cancer is a ZIP1-Deficient Malignancy that could be Effectively Treated with a Zinc Ionophore (Clioquinol) Approach.

Despite decades of research, no efficacious chemotherapy exists for the treatment of prostate cancer. Malignant prostate zinc levels are markedly decreased in all cases of prostate cancer compared to normal/benign prostate. ZIP1 zinc transporter down regulation decreases zinc to prevent its cytotoxic effects. Thus, prostate cancer is a "ZIP1-deficient" malignancy. A zinc ionophore (e.g. Clioquinol) treatment to increase malignant zinc levels is a plausible treatment of prostate cancer. However, skepticism within the clinical/biomedical research community impedes significant progress leading to such a zinc treatment. This report reviews the clinical and experimental background, and presents new experimental data showing Clioquinol suppression of prostate malignancy; which provides strong support for a zinc ionophore treatment for prostate cancer. Evaluation of often-raised opposing issues is presented. These considerations lead to the conclusion that the compelling evidence dictates that a zinc-treatment approach for prostate cancer should be pursued with additional research leading to clinical trials.

Persistent low expression of hZip1 in mucinous carcinomas of the ovary, colon, stomach and lung.

BACKGROUND: Mucinous carcinomas from different organs are morphologically similar and might share similarities at the molecular and biochemical levels that may illuminate their pathogenesis and influence management. The factors involved in the pathogenesis of mucinous carcinomas remain unknown; which is likely one contributor to the current dearth of biomarkers for detection. Because zinc changes are implicated in some cancers e.g., prostate; we assessed the possibility of a similar role in mucinous carcinomas. METHODS: The goal of the current work is to study the expression of hZip1 by immunohistochemistry in mucinous carcinomas as compared with non-neoplastic epithelia and conventional carcinomas. Tissue microarray slides containing mucinous carcinomas of the ovary (n = 35), colon (n = 51), stomach (n = 32) and lung (n = 21) were used. RESULTS: hZip1 showed persistent low expression in mucinous compared to ovarian serous carcinomas and normal tissue (P < 0.05), colonic adenocarcinoma and normal mucosa (P < 0.001), and gastric adenocarcinoma and normal epithelium (P < 0.05). hZip1 also showed low expression in pulmonary mucinous carcinomas. CONCLUSIONS: hZip1 is consistently decreased in mucinous carcinomas from a variety of organs. Despite the fact that these preliminary findings are unlikely to be of much diagnostic significance, these findings suggest that hZip1 plays a fundamental role in the carcinogenesis of mucinous tumors.

The cytotoxic role of RREB1, ZIP3 zinc transporter, and zinc in human pancreatic adenocarcinoma.

Pancreatic cancer (ductal adenocarcinoma) remains a deadly cancer with ~85% mortality, and a 5-year survival rate of ~6% or less for the past 30 years. The factors and events associated with the development of pancreatic cancer are poorly identified. As such, effective biomarkers for early detection of malignancy are lacking. Efficacious chemotherapy once the cancer is identified does not exist. Recent clinical studies have revealed that the zinc levels are consistently and markedly decreased in adenocarcinoma as compared with normal/benign pancreatic tissue. The decreased zinc is exhibited in well-differentiated malignancy and in progressing malignancy, and also exists throughout the development of PanIN. Concurrent with the decrease in zinc, RREB1 transcription factor and ZIP3 zinc uptake transporter are downregulated. Thus, a RREB1/ZIP3/Zinc transformation appears to be an early event in the development of pancreatic cancer. We propose that this transformation is necessary to prevent the accumulation of high cellular zinc levels, which result in cytotoxic effects on the developing malignant cells. This report now demonstrates that exposure of Panc1 cells to physiological concentrations of zinc that result in increased zinc uptake and accumulation also inhibits cell proliferation. The study further shows that ZIP3 is the important transporter required for the accumulation of zinc and its inhibition of proliferation. RREB1 is identified as the positive regulator of ZIP3 expression. Therefore, the pathway of RREB1/ZIP3/Zinc and its downregulation during oncogenesis exist to prevent the accumulation of cytotoxic levels of zinc during the development and progression of the malignant cells in pancreatic adenocarcinoma.

The status of zinc in the development of hepatocellular cancer: an important, but neglected, clinically established relationship.

Liver cancer (hepatocellular carcinoma, HCC) is increasing worldwide. About 75% of HCC cases result in death generally within one year. The factors responsible for the initiation and progression of HCC remain largely unknown and speculative, thereby impeding advancements in the development of effective therapeutic agents and biomarkers for early detection of HCC. A consistent marked decrease in zinc in HCC tumors compared with normal liver is an established clinical relationship, which occurs in virtually all cases of HCC. However, this relationship has been largely ignored by the contemporary clinical and research community. Consequently, the factors and mechanisms involved in this relationship have not been addressed. Thus, the opportunity and potential for its employment as biomarkers for early identification of malignancy, and for development of a chemotherapeutic approach have been lacking. This presentation includes a review of the literature and the description of important recent and new data, which provide the basis for a concept of the role of zinc in the development of HCC. The basis is presented for characterizing HCC malignancy as ZIP14-deficient tumors, and its requirement to prevent zinc cytotoxic effects on the malignant cells. The potential for an efficacious zinc treatment approach for HCC is described. The involvement of zinc in the predisposition for HCC by chronic liver disease/cirrhosis is presented. Hopefully, this presentation will raise the awareness, interest, and support for the much needed research in the implications of zinc in the development and progression of HCC.

Evidence that Osteoblasts are Specialized Citrate-producing Cells that Provide the Citrate for Incorporation into the Structure of Bone.

Citrate is a major component of bone in all vertebrates, but its implications in bone have remained largely unknown. Recent studies identified that citrate is incorporated into the structure of the hydroxyapatite nanocrystal/collagen complex; and is essential for the important biomechanical properties of bone. This raises the important question, "What is the source of citrate for incorporation into bone?"; A question that heretofore had remained unresolved. Studies in this report were designed to determine the plausibility of our concept that the osteoblasts are specialized citrate-producing cells, which provide the citrate that is incorporated into the structure of bone; and that osteogenic differentiation of mesenchyme cells leads to the development of the citrate-producing osteoblasts. The results demonstrated that primary human osteoblasts exhibit the capability of citrate-production. Undifferentiated mesenchyme cells do not exhibit the capability of citrate production; and osteogenic differentiation results in citrate-producing osteoblasts. The up-regulation of zinc uptake transporter ZIP1 is essential for the manifestation of the citrate-producing capability of the osteoblasts. We determined that osteoblast transport of citrate from plasma is not a likely source of citrate in bone. Thus, this study establishes for the first time that the osteoblasts are specialized citrate-producing cells that provide the citrate for incorporation into the structure of bone; and that mesenchyme cell osteogenesis leads to differentiated citrate-producing osteoblasts. This is a new understanding; which must include the osteogenic development of citrate-producing osteoblasts, and the process of "citration" in concert with mineralization during bone formation. It also provides a new understanding of the role of bone in the homeostatic maintenance of plasma citrate concentration.

The status of citrate in the hydroxyapatite/collagen complex of bone; and Its role in bone formation.

BACKGROUND: It has been known for more than 70 years that citrate is a major component of bone; comprising 1-2% weight of bone, and a concentration that is ~5-25-fold greater than the citrate concentration of most other tissues. This relationship exists in humans and in all vertebrates; which reveals that it is an indispensible and essential structural/functional component of bone. However, its implications relating to the structure and properties of bone, to the process of bone formation and regeneration, to bone disorders, and other issues have remained largely unknown and unaddressed. Recent studies have identified citrate as a structural component of the apatite nanocrystal/collagen complex, which is essential for imparting the bone properties of stability, strength, and resistance to fracture. This raises the issues of the status of citrate, and its source in normal bone formation. METHODS: The present report investigated the association of citrate with the hydroxyapatite (mineral) component and with the collagen component of human cortical bone preparations. The bone preparations were subjected to demineralization procedures to extract the mineral component; followed by extraction of the collagen component in the residual demineralized bone. The extracts were assayed for citrate, calcium, and collagen. RESULTS: The results reveal, for the first time, the existence of two major pools of citrate in bone. One pool comprising ~65-80% of the total citrate is associated with the hydroxyapatite component; and another pool comprising ~20-35% of the total citrate is tightly bound to the collagen component of the apatite nanocrystal/collagen complex. CONCLUSIONS: Citrate is an indispensible chemical and structural component of the apatite nanocrystal/collagen complex; and is required for manifestation of the biomechanical properties of bone. These results lead to a new concept of bone formation in which citrate incorporation ("citration") in concert with mineralization must be included in the process of bone formation. Along with this relationship, osteoblast citrate production has recently been identified as the likely source of citrate. It is now evident that the role of citrate in normal bone formation and its implications in bone disorders and defects, and in bone repair and regeneration, now requires renewed attention and support for much needed research.