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Summary

Calcium sensing receptor (CASR) is a G-protein couple receptor which plays a key role in calcium homeostasis in
vertebrates. Its extracellular domain is sensitive to divalent cations, aminoacids and polyamines. In parathyroid
glands, CASR activation causes parathyroid hormone (PTH) reduction and subsequently a decrease in blood calcium concentration. In PTH-dependent disorders, e.g. primary and secondary hyperparathyroidism (HPT), the need for therapeutic options other than surgery led to the synthesis of various allosteric CASR agonists (calcimimetics), such as cinacalcet. Cinacalcet is the only calcimimetic approved for HPT secondary to chronic kidney disease (CDK), parathyroid carcinoma, and, in some countries, primary HPT. Clinical trials showed that cinacalcet reduced PTH and calcemia both in CDK and primary HPT, lowering the risk of bone fractures, surgery, and cardiovascular complications in the former patients. Long-term safety and pharmacoeconomics have to be fully tested yet. Few both in vitro and in vivo studies showed an association between Arg990Gly-CASR polymorphism and cinacalcet sensitivity, though in patients with severe CASR inactivating mutations the drug substantially retained its positive clinical effects. Recently, a new class of allosteric antagonists of CASR, i.e. calcilytics, has been synthesized. Calcilytics are structurally similar to calcimimetics, but exert their effects acting on a different allosteric site. Infusion of calcilytics was followed by transient rise in PTH and calcium. One of these compounds, ronacaleret, was able to increase femur BMD in post menopausal women, but with induction of mild hyperparathyroidism. In the future, calcilytics may contribute to the osteoporosis treatment choice.


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Dose-Dependent ATP Depletion and Cancer Cell Death following Calcium Electroporation, Relative Effect of Calcium Concentration and Electric Field Strength

Emilie Louise Hansen1, Esin Bengisu Sozer2, Stefania Romeo3, Stine Krog Frandsen1, P. Thomas Vernier2, Julie Gehl1*

Abstract

Background

Electroporation, a method for increasing the permeability of membranes to ions and small molecules, is used in the clinic with chemotherapeutic drugs for cancer treatment (electrochemotherapy). Electroporation with calcium causes ATP (adenosine triphosphate) depletion and cancer cell death and could be a novel cancer treatment. This study aims at understanding the relationship between applied electric field, calcium concentration, ATP depletion and efficacy.

Methods

In three human cell lines—H69 (small-cell lung cancer), SW780 (bladder cancer), and U937 (leukaemia), viability was determined after treatment with 1, 3, or 5 mM calcium and eight 99 μs pulses with 0.8, 1.0, 1.2, 1.4 or 1.6 kV/cm. Fitting analysis was applied to quantify the cell-killing efficacy in presence of calcium. Post-treatment intracellular ATP was measured in H69 and SW780 cells. Post-treatment intracellular ATP was observed with fluorescence confocal microscopy of quinacrine-labelled U937 cells.

Results

Both H69 and SW780 cells showed dose-dependent (calcium concentration and electric field) decrease in intracellular ATP (p<0.05) and reduced viability. The 50% effective cell kill was found at 3.71 kV/cm (H69) and 3.28 kV/cm (SW780), reduced to 1.40 and 1.15 kV/cm (respectively) with 1 mM calcium (lower EC50 for higher calcium concentrations). Quinacrine fluorescence intensity of calcium-electroporated U937 cells was one third lower than in controls (p<0.0001).


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Eva C. Schwarz, Bin Qu, Markus Hoth ⁎
Department of Biophysics, Saarland University, Homburg, Germany

Abstract

Killing cancer cells by cytotoxic T lymphocytes (CTL) and by natural killer (NK) cells is of vital importance.
Cancer cell proliferation and apoptosis depend on the intracellular Ca2+ concentration, and the expression
of numerous ion channels with the ability to control intracellular Ca2+ concentrations has been correlated
with cancer. A rise of intracellular Ca2+ concentrations is also required for efficient CTL and NK cell function
and thus for killing their targets, in this case cancer cells. Here, we review the data on Ca2+- dependent killing
of cancer cells by CTL and NK cells. In addition, we discuss emerging ideas and present a model how Ca2+
may be used by CTL and NK cells to optimize their cancer cell killing efficiency. This article is part of a Special
Issue entitled: 12th European Symposium on Calcium.

 


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High calcium consumption may confer a reduced risk of colorectal cancer.1,2 Dai and colleagues3 recently reported in a case-control study that intake of calcium may be associated with a decreased risk of colorectal adenoma only when the dietary calcium:magnesium intake ratio is low. This finding provides one possible interpretation for
inconsistencies in previous studies of the association of calcium intake with risk of
colorectal neoplasia.4

Belonging to the same family in the periodic table, calcium (Ca2+) and magnesium (Mg2+) share the same homeostatic control system and have the potential to antagonize each other physiologically.5 A high calcium intake reduces absorption of both magnesium and calcium,6 whereas moderate magnesium deprivation results in negative magnesium balance but increased calcium retention7. Due to the potential competition between magnesium and
calcium, we hypothesized that the dietary calcium:magnesium ratio may modify the effects of calcium supplementation on colorectal carcinogenesis.

We sought to test this hypothesis using data from a randomized clinical trial of calcium supplementation (1200 mg/day) to prevent adenoma recurrence over a 4-year period. The outcome measure in this analysis was the recurrence of adenomas during the pre-specified main risk period (i.e. after a year-1 colonoscopy up to and including a year-4 examination)2. A validated semi-quantitative food frequency questionnaire (FFQ) was given at study entry
to assess usual diet.

Consistent with our hypothesis,3 we found suggestions that the baseline dietary calcium:magnesium intake ratio modified the effect of calcium treatment on adenoma recurrence. Among subjects with the intake ratio above the median, calcium supplementation had no effect on the risk of one or more recurrent adenoma (relative risk [RR]=0.98 [95% confidence interval (CI)=0.75–1.28]) (Table). In contrast, among those with the baseline ratio less than or equal to the median, calcium treatment was associated with reduced risk (RR=0.68 [95%CI=0.52–0.90]; test for interaction, P= 0.075).


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Kanchana. N1, Saikumar. P2 1-Department of physiology / Sree Balaji Medical College, Bharath University, Chennai India / Second year Physiology PG 2- Department of physiology / Sree Balaji Medical College, Bharath University, Chennai India / Professor and HOD

Abstract:

Introduction: Hyperglycemia in Diabetes Mellitus is known to have its effect on almost all body system through alterations in structural and biochemical changes in tissues.From this study, it is hypothesized that alteration in calcium flux may adversely affect the insulin secretion as it is a calcium-dependent process.

Aim And Objectives: This study was done to estimate the serum calcium levels in type 2 Diabetes mellitus.

Objectives:

  1. Estimation of blood glucose levels in all subjects.
  2. Estimation of serum calcium levels in diabetes and non-diabetes.
  3. Compare the serum calcium levels in diabetes and non-diabetes.

Materials and methods:

Case control study.

Study Design: Diabetes subjects (cases) n=50 Age and sex matched

Diabetes subjects (cases) n=50 Age and sex matched

Age and sex matched non diabetes (controls) n=50

Plasma glucose levels was estimated by GOD-POD method.Serum calcium level was estimated by calcium Arsenazo method for all subjects at central lab of SBMCH,Chennai.

Results And Conclusion: Results were analyzed using anova single factor.f statistical was greater than f critical value.

A negative correlation was observed between serum calcium levels and plasma blood glucose levels. Also the p value was found to be less than 0.05 which confirmed that correlation was statistically significant.


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Lydia B. Zablotska • Zhihong Gong • Furong Wang • Elizabeth A. Holly • Paige M. Bracci

 

Abstract

Objective The aim of this study was to evaluate a complex association among intake of dietary vitamin D, calcium,
and retinol, and pancreatic cancer risk. Methods Pancreatic cancer cases (n = 532) diagnosed in 1995–1999 were identified using rapid case ascertainment methods and were frequency matched to population-based controls (n = 1,701) in the San Francisco Bay Area. Detailed dietary data were collected during in-person interviews using a validated semi-quantitative food frequency questionnaire. Adjusted unconditional logistic regression was used to estimate odds ratios (ORs) and confidence intervals.

Results In men, increased pancreatic cancer risk was associated with currently recommended dietary vitamin D intake levels (highest (C450 IU/day) vs. lowest (\150 IU/ day) intake, OR = 2.6, trend-p = 0.009) and total vitamin D intake from diet and supplements (for \800 IU/day). ORs for dietary vitamin D intake remained increased after adjustment for intake of retinol and calcium, although confidence intervals included unity. Stratified analyses showed that ORs were higher among men with a lower intake of retinol and lower physical activity but there was no evidence of statistical interaction. No associations with vitamin D intake were observed among women, although ORs typically were elevated. ORs increased with increased dietary calcium intake among men (trend-p = 0.008) and not women.

Conclusions Our results among men showing an increased risk of pancreatic cancer associated with dietary
intake of vitamin D and of calcium require confirmation in further studies. Continued investigation is needed to clarify the complex role of vitamin D and calcium in pancreatic cancer risk and to determine their optimal intake level and preventive effects for pancreatic cancer.

 


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Dairy products, calcium, and prostate cancer risk in the Physicians’ Health Study

June M Chan, Meir J Stampfer, Jing Ma, Peter H Gann, J Michael Gaziano, and Edward L Giovannucci

ABSTRACT

Background: A high calcium intake, mainly from dairy products, may increase prostate cancer risk by lowering concentrations of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], a hormone thought to protect against prostate cancer. The results of epidemiologic studies of this hypothesis are inconclusive.

Objective: We investigated the association between dairy product and calcium intakes and prostate cancer risk in the
Physicians’ Health Study, a cohort of male US physicians.

Design:

At baseline, the men answered abbreviated dietary questionnaires. During 11 y of follow-up, we documented 1012 incident cases of prostate cancer among 20 885 men. We estimated dairy calcium intake on the basis of consumption of 5 major dairy products and used logistic regression to estimate relative risk.

Results:

At baseline, men who consumed >600 mg Ca/d from skim milk had lower plasma 1,25(OH)2D3 concentrations than did those consuming ≤150 mg Ca/d [71 compared with 85 pmol/L (30.06 compared with 35.64 pg/mL); P = 0.005]. Compared with men consuming ≤0.5 daily servings of dairy products, those consuming > 2.5 servings had a multivariate relative risk of prostate cancer of 1.34 (95% CI: 1.04, 1.71) after adjustment for baseline
age, body mass index, smoking, exercise, and randomized treatment assignment in the original placebo-controlled trial. Compared with men consuming ≤150 mg Ca/d from dairy products, men consuming > 600 mg/d had a 32% higher risk of prostate cancer (95% CI: 1.08, 1.63).

Conclusions:

These results support the hypothesis that dairy products and calcium are associated with a greater risk of prostate cancer.

Am J Clin Nutr 2001;74:549–54.


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Psoriasis and Altered Calcium Metabolism: Downregulated Capacitative Calcium Influx and Defective Calcium-Mediated Cell Signaling in Cultured Psoriatic Keratinocytes1

Seija-Liisa Karvonen,*2 Timo Korkiama ki,*2 Heli Yla -Outinen,* Marja Nissinen,* Harri Teerikangas,:j Kati Pummi,§ Jaakko Karvonen,t and Juha Peltonen*

*Department of Anatomy and Cell Biology, tDepartment of Dermatology, and :jDepartment of 
Surgery, University of Oulu, Oulu, Finland; §Department of Medical Biochemistry, University of Turku, Turku, Finland; <Department of  Dermatology, University Hospital of Tampere, Tampere, Finland

 

Intracellular calcium plays an important part in the regulation of proliferation and differentiation of keratinocytes. Detached from their in vivo environment, cultured psoriatic keratinocytes were investigated by monitoring free intracellular calcium concentration, which was measured using fura-2/AM as a calcium-sensitive probe. The mean increase in intracellular calcium of psoriatic keratinocytes was significantly reduced compared with control keratinocytes when intracellular calcium stores were mobilized from endoplasmic reticulum with thapsigargin. This
find- ing suggests defective capacitative calcium influx of psoriatic cells. Intracellular calcium stores were simi- lar in psoriatic and control keratinocytes, when extracellular calcium was chelated with ethylenegly-col-bis(β-aminoethyl ether)-N,N,N’,N’,-tetraacetic acid and intracellular calcium was depleted with thapsigargin. Mechanical wounding of keratinocyte monolayer resulted in a significantly reduced rise in intracellular calcium of psoriatic cells in low (< 0.1 mM) and high (1.8 mM) extracellular calcium suggesting defective intercellular coupling of psoriatic keratinocytes. Blocking of gap-junctions with heptanol in wounded keratinocytes did not affect the intracellular calcium response in psoriatic keratino- cytes in contrast to healthy keratinocytes. Adding adenosine triphosphate to culture medium resulted in a more pronounced intracellular calcium increase than thapsigargin in psoriatic keratinocytes, suggest-
ing that inositol triphosphate-mediated, P2-puriner- gic signaling was enhanced in these cells. Moreover, psoriatic keratinocytes maintained their defective responses up to at least fifth passage suggesting that psoriatic keratinocytes have an inborn error in cal- cium metabolism, rather than a localized defect in response to altered extracellular calcium gradient observed in vivo. Key words: keratinocyte cultures/intra- cellular calcium/gap-junctions/P2-purinergic receptors. ] Invest Dermatol 114:693-700, 2000

 

 

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a comparison of bleomycin and calcium, calcium compounds, and pulsing conditions

Stine Krog Frandsen a, Hanne Gissel b, Pernille Hojman c, Jens Eriksena, d, Julie Gehl a,⁎

 

Abstract

Background: Electroporation with calcium (calcium electroporation) can induce ATP depletion-associated cellular
death. In the clinical setting, the cytotoxic drug bleomycin is currently used with electroporation (electrochemotherapy) for palliative treatment of tumors. Calcium electroporation offers several advantages
over standard treatment options: calciumis inexpensive and may readily be applied without special precautions,
as is the case with cytostatic drugs. Therefore, details on the use of calcium electroporation are essential for
carrying out clinical trials comparing calcium electroporation and electrochemotherapy.
Methods: The effects of calcium electroporation and bleomycin electroporation (alone or in combination) were
compared in three different cell lines (DC-3F, transformed Chinese hamster lung fibroblast; K-562, human leukemia; and murine Lewis Lung Carcinoma). Furthermore, the effects of electrical pulsing parameters and calcium
compound on treatment efficacy were determined.

Results:

Electroporation with either calcium or bleomycin significantly reduced cell survival (p b 0.0001),
without evidence of a synergistic effect. Cellular death following calcium or bleomycin treatment occurred at
similar applied voltages, suggesting that similar parameters should be applied. At equimolar concentrations,
calcium chloride and calcium glubionate resulted in comparable decreases in cell viability.

Conclusions:

Calcium electroporation and bleomycin electroporation significantly reduce cell survival at similar
applied voltage parameters. The effect of calcium electroporation is independent of calcium compound.
General significance: This study strongly supports the use of calcium electroporation as a potential cancer therapy
and the results may aid in future clinical trials.

 

 

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Stine Krog Frandsen1, Hanne Gissel2, Pernille Hojman3, Trine Tramm4, Jens Eriksen1,5, and Julie Gehl1

Abstract
Electroporation of cells with short, high-voltage pulses causes a transient permeabilization of cell membranes
that permits passage of otherwise nonpermeating ions and molecules. In this study, we illustrate how  lectroporation with isotonic calcium can achieve highly effective cancer cell kill in vivo. Calciumelectroporation elicited dramatic antitumor responses in which 89% of treated tumors were eliminated. Histologic analyses indicated complete tumor necrosis. Mechanistically, calcium electroporation caused acute ATP depletion likely due to a combination of increased cellular use of ATP, decreased production of ATP due to effects on the mitochondria,
as well as loss of ATP through the permeabilized cell membrane. Taken together, our findings offer a preclinical
proof of concept for the use of electroporation to load cancer cells with calcium as an efficient anticancer treatment.
Electroporation equipment is already used clinically to enhance the delivery of chemotherapy to superficial tumors, with trials on internal tumors in progress, enabling the introduction of calcium electroporation to clinical use. Moreover, the safety profile, availability, and low cost of calcium facilitate access to this technology for many cancer patients in developed and developing countries. Cancer Res; 72(6); 1336–41. 2012 AACR.

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