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author:("seladin, D")
1.  CK2 and its role in Wnt and NF-κB signaling: Linking development and cancer 
CK2 is a highly conserved tetrameric serine/threonine kinase present in all eukaryotic organisms. It is constitutively active, and appears to be regulated by level of expression and activity, and subcellular localization. In turn, it has been postulated to control the function of many proteins through changes in phosphorylation that affect protein stability, proteinprotein interactions, and subcellular localization. Through these mechanisms, CK2 regulates many fundamental cellular properties. An enzyme that carries out such a master regulatory function is likely to be important in organismic development and in cancer. We have shown that overexpression of CK2 catalytic subunits is capable of promoting tumorigenesis, and that loss of CK2 catalytic subunits in development can be lethal. Through studies in cells, mice, and frogs, we and others have identified the Wnt and NF-κB pathways as two key signal transduction pathways that are regulated by CK2 activity, in embryonic development and in cancer. These results suggest that inhibiting CK2 could be useful in treating cancer, but dangerous to developing organisms. (Part of a Multi-author Review)
doi:10.1007/s00018-009-9153-z
PMCID: PMC3905806  PMID: 19387549
Protein kinase CK2; casein kinase II; Wnt; NF-κB; carcinogenesis; epithelial-to-mesenchymal transition; development
2.  Cancer-testis antigen expression and immunogenicity in AL amyloidosis 
Blood Cancer Journal  2012;2(9):e90-.
Light-chain amyloidosis (AL) is a plasma cell dyscrasia closely related to multiple myeloma. In multiple myeloma, the cancer-testis antigens (CTAs) CT7 (MAGE-C1), CT10 (MAGE-C2) and MAGE-A CTAs are expressed in up to 80% of cases. In this study, we investigated the expression and immunogenicity of several CTAs in patients with AL amyloidosis in a total of 38 bone marrow specimens by employing standard immunohistochemistry techniques on paraffin-embedded archival tissues. Plasma samples from 35 patients (27 with matched bone marrow samples) were also analyzed by ELISA for sero reactivity to a group of full-length CTA proteins. CT7 was present in 25/38 (66%) while CT10 was demonstrated in 3/38 and GAGE in 1/38 AL amyloid cases. The expression pattern was mostly focal. There were no significant differences with regard to organ involvement, response to treatment, or prognosis in CTA positive compared to negative cases. None of the specimens showed spontaneous humoral immunity to CT7, but sero reactivity was observed in individual patients to other CTAs. This study identifies CT7 as the prevalent CTA in plasma cells of patients with AL amyloidosis. Further analyses determining the biology of CTAs in AL amyloidosis and their value as potential targets for immunotherapy are warranted.
doi:10.1038/bcj.2012.32
PMCID: PMC3461704  PMID: 22983433
AL amyloidosis; cancer-testis antigens; stem cell transplantation
3.  Mineralocorticoid modulation of rabbit medullary collecting duct acidification. A sodium-independent effect. 
Rabbit medullary collecting duct (MCD) from inner stripe of outer medulla has been identified as a major distal nephron acidification site. The isolated, perfused tubule technique was used to examine the roles of mineralocorticoid and glucocorticoid in regulation of MCD acidification. Surgical adrenalectomy reduced bicarbonate reabsorptive rate (JHCO3, pmol X mm-1 X min-1) from the normal of 9.79 +/- 1.21 to 0.67 +/- 1.1. Chronic administration of deoxycorticosterone acetate (DOCA) increased JHCO3 of MCD significantly to 18.02 +/- 1.62 whereas chronic dexamethasone administration did not affect JHCO3. The direct effects of aldosterone and dexamethasone upon MCD acidification were examined by perfusing tubules harvested from adrenalectomized rabbits in the presence of aldosterone or dexamethasone. Aldosterone, at 5 X 10(-8) M, increased JHCO3 significantly from 1.27 +/- 0.28 to 3.09 +/- 0.34. At 10(-6) M, aldosterone produced a greater increase in JHCO3 from 0.67 +/- 1.1 to 9.39 +/- 1.59. In vitro dexamethasone treatment had no effect on JHCO3. Studies examining the sodium dependence of aldosterone-stimulated acidification demonstrated that JHCO3 in tubules harvested from normal and deoxycorticosterone acetate-treated animals was unaffected by total replacement of sodium with tetramethylammonium. Likewise, luminal amiloride (5 X 10(-5) M) had no effect on JHCO3 in tubules harvested from adrenalectomized and normal animals. Moreover, the acute, in vitro stimulatory effect of aldosterone was seen to occur in the presence of luminal amiloride. These studies define a mammalian distal nephron segment that possesses major acidifying capacity, which is modulated by mineralocorticoid but independent of luminal sodium.
PMCID: PMC1129162  PMID: 6874954
4.  Anion dependence of rabbit medullary collecting duct acidification. 
Journal of Clinical Investigation  1983;71(5):1505-1508.
Rabbit medullary collecting duct (MCD) acidification has been demonstrated to occur by means of a sodium-independent, aldosterone-stimulated mechanism. We have examined the anionic dependence of this process by means of the isolated perfused tubule technique. Total replacement of perfusate chloride with gluconate enhanced tubular bicarbonate reabsorption (JHCO3), from a basal rate of 10.7 +/- 1.0 pmol X mm-1 X min-1 to a rate of 15.01 +/- 1.0 pmol X mm-1 X min-1. Removal of bath chloride, with and without removal of perfusate chloride completely abolished acidification. Bath, but not luminal 4-acetamido-4' isothiocyano-2,2'-disulfonic stilbene provoked a marked decrease in JHCO3 from 10.1 +/- 1.2 pmol X mm-1 X min-1 to 2.3 +/- 0.3 pmol X mm-1 X min-1. Measurement of chloride reabsorptive rate (JCl) revealed colinearity between JHCO3 (9.18 +/- 0.9 pmol X mm-1 X min-1) and JCl (9.75 +/- 1.18 pmol X mm-1 X min-1). We propose a model of mammalian distal nephron acidification in which (a) cellular base exit is effected by means of a basolateral membrane Cl-base exchanger and (b) net electroneutrality of electrogenic proton secretion is maintained by the parallel movement of an anionic species, functionally chloride.
PMCID: PMC437016  PMID: 6853724
5.  Direct determination of PCO2 in the rat renal cortex. 
Journal of Clinical Investigation  1978;62(2):338-348.
The mechanism by which the kidney reabsorbs sodium bicarbonate could be a result of (a) H+ secretion, (b) direct HCO3- reabsorption, or (c) a combination of both processes. Most of the studies which have supported the H+ secretory theory have involved the assumption that tubular fluid and arterial PCO2 were equal. We have utilized a new PCO2 microelectrode to directly determine in situ PCO2 of tubular fluid and stellate vessel blood in the cortex of the rat kidney during control conditions and after alterations in acid-base status. In 21 control rats, proximal tubular fluid PCO2 exceeded systemic arterial PCO2 (deltaCO2) by 25.9 +/- 0.92 mm Hg (P less than 0.001). The values obtained for both distal tubular fluid and stellate vessel blood were not significantly different from proximal tubular PCO2. Evaluation of PCO2 in the proximal tubules of Munich-Wistar rats did not reveal evidence for a declining profile for PCO2 along the length of the nephron. When proximal bicarbonate reabsorption was increased or decreased acutely by alterations in acid-base status, deltaPCO2 changed in paralle. Furthermore, benzolamide administration significantly reduced deltaPCO2. We conclude: (a) that the PCO2 in tubular fluid is significantly greater than systemic arterial PCO2, (b) that there is no tendency for the observed PCO2 to fall along the proximal tubule, (c) the mean PCO2 in the proximal and distal tubules as well as the stellate vessle is not significantly different, thereby rendering the concept of a "diffusion barrier" for CO2 in the proximal tubule unlikely, and (d) the level of renal cortical PCO2 appears to vary directly with the magnitude of bicarbonate reabsorption.
PMCID: PMC371771  PMID: 670396
6.  Evidence against bicarbonate reabsorption in the ascending limb, particularly as disclosed by free-water clearance studies. 
Bicarbonate reabsorption in the thick ascending limb of Henle's loop was examined by studies of free-water clearance (CH2O) and free-water reabsorption (TcH2O). During maximal water diuresis in the dog, CH2O/GFR was taken as an indes of sodium reabsorption in, and urine flow (V/GFR) as an index of delivery of filtrate to, this scarbonate, infusion of a nonreabsorbable solute (hypotonic mannitol) and administration of an inhibitor of bicarbonate reabsorption (acetaent, but less than that achieved with hypotonic saline infusion. This suggests that sodium that sodium bicarbonate is not reabsorbed in the ascending limb. Rather, it is the sodium chloride, swept out of the proximal tubule by osmotic diuresis due to nonreabsorbed mannitol or sodium bicarbonate, that is reabsorbed in the ascending limb thereby increasing CH2O, whereas the nonreabsorption of mannitol and sodium bicarbonate results in a depressed CH20 per unit V when compared with hypotonic saline. V/GFR is not a satisfactory index of delivery to the ascending limb during osmotic diuresis, since it includes water obligated by nonreabsorbable solutes. When a better index of delivery, the sum of the clearances of chloride (CC1) and free-water (CH2O) is used, hypotonic bicarbonate infusion, hypotonic mannitol infusion and acetazolamide administration increase CH2O/GFR per unit delivery to the same extent as odes hypotonic saline infusion. Studies in dogs and rats on TcH2O also indicate that sodium bicarbonate is an impermeant solute in the ascending limb. Osmotic diuresis due to sodium bicarbonate diuresis, produced either by inhibition of sodium bicarbonate reabsorption (acetazolamide, L-lysine mono-hydrochloride) or infusion of sodium bicarbonate, or mannitol diuresis both produced marked chloruresis and increased TcH2O to the same extent as did hypertonic saline infusion. If chloride excretion was almost eliminated by hemodialysis against a chloride-free dialysate (dogs) or prolonged feeding of a salt-free diet (rats), TcH2O formation was unimpaired if hypertonic saline was infused but virtually obliterated during mannitol or sodium bicarbonate diuresis. Sodium reabsorption in the ascending limb, therefore, appears to be dependent upon chloride as the accompanying anion. At any given rate of bicarbonate excretion, more cloride is delivered out of the proximal tubule (as estimated from CC1 + CH2O) with hypotonic sodium bicarbonate infusion than with acetazolamide administration. This suggests that magnitude of the chlorutesis accompanying bicarbonate diuresis depends, not only on osmotic diuresis due to nonreabsorbed sodium bicarbonate, but also on the extent to which concomitant changes in effective extracellular volume influence overall sodium chloride reabsorption.
PMCID: PMC2595177  PMID: 1202762
7.  Characteristics of salt and water transport in superficial and juxtamedullary straight segments of proximal tubules. 
Journal of Clinical Investigation  1975;55(6):1269-1277.
The purpose of the present studies was to characterize the nature of salt and water transport out of the superficial (SF) and juxtamedullary (JM) straight segments of rabbit proximal tubules as examined by in vitro microperfusion techniques. When the perfusate consisted of a solution simulating ultrafiltrate of plasma, there were no differences between SF and JM straight tubules in either net reabsorption of fluid (SF=0.47 nl/mm per min; JM=0.56 nl/mm per min) or in transtubular potential difference (PD) (SF=-2.1 mV; JM=-1.8 mV). Removal of glucose and alanine from the perfusate had no effect on the magnitude of the PD in either straight segment. Ouabain decreased both the net reabsorptive rates and the PD. Isosmolal replacement of NaCL by Na-cyclamate (a presumed impermeant anion) in the perfusate and the bath caused an increase in luminal negativity in both segments wheras similar substitution of NaCL by choline-CL (nontransported cation) changed the PD TO NEAR ZERO. These studies, therefore, suggest that sodium is transported out of the proximal straight tubules by an active noncoupled process that generates a PD (electrogenic process). When the perfusate consisted of a solution with a high chloride concentration (resulting from greater HCO3 than CI reabsorption in the proximal convoluted tubule), different PDs in SF and JM tubules were generated: SF=+1.6 plus or minus 0.2 mV; JM=-1.3 plus or minus 0.3 mV. This difference in PD was attributed to relative differences in Na and CI permeabilities in these two segments. Electrophysiological and isotopic estimates of the chloride to sodium permeability revealed that the SF tubule is about twice as permeant to chloride than to sodium whereas the JM tubules are approximately twice as permeant to sodium than to chloride. It is concluded that the mechanism of active sodium transport in the straight segment of proximal tubule differs from that of the convoluted segment and that both the SF and JM straight segments differ from each other with respect os sodium and chloride permeability.
PMCID: PMC301882  PMID: 1133172
8.  Factors governing the transepithelial potential difference across the proximal tubule of the rat kidney. 
Journal of Clinical Investigation  1974;53(2):454-464.
Previous measurements of the transepithelial potential difference (PD) of the proximal tubule have yielded widely conflicting values (range -20 to +3 mV). In a recent study, Kokko has demonstrated that the PD of the in vitro perfused isolated proximal tubule of the rabbit varies in a predictable way from -6 to +3 mV, depending on the concentration of chloride, bicarbonate, glucose, and amino acids in the perfusing solution. The present micropuncture study examines the effect of tubular fluid composition on the PD profile along the proximal tubule of the in vivo rat kidney. Low resistance measuring electrodes with large tips (3-5 microns OD) filled with 3 M KCl, were used to provide stable PD recordings. Experiments were performed to validate the use of these electrodes. Transepithelial PD measurements were made in immediate postglomerular segments identified by injection of dye into Bowman's space of accessible surface glomeruli and in randomly selected more distal segments of the proximal tubule. In the control state, the first loop was found to have a small but consistently negative PD which could be obliterated by an infusion of phloridzin. In contrast, the PD in later segments was consistently positive. Infusion of acetazolamide abolished the positive PD in the later segments. Acetazolamide and glucose infusion resulted in a negative PD which was abolished by the additional infusion of phloridzin. These data provide evidence that glucose reabsorption is electrogenic and can account for the small negative PD normally present in the early proximal tubule. The positive PD in later segments appears to be a passive chloride diffusion potential. This positive potential is discussed as an important electrochemical driving force for significant passive reabsorption of sodium in the proximal tubule.
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PMCID: PMC301488  PMID: 11344559
10.  Resting transmembrane potential difference of skeletal muscle in normal subjects and severely ill patients 
The resting membrane potential difference (Em) of skeletal muscle was measured in 26 normal human subjects, 7 patients with mild illness, and 21 patients with severe, debilitating medical disorders. A closed transcutaneous approach to the muscle was made by needle puncture and the Em was measured utilizing standard Ling electrodes. Measurements revealed an Em of -88 ±3.8 mv in healthy subjects and -89 ±2.1 mv in patients hospitalized for minor medical problems. The mean Em in 21 in-hospital patients, judged to be severely ill clinically from a variety of causes, was -66.3 ±9.0 mv. Open deltoid muscle biopsies were performed in 7 of the healthy subjects and in 13 of the severely ill group. Estimation of the intra-extracellular water partition was made by calculating the chloride space from the previously measured Em. Analysis of the muscle samples revealed no significant difference in the intra-extracellular potassium ratios of the two groups biopsied. Intracellular Na+ concentrations were uniformly increased in the muscle samples of the severely ill subjects and averaged 42.3% higher than those of the normal subjects. The mechanisms which might account for the elevation of intracellular Na+ and a depression of Em independent of changes in intra-extracellular K+ ratios are discussed and it is suggested that this defect may be a generalized cellular abnormality which is a common quality of serious illnesses.
PMCID: PMC291892  PMID: 5101298

Results 1-14 (14)