Search

We previously characterized a H + transport pathway in medullary thick ascending limb nephron segments that when activated stimulated the production of superoxide by nicotinamide adenine dinucleotide phosphate oxidase. Importantly, the activity of this pathway was greater in Dahl salt-sensitive rats than salt-resistant (SS.13 BN ) rats, and superoxide production was enhanced in low Na + media. The goal of this study was to determine the molecular identity of this pathway and its relationship to Na + . We hypothesized that the voltage-gated proton channel, HV1, was the source of superoxide-stimulating H + currents. To test this hypothesis, we developed HV1 −/− null mutant rats on the Dahl salt-sensitive rat genetic background using zinc-finger nuclease gene targeting. HV1 could be detected in medullary thick limb from wild-type rats. Intracellular acidification using an NH 4 Cl prepulse in 0 sodium/BaCl 2 containing media resulted in superoxide production in thick limb from wild-type but not HV1 −/− rats ( P I 0.005 versus 0.002 U/s, P =0.046, respectively). Superoxide production was enhanced by low intracellular sodium (−/− rats compared with wild-type Dahl salt-sensitive rats. We conclude that HV1 is expressed in medullary thick ascending limb and promotes superoxide production in this segment when intracellular Na + is low. HV1 contributes to the development of hypertension and renal disease in Dahl salt-sensitive rats.

We have recently demonstrated that both cellular acidification and low intracellular [Na] promote NADPH oxidase activity in mTAL via activation of the voltage-gated proton channel Hv1. NH4+ is norm...

Oxidative stress in the renal outer-medulla contributes to the development of hypertension and renal disease in Dahl salt-sensitive (SS) rats. We have previously demonstrated that an unknown proton channel is responsible for enhanced superoxide production in medullary thick ascending limb (mTAL) of SS rats. We hypothesized that HV1 is responsible for superoxide producing H+ currents and is expressed in mTAL of SS rats. In order to test our hypothesis we quantitated HV1 mRNA (RT-PCR) and protein (immunohistochemistry) specifically within mTAL of wild-type SS rats and in a HV1-/- strain of Dahl SS rats in which we mutated the HV1 gene using a Zn-finger nuclease. We confirmed complete loss of Hv1 protein in HV1-/- rats both by whole-cell voltage clamp of peritoneal macrophages and by Western blot/anti-HV1 staining in spleen (positive control tissue). Using the same antibody, HV1 protein expression was found to be significantly greater in mTAL of wild-type rats compared to presumed background in HV1-/- rats (...

This report describes a novel approach to cancer therapy that targets genes that are preferentially alternatively spliced and expressed in leukemia. We developed CD44v6 and CD44v8 splicing constructs fused with GFP or a humanized fragment of Pseudomonas aeruginosa exotoxin A (hPE24). Transfection of K562 leukemia cells with the GFP-linked splicing constructs led to subsequent production of detectable levels of GFP. Transfection of K562 cells with the hPE24-linked splicing constructs led to significant reduction of cell viability and an increase in the induction of apoptosis. Normal human PBMCs were unaffected by following transfection with these constructs.

Intravenous leiomyomatosis (IVL) is a rare smooth-muscle proliferation arising from a uterine myoma and occasionally extending into cardiac chambers.A series of 10 consecutive patients with histologically and surgically proven intracardiac IVL between 2000 and 2010 in our hospital were reviewed. The echocardiographic features of 10 cases with IVL and extensive spread into the right-sided cardiac chambers were described for the first time. All patients were female and the mean age was 42±7 years old. The first symptoms of six patients (60%) were exertional dyspnea and palpitation of cardiac origin. Echocardiography showed that all the tumors originated from the inferior vena cava (IVC) and located in cardiac right chambers (70% in right atrium alone, 30% in right ventricle and atrium). Eight masses (80%) were oval, whereas the others (20%) were serpentine, all with well-demarcated borders and most (70%) with heteroechogenic texture. Five tumors (50%) intermittently prolapsed into right ventricle through the tricuspid valve. Two patients with nodules adhering to the top of the tumors had pulmonary tumorous thromboembolism.Echocardiography is a simple and important technique to diagnose IVL with intracardiac extension. This disease should be considered in a female patient presenting with an extensive mass from IVC with well-demarcated border in the right-sided cardiac chambers.

In the current study, we examined the potential significance of CD44 expression on lymphokine-activated killer (LAK) cells in their interaction and killing of melanoma cells. Stimulation of splenocytes with IL-2 led to a significant increase in the expression of CD44 on T cells, NK cells, and NKT cells. Treatment of melanoma-bearing CD44 WT mice with IL-2 led to a significant reduction in the local tumor growth while treatment of melanoma-bearing CD44 KO mice with IL-2 was ineffective at controlling tumor growth. Furthermore, the ability of splenocytes from IL-2-treated CD44 KO mice to kill melanoma tumor targets was significantly reduced when compared to the anti-tumor activity of splenocytes from IL-2-treated CD44 WT mice. The importance of CD44 expression on the LAK cells was further confirmed by the observation that adoptively transferred CD44 WT LAK cells were significantly more effective than CD44 KO LAK cells at controlling tumor growth in vivo. Next, the significance of the increased expression of CD44 in tumor killing was examined and showed that following stimulation with IL-2, distinct populations of cells with low (CD44(lo)) or elevated (CD44(hi)) expression of CD44 are generated and that the CD44(hi) cells are responsible for killing of the melanoma cells. The reduced killing activity of the CD44 KO LAK cells did not result from reduced activation or expression of effector molecules but was due, at least in part, to a reduced ability to adhere to B16F10 tumor cells.

This chapter examines the similarities and differences between the concepts of transformational leadership as developed within North America and the Confucian idea of transformation. It argues that Confucian tradition encompasses the essential elements embedded in the concept of transformational leadership. The former differentiates from the latter in its deeper degree of transformation, emphasis on morality and culture, and its focus on transformation from the inside outwards. The two greatest educators in Chinese history, Confucius and Cai Yuanpei, are evaluated in terms of their transformational leadership qualities in the Western sense. By looking at Confucius and Cai Yuanpei as successful transformational leaders, the chapter identifies four important factors from Chinese cases that may contribute to the success of this type of leadership. Implications of this comparison are discussed as they may inform the knowledge, research and practices of transformational leadership.

Human 3beta-hydroxysteroid dehydrogenase/isomerase type 1 (3beta-HSD1) is a critical enzyme in the conversion of DHEA to estradiol in breast tumors and may be a target enzyme for inhibition in the treatment of breast cancer in postmenopausal women. Human 3beta-HSD2 participates in the production of cortisol and aldosterone in the human adrenal gland in this population. In our recombinant human breast tumor MCF-7 Tet-off cells that express either 3beta-HSD1 or 3beta-HSD2, trilostane and epostane inhibit the DHEA-induced proliferation of MCF-7 3beta-HSD1 cells with 12- to 16-fold lower IC(50) values compared to the MCF-7 3beta-HSD2 cells. The compounds also competitively inhibit purified human 3beta-HSD1 with 12- to 16-fold lower K(i) values compared to the noncompetitive K(i) values measured for human 3beta-HSD2. Using our structural model of 3beta-HSD1, trilostane or 17beta-acetoxy-trilostane was docked in the active site of 3beta-HSD1, and Arg195 in 3beta-HSD1 or Pro195 in 3beta-HSD2 was identified as a potentially critical residue (one of 23 non-identical residues in the two isoenzymes). The P195R mutant of 3beta-HSD2 were created, expressed and purified. Kinetic analyses of enzyme inhibition suggest that the high affinity, competitive inhibition of 3beta-HSD1 by trilostane and epostane may be related to the presence of Arg195 in 3beta-HSD1 vs. Pro195 in 3beta-HSD2.

A SAR-GMTI algorithm based on space-time adaptive processing (STAP) in frequency domain by multi-channel SAR is proposed. The paper deduces the theoretical formula of the clutter suppression in-depth based on frequency STAP and finds that the output is a chirp signal and similar to the input signal of the moving targets before suppressed, so FrFT is chosen to detect them and estimate their moving parameters. The analyses in theory and simulator results show that our new algorithm is effective.

Exposure to bacterial superantigens, such as staphylococcal enterotoxin B (SEB), can lead to the induction of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). In the current study we investigated the role of CD44 in ALI/ARDS. Intranasal exposure of CD44 wild type (CD44 WT) mice to SEB led to a significant increase in the expression of CD44 on lung mononuclear cells. CD44 knockout (CD44 KO) mice developed significantly reduced SEB-induced ALI/ARDS, compared to similarly treated CD44 WT mice. Deletion of CD44 did not have a significant effect on lymphocyte activation, apoptosis or inflammatory cytokine production. However, mononuclear cell migration to the lungs of SEB-exposed CD44 KO mice was significantly reduced when compared to mononuclear infiltration in the lungs of SEB-exposed CD44 WT mice. Mechanistically, deletion of CD44 led to reduced ability of SEB-exposed spleen cells to bind to lung epithelial cells. Finally, treatment of SEB-exposed mice with anti-CD44 mAbs led to a significant reduction in vascular permeability, prevented inflammatory cells infiltration in the lungs and reduced the ability of SEB-exposed splenocytes to adhere to epithelial cells. Together, these results demonstrate an important role of CD44 in SEB-induced lung injury and suggest the possibility of targeting CD44 for the treatment of SEB-induced ALI/ARDS.

Lymphokine-activated killer cells play an important role in various immunologically-based treatments of cancer, including in the use of IL-2 therapy for the treatment of malignant melanoma. In previous studies, we demonstrated that the expression of CD44 on splenocytes is significantly elevated following exposure to IL-2. Therefore, in the current study we examined the potential significance of CD44 expression on lymphokine activated killer (LAK) cells in their interaction and killing of melanoma cells. Stimulation of splenocytes with IL-2 led to a significant increase in the expression of CD44 on T cells, NK cells and NKT cells. Treatment of melanoma bearing CD44WT mice with IL-2 led to a significant reduction in the local tumor growth while treatment of melanoma bearing CD44KO mice with IL-2 was ineffective at controlling tumor growth. Furthermore, the ability of splenocytes from IL-2 treated CD44KO mice to kill melanoma tumor targets was significantly reduced when compared to the anti-tumor activity of splenocytes from IL-2 treated CD44WT mice. The importance of CD44 expression on the LAK cells was further confirmed by the observation that adoptively transferred IL-2-activated splenocytes from CD44KO mice were significantly less effective at controlling tumor growth in vivo. Next the significance of the increased expression of CD44 in tumor killing was examined and showed that following stimulation with IL-2, distinct populations of cells with low (CD44lo) or elevated (CD44hi) expression of CD44 are generated and that the CD44hi cells are responsible for killing of the melanoma cells. The reduced killing activity of the CD44KO LAK cells did not result from reduced activation or expression of effector molecules but was due, at least in part, to a reduced ability to adhere to B16F10 tumor cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 779. doi:10.1158/1538-7445.AM2011-779