Humoral Response after SARS-CoV-2 mRNA Vaccination in a Cohort of Hemodialysis Patients and Kidney Transplant Recipients

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Efficacy and mechanism of action of Deguelin in suppressing metastasis of 4T1 cells

Cancer related deaths in breast cancer patients are due to metastasis of the disease. Murine 4T1 cells (Murine mammary cancer cell line developed from 6-thioguanine resistant tumor) provide an excellent research tool for metastasis related studies because these cells are highly aggressive and readily metastasize to the lungs. In this study we determined the effect of Deguelin on in vivo/vitro growth and metastasis of 4T1 cells. Deguelin inhibited the in vitro growth of 4T1 cells in a time and dose dependent manner accompanied with reduced nuclear PCNA immunostaining. In cells treated with Deguelin, reduced expression of nuclear c-Met, and its downstream targets such p-ERK and p-AKT was observed. Deguelin reduced the cell migration in 4T1 cells as determined by scratch wound assay. Combined treatment with Deguelin + ERK or PI3K/AKT inhibitor had no additional effect on cell migration. These results indicated that the action of Deguelin on cell migration may be mediated by AKT and ERK mediated signaling pathways. In vivo, Deguelin treatment significantly inhibited growth of 4T1 cells. Deguelin also reduced the occurrence of metastatic lung lesions by 33 % when cells were injected intravenously into Balb/c female mice. There was no difference in the body weight, nor was there a difference in liver and spleen weights between vehicle treated-control and Deguelin-treated animals, which indicated that Deguelin was nontoxic at the dose used in the present study. These results provide rationale for developing Deguelin as a chemotherapeutic agent for triple negative breast cancer patients.     

Vitamin D and breast cancer: Emerging concepts

The benefit of vitamin D in cancer prevention and to certain extent therapy has been well recognized. The active form of vitamin D, 1,25-dihydroxycholecalciferol (1,25(OH)2 D3) is a natural ligand for vitamin D receptor (VDR). Since 1,25(OH)2D3 exerts toxic effects at a concentration that is beneficial, nearly 1500 analogs of vitamin D have been synthesized and evaluated for their efficacy in a variety of carcinogenesis and human cancer models both in vitro and in vivo. Among these only a handful of them have been approved for evaluation in clinical trials for leukemia, breast, prostate and colon cancers. The mechanism of vitamin D action is mediated by the nuclear VDR and the signaling cascade for its action is extensively reported. In this review we focus on the newer concepts for vitamin D action. These include (1) differential effects of vitamin D in maintaining cell proliferation when the cells are under stress but suppressing cell growth when the cells are transformed; (2) functional significance of VDR polymorphism in potential vitamin D responsiveness; (3) regulation of constitutive splicing of vitamin D target gene, CYP24a, by the hormone and its significance; and (4) regulation of microRNA by vitamin D in breast cancer. It is anticipated that the new work in these selective areas would expand the understanding of vitamin D in breast cancer prevention and therapy.     

Lysophosphatidic acid targets vascular and oncogenic pathways via RAGE signaling

The endogenous phospholipid lysophosphatidic acid (LPA) regulates fundamental cellular processes such as proliferation, survival, motility, and invasion implicated in homeostatic and pathological conditions. Hence, delineation of the full range of molecular mechanisms by which LPA exerts its broad effects is essential. We report avid binding of LPA to the receptor for advanced glycation end products (RAGE), a member of the immunoglobulin superfamily, and mapping of the LPA binding site on this receptor. In vitro, RAGE was required for LPA-mediated signal transduction in vascular smooth muscle cells and C6 glioma cells, as well as proliferation and migration. In vivo, the administration of soluble RAGE or genetic deletion of RAGE mitigated LPA-stimulated vascular Akt signaling, autotaxin/LPA-driven phosphorylation of Akt and cyclin D1 in the mammary tissue of transgenic mice vulnerable to carcinogenesis, and ovarian tumor implantation and development. These findings identify novel roles for RAGE as a conduit for LPA signaling and suggest targeting LPA–RAGE interaction as a therapeutic strategy to modify the pathological actions of LPA.Endogenous phospholipids such as lysophosphatidic acid (LPA) regulate cellular signal transduction cascades implicated in diverse homeostatic and pathological conditions, from vascular signaling and tumorigenesis to neuropathic pain, as examples (Moolenaar et al., 2004; Lin et al., 2010). Thus, it is not surprising that the production of LPA is tightly regulated. The control of LPA levels occurs largely through the action of the enzyme autotaxin (atx), the principal source of LPA in the tissues (Georas, 2009; Pamuklar et al., 2009). In the vasculature and in tumors, LPA stimulates cellular proliferation, survival, motility, invasion, and production of growth factors (Moolenaar et al., 2004; Lin et al., 2010). LPA exerts homeostatic effects in development, but in adult organisms recrudescence of LPA signaling in stressed tissues is met with pathological responses such as neointimal expansion and tumor growth and metastasis (Moolenaar et al., 2004; Smyth et al., 2008; Lin et al., 2010). Although it is known that LPA interacts with G protein–coupled receptors (GPCRs), not all LPA activities can be explained by GPCR signaling. A potential role for an intracellular receptor has been proposed; further, unidentified LPA receptors or possibly nonreceptor pathways have been implicated in the biological actions of this lipid (McIntyre et al., 2003; Choi et al., 2010; Chun et al., 2010). Despite the high interest in LPA signaling, the identity of non-GPCR receptors has remained elusive. Because the receptor for advanced glycation end products (RAGE) has been implicated in vascular signaling, atherosclerosis, and tumorigenesis (Yan et al., 2010), we surmised that RAGE might mediate some of the biological effects of LPA and provide here substantial evidence in support of this hypothesis.     

Assessment of heparin binding to the AN69 ST hemodialysis membrane: I. Preclinical studies

The AN69 ST membrane was designed to render the surface of the native polyacrylonitrile polymer less cationic. This was achieved by layering the membrane with the polycationic biopolymer polyethyleneimine. This new membrane is able to bind heparin to its surface, through electrical interactions, without altering the reactivity of the sulfonate groups of the membrane, regularly distributed in the membrane bulk. The kinetics of unfractionated or low-molecular-weight heparins were studied in vitro and in vivo in sheep. Encouraging results were obtained indicating that heparin-coated hemodialyzers are potent anticoagulants. Priming the AN69 ST membrane-equipped hemodialyzer with heparin, as in regular hemodialysis, could allow drastic reduction of heparin consumption in hemodialysis.     

Icodextrin-induced peritonitis: study of five cases and comparison with bacterial peritonitis

BACKGROUND: An epidemic of aseptic peritonitis related to the presence of peptidoglycan contaminant in some batches of icodextrin solution (Extraneal, Baxter Healthcare Corporation) occurred in Europe in the first six months of 2002. METHODS: By case-control study we examined the clinical and biologic features of 5 patients with icodextrin-induced peritonitis (group AP) and compared them with 7 patients with bacterial peritonitis (group BP) recruited in our clinical center between January and June 2002. RESULTS: Diagnosis of icodextrin-induced peritonitis was confirmed in all cases by a positive reintroduction test with contaminated batches of icodextrin. No recurrence was observed on re-exposure to icodextrin free of peptidoglycan. Skin tests were positive with contaminated icodextrin in 2 of 5 patients, while they were negative with icodextrin solution free of peptidoglycan (<0.6 ng/mL). During peritonitis, serum level of C-reactive protein (CRP) was lower in group AP (42.4 +/- 34 mg/L) than in group BP (135 +/- 59 mg/L) (P= 0.01). Leukocyte number in peritoneal dialysis effluent was lower in group AP (284 +/- 101/mm3), with a lower neutrophil/monocyte ratio (N/M = 0.67) than in group BP (1410 +/- 973/mm3; N/M = 4) (P < 0.05). A low number of peritoneal fluid eosinophilia (11 +/- 8%) was detected in group AP. CONCLUSION: Icodextrin-induced peritonitis was associated with a burst of intraperitoneal cytokines. The phenotype of peritoneal neutrophils was different between aseptic and bacterial peritonitis, indicating that inflammatory stimuli that activate neutrophils in both types of peritonitis are clearly distinct. Finally, peritoneal injury measured by weight gain, peritoneal permeability, and CA125 concentration seemed to be less severe during icodextrin-induced peritonitis than during bacterial peritonitis.     

Expression of Androgen Receptor Is Negatively Regulated By p53

Increased expression of androgen receptor (AR) in prostate cancer (PC) is associated with transition to androgen independence. Because the progression of PC to advanced stages is often associated with the loss of p53 function, we tested whether the p53 could regulate the expression of AR gene. Here we report that p53 negatively regulates the expression of AR in prostate epithelial cells (PrECs). We found that in LNCaP human prostate cancer cells that express the wild-type p53 and AR and in human normal PrECs, the activation of p53 by genotoxic stress or by inhibition of p53 nuclear export downregulated the expression of AR. Furthermore, forced expression of p53 in LNCaP cells decreased the expression of AR. Conversely, knockdown of p53 expression in LNCaP cells increased the AR expression. Consistent with the negative regulation of AR expression by p53, the p53-null HCT116 cells expressed higher levels of AR compared with the isogenic HCT116 cells that express the wildtype p53. Moreover, we noted that in etoposide treated LNCaP cells p53 bound to the promoter region of the AR gene, which contains a potential p53 DNA-binding consensus sequence, in chromatin immunoprecipitation assays. Together, our observations provide support for the idea that the loss of p53 function in prostate cancer cells contributes to increased expression of AR.