Reconstitution of T-Cell Subsets Following Thymoglobulin-Induced Depletion in High Immunologic Risk and Donation After Cardiac Death Renal Transplant Recipients.

Introduction: Depletion therapy in high immunologic risk (HR) patients by antithymocyte globulin (rATG) induces lymphopenia and subsequent compartmental repopulation of T-cell subsets. rATG is also given to patients receiving kidneys from donations after cardiac death (DCDs) to mitigate innate immune activation associated with the DCD process.

Methods: We compared the T-cell response with rATG in both HR and DCD kidney recipients.

Endogenous HS production deficiencies lead to impaired renal erythropoietin production.

Introduction: Patients suffering from chronic kidney disease (CKD) experience a number of associated comorbidities, including anemia. Relative deficiency in renal erythropoietin (EPO) production is thought to be a primary cause of anemia. Interestingly, CKD patients display low levels of hydrogen sulfide (HS), an endogenously derived renal oxygen sensor.

CORM-401 Reduces Ischemia Reperfusion Injury in an Ex Vivo Renal Porcine Model of the Donation After Circulatory Death.

Background: Carbon monoxide (CO) inhalation protects organ by reducing inflammation and cell death during transplantation processes in animal model. However, using CO in clinical transplantation is difficult due to its delivery in a controlled manner. A manganese-containing CO releasing molecules (CORM)-401 has recently been synthesized which can efficiently deliver 3 molar equivalents of CO.

A novel approach to off-clamp partial nephrectomy demonstrates significant improvements in renal injury in an experimental porcine model.

Introduction: We sought to design a partial nephrectomy (PN) with contralateral total nephrectomy porcine model and assess the underlying mechanisms of ischemia reperfusion injury (IRI) after PN using a novel, clinically approved resection device.

Methods: Domestic male pigs (n=9) underwent left lower pole PN, allocated to either standard (Group 1) or no ischemia PN (Group 2), followed by contralateral nephrectomy. Biochemical studies were performed at baseline, Day 2, and Day 7; after sacrifice, kidneys were processed for histological analysis.

A Hibernation-Like State for Transplantable Organs: Is Hydrogen Sulfide Therapy the Future of Organ Preservation?

Significance: Renal transplantation is the treatment of choice for end-stage renal disease, during which renal grafts from deceased donors are routinely cold stored to suppress metabolic demand and thereby limit ischemic injury. However, prolonged cold storage, followed by reperfusion, induces extensive tissue damage termed cold ischemia/reperfusion injury (IRI) and puts the graft at risk of both early and late rejection. Recent Advances: Deep hibernators constitute a natural model of coping with cold IRI as they regularly alternate between 4°C and 37°C.

Hydrogen Sulfide Induced Erythropoietin Synthesis is Regulated by HIF Proteins.

Purpose: Anemia of end stage renal disease affects 90% of patients on hemodialysis and it is a tremendous concern of patients and health care providers. Renal disease creates a state of renal hypoxia, which may contribute to a lack of erythropoietin production from the kidney when low oxygen levels are sensed. This necessitates the use of exogenous erythropoietin preparations.

MiRNA-29a as a tumor suppressor mediates PRIMA-1Met-induced anti-myeloma activity by targeting c-Myc.

The proto-oncogene c-Myc plays substantial role in multiple myeloma (MM) pathogenesis and is considered a potential drug target. Here we provide evidence of a novel mechanism for PRIMA-1Met, a small molecule with anti-tumor activity in phase I/II clinical trial, showing that PRIMA-1Met induces apoptosis in MM cells by suppressing c-Myc and upregulating miRNA-29a. Our study further demonstrates that miRNA-29a functions as a tumor suppressor which targets c-Myc.

PRIMA-1Met induces apoptosis in Waldenström's Macroglobulinemia cells independent of p53.

PRIMA-1Met has shown promising preclinical activity in various cancer types. However, its effect on Waldenström's Macroglobulinemia (WM) cells as well as its exact mechanism of action is still elusive. In this study, we evaluated the anti- tumor activity of PRIMA-1Met alone and in combination with dexamethasone or bortezomib in WM cell lines and primary samples.

miR-137 and miR-197 Induce Apoptosis and Suppress Tumorigenicity by Targeting MCL-1 in Multiple Myeloma.

Purpose: Deregulation of miRNA has been implicated in the pathogenesis of multiple myeloma. We identified miR-137 and miR-197, mapped to the chromosome 1p (12)-(21) deletion region, and examined their antimyeloma activity as tumor suppressors.

Experimental Design: The expression of miR-137/197 was examined in multiple myeloma and normal plasma cells by qRT-PCR.

PRIMA-1Met/APR-246 displays high antitumor activity in multiple myeloma by induction of p73 and Noxa.

Targeting p53 by the small-molecule PRIMA-1(Met)/APR-246 has shown promising preclinical activity in various cancer types. However, the mechanism of PRIMA-1(Met)-induced apoptosis is not completely understood and its effect on multiple myeloma cells is unknown. In this study, we evaluated antitumor effect of PRIMA-1(Met) alone or its combination with current antimyeloma agents in multiple myeloma cell lines, patient samples, and a mouse xenograft model.

Targeting p53 by small molecules in hematological malignancies.

p53 is a powerful tumor suppressor and is an attractive cancer therapeutic target. A breakthrough in cancer research came from the discovery of the drugs which are capable of reactivating p53 function. Most anti-cancer agents, from traditional chemo- and radiation therapies to more recently developed non-peptide small molecules exert their effects by enhancing the anti-proliferative activities of p53.

Targeting p53 via JNK pathway: a novel role of RITA for apoptotic signaling in multiple myeloma.

The low frequency of p53 alterations e.g., mutations/deletions (∼10%) in multiple myeloma (MM) makes this tumor type an ideal candidate for p53-targeted therapies.

p53 nuclear expression correlates with hemizygous TP53 deletion and predicts an adverse outcome for patients with relapsed/refractory multiple myeloma treated with lenalidomide.

del(17p13)(TP53) seems to be an independent poor prognostic factor in patients with relapsed/refractory multiple myeloma (MM) receiving lenalidomide. However, whether aberrant p53 nuclear expression detected by immunohistochemical analysis can be used as a surrogate marker for del(17p13)(TP53) in prognostic evaluation of lenalidomide-treated relapsed/refractory MM remains unclear. The p53 expression in myeloma cells from 88 patients was evaluated by immunohistochemical analysis, and 17p13(TP53) gene status was examined by fluorescence in situ hybridization (FISH).

RITA inhibits multiple myeloma cell growth through induction of p53-mediated caspase-dependent apoptosis and synergistically enhances nutlin-induced cytotoxic responses.

Mutations or deletions of p53 are relatively rare in multiple myeloma (MM), at least in newly diagnosed patients. Thus, restoration of p53 tumor suppressor function in MM by blocking the inhibitory role of murine double minute 2 (MDM2) is a promising and applicable therapeutic strategy. RITA and nutlin are two new classes of small molecule MDM2 inhibitors that prevent the p53-MDM2 interaction.

Molecular mechanisms of nutlin-induced apoptosis in multiple myeloma: evidence for p53-transcription-dependent and -independent pathways.

Multiple myeloma (MM) is an incurable plasma cell malignancy in which p53 is rarely mutated. Thus, activation of the p53 pathway by a small molecule inhibitor of the p53-MDM2 interaction, nutlin, in MM cells retaining wild type p53 is an attractive therapeutic strategy. Recently we reported that nutlin plus velcade (a proteasome inhibitor) displayed a synergistic response in MM.

CKS1B nuclear expression is inversely correlated with p27Kip1 expression and is predictive of an adverse survival in patients with multiple myeloma.

Background: CKS1B is a member of the highly conserved cyclin kinase subunit 1 (CKS1) family that interacts with cyclin-dependent kinases and plays an important role in cell cycle progression. We and others have shown that CKS1B amplification located on chromosome 1q21 is an adverse prognostic factor in multiple myeloma, but its relationship with CKS1B nuclear protein expression, is unclear. The aim of this study was to correlate nuclear CKS1B protein immunoreactivity, 1q21 amplification status, p27(Kip1) expression and survival in patients with newly-diagnosed multiple myeloma.

MDM2 antagonist nutlin plus proteasome inhibitor velcade combination displays a synergistic anti-myeloma activity.

Mutliple myeloma (MM) has one of the poorest prognosis of the hematological malignancies and novel therapeutic approaches are needed. Therapeutic induction of p53 might be important to evaluate the drugs either individually or in combination. Direct inhibition of MDM2 function by an MDM2 antagonist nutlin or blocking proteasomal degradation of p53 by a selective proteasome inhibitor velcade can stabilize p53 and activate the p53 apoptotic signaling pathway.

Irradiation with carbon ion beams induces apoptosis, autophagy, and cellular senescence in a human glioma-derived cell line.

Purpose: We examined biological responses of human glioma cells to irradiation with carbon ion beams (C-ions).

Methods And Materials: A human glioma-derived cell line, NP-2, was irradiated with C-ions. Apoptotic cell nuclei were stained with Hoechst 33342.

Pharmacological activation of the p53 pathway in haematological malignancies.

p53 gene mutations are rarely detected at diagnosis in common haematological cancers such as multiple myeloma (MM), acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL) and Hodgkin's disease (HD), although their prevalence may increase with progression to more aggressive or advanced stages. Therapeutic induction of p53 might therefore be particularly suitable for the treatment of haematological malignancies. Some of the anti-tumour activity of current chemotherapeutics has been derived from activation of p53.

Formation of vesicular stomatitis virus pseudotypes bearing surface proteins of hepatitis B virus.

It has been difficult to propagate and titrate hepatitis B virus (HBV) in tissue culture. We examined whether vesicular stomatitis virus (VSV) pseudotypes bearing HBV surface (HBs) proteins infectious for human cell lines could be prepared. For this, expression plasmids for three surface proteins, L, M, and S, of HBV were made.