Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma

The mechanisms by which multiple myeloma (MM) cells migrate and home to the bone marrow are not well understood. In this study, we sought to determine the effect of the chemokine SDF-1 (CXCL12) and its receptor CXCR4 on the migration and homing of MM cells. We demonstrated that CXCR4 is differentially expressed at high levels in the peripheral blood and is down-regulated in the bone marrow in response to high levels of SDF-1. SDF-1 induced motility, internalization, and cytoskeletal rearrangement in MM cells evidenced by confocal microscopy. The specific CXCR4 inhibitor AMD3100 and the anti-CXCR4 antibody MAB171 inhibited the migration of MM cells in vitro. CXCR4 knockdown experiments demonstrated that SDF-1-dependent migration was regulated by the P13K and ERK/ MAPK pathways but not by p38 MAPK. In addition, we demonstrated that AMD3100 inhibited the homing of MM cells to the bone marrow niches using in vivo flow cytometry, in vivo confocal microscopy, and whole body bioluminescence imaging. This study, therefore, demonstrates that SDF-1/CXCR4 is a critical regulator of MM homing and that it provides the framework for inhibitors of this pathway to be used in future clinical trials to abrogate MM trafficking.     

Antileukemic effects of the novel, mutant FLT3 inhibitor NVP-AST487: effects on PKC412-sensitive and -resistant FLT3-expressing cells

An attractive target for therapeutic intervention is constitutively activated, mutant FLT3, which is expressed in a subpopulation of patients with acute myelocyic leukemia (AML) and is generally a poor prognostic indicator in patients under the age of 65 years. PKC412 is one of several mutant FLT3 inhibitors that is undergoing clinical testing, and which is currently in late-stage clinical trials. However, the discovery of drug-resistant leukemic blast cells in PKC412-treated patients with AML has prompted the search for novel, structurally diverse FLT3 inhibitors that could be alternatively used to override drug resistance. Here, we report the potent and selective antiproliferative effects of the novel mutant FLT3 inhibitor NVP-AST487 on primary patient cells and cell lines expressing FLT3-ITD or FLT3 kinase domain point mutants. NVP-AST487, which selectively targets mutant FLT3 protein kinase activity, is also shown to override PKC412 resistance in vitro, and has significant antileukemic activity in an in vivo model of FLT3-ITD(+) leukemia. Finally, the combination of NVP-AST487 with standard chemotherapeutic agents leads to enhanced inhibition of proliferation of mutant FLT3-expressing cells. Thus, we present a novel class of FLT3 inhibitors that displays high selectivity and potency toward FLT3 as a molecular target, and which could potentially be used to override drug resistance in AML.     

6]-gingerol induces Ca2+ mobilization in Madin-Darby canine kidney cells

[6]-gingerol, a major phenolic compound derived from ginger (Zingiber officinale), is a potential chemopreventive compound that can induce stress in cancer cells and cause apoptotic cell death. This study examines the early signaling effects of [6]-gingerol on renal cells. It was found that [6]-gingerol caused a slow and sustained rise of [Ca2+]i in a concentration-dependent manner. [6]-gingerol also induced a [Ca2+]i rise when extracellular Ca2+ was removed, but the magnitude was reduced by 80%. Depletion of intracellular Ca2+ stores with CCCP, a mitochondrial uncoupler, did not affect the action of [6]-gingerol. In a Ca2+-free medium, the [6]-gingerol-induced [Ca2+]i rise was partially abolished by depleting stored Ca2+ with thapsigargin (an endoplasmic reticulum Ca2+ pump inhibitor). The elevation of [6]-gingerol-caused [Ca2+]i in a Ca2+-containing medium was not affected by modulation of protein kinase C activity. The [6]-gingerol-induced Ca2+ influx was blocked by nicardipine. U73122, an inhibitor of phospholipase C, abolished ATP (but not [6]-gingerol)-induced [Ca2+]i rise. These findings suggest that [6]-gingerol induces a significant rise in [Ca2+]i in MDCK renal tubular cells by stimulating both extracellular Ca2+ influx and thapsigargin-sensitive intracellular Ca2+ release via as yet unidentified mechanisms.     

Incidence and risk factors for pulmonary mycosis in kidney transplantation

IntroductionPulmonary mycosis, a severe complication following kidney transplantation, is associated with a high rate of mortality. The incidence of and independent risk factors for its development have not been well studied.MethodsWe retrospectively reviewed 2573 kidney transplant recipients. Patients were divided into case and control groups based on a diagnosis of pulmonary mycosis. The recipient baseline characteristics, posttransplant complications, immunosuppressive regimens and antibiotic usages were analyzed to identify independent risk factors.ResultsThe total incidence of pulmonary mycosis among kidney recipients was 2.1%. Upon univariate analysis, patients in the case group differed significantly from the controls based upon: older age, higher retransplantation rate, longer dialysis time, induction with ATG or anti-CD25 monoclonal antibodies, maintenance treatment with FK506 or MMF, broad-spectrum antibiotics, higher incidences of acute rejection episodes, DGF, impaired liver function, leukopenia, cytomegalovirus infection, and delayed incisional healing (P < .05). Multivariate analysis showed that older age, retransplantation, ATG induction, FK506/MMF, broad-spectrum antibiotics, leukopenia, and delayed incisional healing were independent risk factors for pulmonary mycosis.ConclusionsThe use of more potent immunosuppressive regimens seems to increase the rate of pulmonary mycosis. Patients who have five or more independent risk factors are at high risk for developing pulmonary mycosis.     

Total thyroidectomy replaces subtotal thyroidectomy as the preferred surgical treatment for Graves' disease

BACKGROUND: Total thyroidectomy is increasingly being adopted for patients requiring surgical treatment for Graves' disease based on a comparable surgical risk and the lack of recurrence, as well as the questionable ability of subtotal thyroidectomy to maintain euthyroidism. The purpose of the present paper was to evaluate its safety and efficiency. METHODS: Total thyroidectomy was adopted as part of the routine surgical treatment for Graves' disease from 2000. Patients who underwent subtotal thyroidectomy (STT) from 1995 to 1999 (n = 119) were compared with those who underwent total thyroidectomy (TT) from 2000 to 2003 (n = 98) with respect to immediate postoperative morbidity and long-term outcome. RESULTS: Fourteen (11.8%) and 22 patients (22.4%) required calcium supplement on discharge in the STT and TT groups, respectively (P < 0.05). One (0.8%) and three patients (3.1%) developed permanent hypocalcaemia, respectively. Transient recurrent laryngeal nerve palsy occurred in 9.2% (n = 11) and 5.1% (n = 5) of patients or 5.0% and 2.6% of nerves at risk after STT and TT, respectively. None of the patients had permanent nerve palsy. The estimated blood loss was less and hospital stay shorter after TT. During a mean follow up of 64 months, 86 patients (72.3%) in the STT group required thyroxine replacement and seven patients (5.9%) developed relapse. CONCLUSION: Subtotal thyroidectomy was associated with relapse as well as hypothyroidism in a significant proportion of patients during long-term follow up. Total thyroidectomy can be performed as safely as STT and should be recommended as the procedure of choice for patients requiring surgical treatment for Graves' disease.     

Phosphorus Effects of Mesoporous Bioactive Glass on Occlude Exposed Dentin

In recent studies, sealing of exposed dentinal tubules is generally considered as one of the most effective strategies to treat dentin hypersensitivity. Mesoporous bioactive glass (MBG) is a potential material for treating dentin hypersensitivity due to its highly specific areas for dissolution and re-precipitated reaction for reduction in dentin permeability. The groups of commercial products of PerioGlas^®, synthetic MBG and MBG without phosphorus (MBGNP) were compared. The MBG and MBGNP powders were prepared by the sol-gel method and mixed with different calculated ratios of phosphoric acid (PA) and then was brushed onto dentin surfaces. We used X-ray diffractometer (XRD), scanning electronic microscope (SEM), and Fourier transform infrared spectroscopy (FTIR) to investigate the physiochemistry and the occlusion ability of dentinal tubules. The results showed that MBG paste mixed with PA solution has a better ability for occluding dentinal tubules than MBGNP; it has a short reaction time and good operability. The major crystallite phase of MBG agents was monocalcium phosphate monohydrate [Ca(H₂PO₄)₂·H₂O] in the early stages of the reactions. MBG pastes that were mixed with 30% and 40% PA had the ability to create excellent penetration depth greater than 80 μm. These agents have the potential to treat dentin hypersensitivity.     

Feasibility Evaluation of an Interpersonal and Social Rhythm Therapy Group Delivery Model

The effectiveness of psychotherapies, such as interpersonal and social rhythm therapy (IPSRT), is supported by randomized controlled trials. These trials provide minimal direction regarding feasibility of psychotherapy delivery models. The study purpose was to identify factors facilitating implementation and sustainability of an IPRST group for patients with bipolar disorder. Qualitative data were assessed by the normalization process model (NPM). The results demonstrate feasibility of implementation with experienced clinicians, program coordination, and leadership support. Sustainability challenges include aftercare groups, space, and clinician time. The NPM provides a useful framework for evaluation of factors influencing the feasibility of psychotherapy delivery models.