Primary central nervous system marginal zone B-cell lymphoma arising from the dural meninges: A case report and review of literature.

Primary central nervous system (CNS) marginal zone B-cell lymphoma (MZBCL) arising from the dural meninges is a rare but indolent disease. This malignancy can present in various ways, hence making it difficult to diagnose. Biopsy results dictate an appropriate treatment plan, which commonly consists of a combination of surgical resection, whole brain radiotherapy and systemic therapy.

Differentiation agents increase the potential AraC therapy of AML by reactivating cell death pathways without enhancing ROS generation.

Acute myeloid leukemia (AML) has a poor prognosis and requires new approaches for treatment. We have reported that a combination of vitamin D-based cell differentiation agents (doxercalciferol/carnosic acid [D2/CA]) added following the cytotoxic drug arabinocytosine (AraC) increases AML cell death (CD), a model for improved therapy of this disease. Because AraC-induced CD is known to involve reactive oxygen species (ROS) generation, here we investigated if the modulation of cellular REDOX status plays a role in the enhancement of cell death (ECD) by D2/CA.

Autoimmune Diseases and Rosai-Dorfman Disease Coexist More Commonly than Expected: Two Case Reports.

BACKGROUND The educational objective of this study was to describe 2 case reports in which patients were found to have an autoimmune disease concomitantly with a rare, benign histiocytic disorder known as Rosai-Dorfman disease (RDD). It is unclear if there is an underlying association between autoimmune disease and RDD. Lymphadenopathy, although most frequently seen bilaterally in the cervical region in RDD, may be present anywhere.

Large granular lymphocytic leukemia complicating autoimmune polyglandular syndrome type 1 in siblings.

Autoimmune polyglandular syndrome type 1 (APS1) is a rare autosomal recessive disorder, and large granular lymphocytic leukemia (LGLL) may, even more rarely, complicate APS1. LGLL may be subtle in presentation, but it is imperative to recognize LGLL in APS1 promptly, as outcome may otherwise be fatal, as described herein.

JNK1 as a signaling node in VDR-BRAF induction of cell death in AML.

Numerous clinical studies of vitamin D, its derivatives or analogs, have failed to clearly demonstrate sustained benefits when used for the treatment of human malignant diseases. However, given the strong preclinical evidence of anti-neoplastic activity and the epidemiological associations suggesting that vitamin D compounds may have a place in cancer therapy, attempts are continuing to devise new approaches to their therapeutic use. This laboratory has developed a strategy to enhance the effectiveness of the currently standard therapy of Acute Myeloid Leukemia (AML) by the immediate addition of the vitamin D2 analog Doxercalciferol combined with the plant polyphenol-derived Carnosic acid to AML cells previously treated with Cytarabine (AraC).

Evidence of both von Willebrand factor deposition and factor V deposition onto AL amyloid as the cause of a severe bleeding diathesis.

: Acquired coagulopathies are common; uncommonly, adsorption of coagulation factors from the circulation into the tissues by pathologic amyloid exceeds the body's ability to produce factor and results in acquired factor deficiency. When amyloidosis does cause a coagulopathy, it is most often acquired factor X deficiency, but there are rare reports of amyloidosis being associated with other acquired factor deficiencies. We investigated a case of a severe bleeding diathesis, the cause of which was combined acquired factor V deficiency and concomitant acquired von Willebrand syndrome.

BRAF signals to pro-apoptotic BIM to enhance AraC cytotoxicity induced in AML cells by Vitamin D-based differentiation agents.

Vitamin D has so far not fulfilled its early promise as an antineoplastic agent, in spite of compelling in vitro data. With the aim of bringing vitamin D or its derivatives (VDDs) effectively to the clinic, we developed a two-pronged approach. First, by adding the plant-derived Carnosic Acid (CA) to a vitamin D2 derivative Doxercalciferol we increased its differentiation potency without increasing it hypercalcemic properties.

The role of VDR and BIM in potentiation of cytarabine-induced cell death in human AML blasts.

Acute Myeloid Leukemia (AML) has grave prognosis due to aggressive nature of the disease, the toxicity of standard treatment, and overall low cure rates. We recently showed that AML cells in established culture treated with Cytarabine (AraC) and a differentiation agent combination show enhancement of AraC cytotoxicity. Here we elucidate molecular changes which underlie this observation with focus on AML blasts in primary culture.

Enhancement of arabinocytosine (AraC) toxicity to AML cells by a differentiation agent combination.

Arabinocytosine (AraC, also known as cytarabine) is one of the mainstays of AML therapy, but like other DNA damaging therapeutic agents it is rarely curative by itself. There is an emerging realization that the therapeutic outcomes may be improved by combining AraC with other compounds. Here we report that the addition of a differentiating agent combination immediately following AraC damage to AML blasts, selectively increases the cell kill.

Vitamin D Control of Hematopoietic Cell Differentiation and Leukemia.

It is now well known that in the mammalian body vitamin D is converted by successive hydroxylations to 1,25-dihydroxyvitamin D (1,25D), a steroid-like hormone with pleiotropic properties. These include important contributions to the control of cell proliferation, survival and differentiation, as well as the regulation of immune responses in disease. Here, we present recent advances in current understanding of the role of 1,25D in myelopoiesis and lymphopoiesis, and the potential of 1,25D and analogs (vitamin D derivatives; VDDs) for the control of hematopoietic malignancies.

The MAPK ERK5, but not ERK1/2, inhibits the progression of monocytic phenotype to the functioning macrophage.

Intracellular signaling pathways present targets for pharmacological agents with potential for treatment of neoplastic diseases, with some disease remissions already recorded. However, cellular compensatory mechanisms usually negate the initial success. For instance, attempts to interrupt aberrant signaling downstream of the frequently mutated ras by inhibiting ERK1/2 has shown only limited usefulness for cancer therapy.

ERK 5/MAPK pathway has a major role in 1α,25-(OH)2 vitamin D3-induced terminal differentiation of myeloid leukemia cells.

Vitamin D derivatives, including its physiological form 1α,25(OH)2 vitamin D3 (1,25D), have anti-tumor actions demonstrated in cell culture and confirmatory epidemiological associations are frequently reported. However, their promise for use in the cancer clinic is still incompletely fulfilled, suggesting that a better understanding of the molecular events initiated by these compounds is needed for therapeutic advances. While ERK1/2 has been intensely investigated and is known to transmit signals for cell survival, growth, and differentiation, the role of other MAPK pathways has been studied sporadically.

ERK5 pathway regulates transcription factors important for monocytic differentiation of human myeloid leukemia cells.

Mitogen-activated protein kinases (MAPKs) are important transducers of external signals for cell growth, survival, and other cellular responses including cell differentiation. Several MAPK cascades are known with the MEK1/2-ERK1/2, JNK, and p38MAPKs receiving most attention, but the role of MEK5-ERK5 in intracellular signaling deserves more scrutiny, as this pathway transmits signals that can complement ERK/2 signaling. We hypothesized that the ERK5 pathway plays a role in the control of monocytic differentiation, which is disturbed in myeloid leukemia.

Clinical experience using vitamin d and analogs in the treatment of myelodysplasia and acute myeloid leukemia: a review of the literature.

Despite progress in understanding the biology of acute myeloid leukemia (AML), and despite advances in treatment, the majority of patients with AML die from the disease. The observation that Vitamin D can induce AML blast cells in vitro to differentiate along the monocytic lineage was made 30 years ago; however, it remains to translate this into a clinically meaningful strategy. This is a review of published clinical experience regarding the use of Vitamin D and its analogs, either alone or in combination with other agents, to treat AML.

The pan-caspase inhibitor Q-VD-OPh has anti-leukemia effects and can interact with vitamin D analogs to increase HPK1 signaling in AML cells.

Caspase function is known to be essential for cell death by apoptosis, but it is now increasingly recognized that these proteases also play important roles in other cellular events. Here we report for the first time that inhibition of cellular caspase activity can induce differentiation of AML blasts, and can enhance vitamin D-induced cell differentiation of these cells. This was studied in blasts obtained from nine patients with AML and one patient with CML by ex vivo culture in the presence of Q-VD-OPh (QVD), a pan caspase inhibitor.

Involvement of microRNA181a in differentiation and cell cycle arrest induced by a plant-derived antioxidant carnosic acid and vitamin D analog doxercalciferol in human leukemia cells.

1,25-dihydroxyvitamin D3 (1,25D) has been shown to influence differentiation, cell proliferation and cell death in cultured leukemia cells. However, its clinical use is limited by its hypercalcemic effects. An analog of 1,25D, doxercalciferol (1-D2), has anti-tumor activity, with markedly reduced calcemic effects, which makes it a potential agent for clinical treatment of AML.

Inhibition of Cot1/Tlp2 oncogene in AML cells reduces ERK5 activation and up-regulates p27Kip1 concomitant with enhancement of differentiation and cell cycle arrest induced by silibinin and 1,25-dihydroxyvitamin D(3).

Acute myelogenous leukemia (AML) is a disease characterized by dysregulated cell proliferation associated with impaired cell differentiation, and current treatment regimens rarely save the patient. Thus, new mechanism-based approaches are needed to improve prognosis of this disease. We have investigated in preclinical studies the potential anti-leukemia use of the plant-derived polyphenol Silibinin (SIL) in combination with 1,25-dihydroxyvitamin D3 (1,25D).

Isoforms of p38MAPK gamma and delta contribute to differentiation of human AML cells induced by 1,25-dihydroxyvitamin D₃.

Inhibition of p38MAPK alpha/beta is known to enhance 1,25-dihydroxyvitamin (1,25D)-induced monocytic differentiation, but the detailed mechanism of this effect was not clear. We now show that the enhancement of differentiation becomes apparent with slow kinetics (12-24 h). Interestingly, the inhibition of p38MAPK alpha/beta by their selective inhibitor SB202190 (SB) leads to an upregulated expression of p38MAPK isoforms gamma and delta in 1,25D-treated AML cells, in cell lines and in primary culture.

Silibinin can induce differentiation as well as enhance vitamin D3-induced differentiation of human AML cells ex vivo and regulates the levels of differentiation-related transcription factors.

Induction of terminal differentiation is a conceptually attractive approach for the therapy of neoplastic diseases. Although vitamin D derivatives (deltanoids) can induce differentiation of AML cells in vitro, so far deltanoids have not been successfully brought to the clinic, due to the likelihood of life-threatening hypercalcemia. Here, we incubated freshly obtained blood cells from patients with AML with a plant antioxidant (PAOx), silibinin (SIL), alone or together with a deltanoid.

c-Jun N-terminal kinase 2 (JNK2) antagonizes the signaling of differentiation by JNK1 in human myeloid leukemia cells resistant to vitamin D.

1,25-Dihydroxyvitamin D3 (1,25D) induces differentiation of myeloid leukemia cells, but resistant cells are also encountered. We studied the mechanistic basis for the resistance in a model system using enhancers of 1,25D, the antioxidant carnosic acid and a kinase inhibitor SB202190. Knock-down (KD) of JNK2p54 unexpectedly increased the intensity of differentiation induced by the 1,25D, carnosic acid and SB202190 (DCS) combination.

Induction of differentiation of human leukemia cells by combinations of COX inhibitors and 1,25-dihydroxyvitamin D3 involves Raf1 but not Erk 1/2 signaling.

Differentiation therapy of cancer is being explored as a potential modality for treatment of myeloid leukemia, and derivatives of vitamin D are gaining prominence as agents for this form of therapy. Cyclooxygenase (COX) inhibitors have been reported to enhance 1,25-dihydroxyvitamin D(3) (1,25D)-induced monocytic differentiation of promyeloblastic HL60 cells, but the mechanisms of this effect are not fully elucidated, and whether this potentiation can occur in other types of myeloid leukemia is not known. We found that combination treatment with 1,25D and non-specific COX inhibitors acetyl salicylic acid (ASA) or indomethacin can robustly potentiate differentiation of other types of human leukemia cells, i.

Peripheral monocytes and CD4+ cells are potential sources for increased circulating levels of TGF-beta and substance P in autoimmune myelofibrosis.

Myelofibrosis is an uncommon phenomenon associated with a variety of neoplastic and inflammatory processes. Although there is evidence that cytokines elaborated by clonal malignant hematopoietic cells are implicated in myelofibrosis in primary hematologic disorders, there has been little data to date on the pathophysiology of myelofibrosis in autoimmune disorders. Here we report a case of autoimmune myelofibrosis with pancytopenia.

The rationale for deltanoids in therapy for myeloid leukemia: role of KSR-MAPK-C/EBP pathway.

The evidence for the promising potential for derivatives of Vitamin D (deltanoids) in the treatment of myeloid leukemias is increasing, but currently is not matched by the understanding of the precise mechanisms by which these anti-neoplastic effects are achieved. Unlike solid tumors in which growth retardation by deltanoids appears to result from inhibition of cell proliferation and the promotion of cell death by apoptosis, control of myeloid leukemia proliferation by deltanoids results from the induction of differentiation of the immature myelo-monocytic cells towards functional monocytic cells. We present here the accumulating evidence that a pathway that is initiated by deltanoid activation of Vitamin D receptor (VDR) and leads to monocytic differentiation of human myeloblastic HL60 cells, includes the MEK-ERK and JNK mitogen-activated protein kinases (MAPKs), their positive and negative regulators and a downstream effector C/EBPbeta.

The anti-proliferative effect of neurokinin-A on hematopoietic progenitor cells is partly mediated by p53 activating the 5' flanking region of neurokinin-2 receptor.

The bone marrow (BM) is home to at least two stem cells, hematopoietic (HSC) and mesenchymal. Hematopoiesis is partly regulated through neurokinin-1 (NK-1) and NK-2 belonging to the family of G-protein/7-transmembrane receptors. NK-1 and NK-2 show preference for the neurotransmitters, substance P (SP) and neurokinin-A (NK-A), respectively.