T-cell variant of classical Hodgkin's lymphoma with nodal and cutaneous manifestations demonstrated by single-cell polymerase chain reaction

The atypical cells of CD30(+) cutaneous lymphoproliferative disorders (CD30CLD) are commonly of T-cell origin and frequently have a similar morphology as Hodgkin or Reed-Sternberg cells of Hodgkin's lymphoma (HL). HL is one of the tumors associated with CD30CLD. Although most studies support a B-cell derivation of the tumor cells in HL, recently a few cases of classical HL with T-cell genotype have been reported. We report a patient who presented with CD30CLD whose lymph nodes showed classical HL of mixed cellularity subtype at presentation. By single-cell PCR, the same clonal gene rearrangements of the T cell receptor-beta gene locus could be assigned to the CD30(+) and CD15(+) cells of both skin and lymph node. In a lymph node biopsy specimen taken in relapse after several courses of chemotherapy, the CD30(+) tumor cells were abundant. The T cell-derived tumor cells displayed aberrant expression of the Pax-5 gene in all specimens. A common clonal origin of both CD30CLD and HL of the lymph node in the patient presented here suggests that HL with T-cell genotype exists in association with CD30CLD as well as in sporadic cases and may share clonal origin with the skin tumor.     

N-myristoyltransferase: A potential novel diagnostic marker for colon cancer

Background  

Colon cancer is the second leading cause of cancer deaths in the western world. If detected early, colorectal cancer is one of the most treatable forms of cancer. Unfortunately, very few people are screened. N-myristoyltransferase (NMT) catalyzes myristoylation of various proteins including oncoproteins. We have demonstrated earlier the alteration of NMT activity during the progression of colorectal cancer and established NMT as a putative therapeutic target for cancer.     

Learning-related coordination of striatal and hippocampal theta rhythms during acquisition of a procedural maze task

The striatum and hippocampus are conventionally viewed as complementary learning and memory systems, with the hippocampus specialized for fact-based episodic memory and the striatum for procedural learning and memory. Here we directly tested whether these two systems exhibit independent or coordinated activity patterns during procedural learning. We trained rats on a conditional T-maze task requiring navigational and cue-based associative learning. We recorded local field potential (LFP) activity with tetrodes chronically implanted in the caudoputamen and the CA1 field of the dorsal hippocampus during 6-25 days of training. We show that simultaneously recorded striatal and hippocampal theta rhythms are modulated differently as the rats learned to perform the T-maze task but nevertheless become highly coherent during the choice period of the maze runs in rats that successfully learned the task. Moreover, in the rats that acquired the task, the phase of the striatal-hippocampal theta coherence was modified toward a consistent antiphase relationship, and these changes occurred in proportion to the levels of learning achieved. We suggest that rhythmic oscillations, including theta-band activity, could influence not only neural processing in cortico-basal ganglia circuits but also dynamic interactions between basal ganglia-based and hippocampus-based forebrain circuits during the acquisition and performance of learned behaviors. Experience-dependent changes in coordination of oscillatory activity across brain structures thus may parallel the well known plasticity of spike activity that occurs as a function of experience.     

Effects of hippocampus and medial caudate nucleus lesions on memory for direction information in rats

A delayed matching-to-sample task was designed to assess memory for direction information in rats. During the study phase, rats traversed a maze arm oriented in 1 of 3 directions. After a delay period, a test phase was presented that required a choice between the study phase direction and a foil direction. Once rats reached a learning criterion, probe trials suggested that normal rats favor the use of direction, rather than turning response, information and use vestibular feedback. Rats were then given hippocampus, medial caudate nucleus (MCN), or cortical control lesions. Unlike control rats, those with hippocampus and MCN lesions exhibited marked impairments when retested. However, all rats were able to learn a direction discrimination task. These results suggest that the hippocampus and MCN support processes associated with short-term memory for direction information.     

A double dissociation between the rat hippocampus and medial caudoputamen in processing two forms of knowledge

Rats with hippocampus, medial caudoputamen (CPU), lateral CPU, or control lesions were trained on declarative and procedural knowledge variants of a novel rodent sequential learning task. Medial CPU lesions impaired rats' ability to learn the procedure of running through a sequence of open maze arms but did not disrupt their capacity to explicitly generate (i.e.. "declare") maze arm sequences. Hippocampus lesions produced the opposite set of results. Rats with lateral CPU lesions were not impaired on either version of the task. Transfer tests indicated that control rats predominantly used egocentric cues to solve the procedural task and allocentric spatial cues to solve the declarative task. These findings suggest a double dissociation between the medial CPU and hippocampus in processing egocentric-procedural and allocentric-declarative sequential information, respectively.     

Clonality of cutaneous B-cell infiltrates determined by microdissection and immunoglobulin gene rearrangement.

Diagnosis of primary cutaneous B-cell lymphoma (PCBCL) is supported by the demonstration of a monoclonal B-cell population. Immunoglobulin heavy chain (IgH) gene-rearrangement analysis by polymerase chain reaction (PCR) is a reliable technique to detect B-cell monoclonality in paraffin-embedded tissue, but the presence of numerous reactive B lymphocytes in PCBCL may complicate the interpretation of clonality test results. To test this hypothesis, IgH gene-rearrangement analysis by PCR was performed on paraffin-embedded whole tissue sections of 19 cutaneous B-cell infiltrates diagnosed either as consistent with PCBCL (10 specimens) or unclassified lymphoid infiltrates (ULI) (9 specimens). In specimens that did not show monoclonal bands by IgH gene-rearrangement on DNA extracted from whole tissue sections, clonality assays were repeated on microdissected B-cell subpopulations suspicious for neoplastic cells. In the analysis of whole tissue sections, 4 (40%) of 10 specimens consistent with PCBCL showed one or two monoclonal bands, whereas 9 of 9 ULI specimens showed either a ladder or a smear. Clonality analysis of microdissected B-cell subpopulations showed 3 additional PCBCL specimens (total, 7 of 10) and 1 ULI specimen (total, 1 of 9) with unequivocal and reproducible monoclonal bands. Addition of microdissection increases the sensitivity of PCR-based B-cell clonality assay in PCBCL compared with analysis performed on the whole section (70% versus 40% monoclonal cases) and allows the recognition of a dominant clone in ULI specimens, possibly representing early PCBCL.     

Loss of functional cell surface transforming growth factor β (TGF-β) type 1 receptor correlates with insensitivity to TGF-β in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in Western countries, and there is significant variability in survival within CLL clinical stages. Earlier studies showed that CLL cells produce and are usually growth inhibited by transforming growth factor β type 1 (TGF-β1), suggesting a mechanism for the clinically indolent course of most CLL. Here we studied the mechanism by which CLL cells from about one-third of the patients are insensitive to TGF-β1. Of the 13 patients studied, CLL cells isolated from the peripheral blood of 8 patients were sensitive to growth inhibition by TGF-β1, as determined by incorporation of tritiated thymidine, whereas those from 5 patients were completely resistant to TGF-β1. As judged by binding of radiolabeled TGF-β1 followed by cross-linking and immunoprecipitation with anti-receptor antisera, CLL cells sensitive to TGF-β1 exhibited normal cell surface expression of both types 1 and 2 TGF-β receptors. In contrast, all CLL cells resistant to TGF-β1 exhibited no detectable surface type I receptors able to bind TGF-β1, but normal expression of type II receptors. Both TGF-β1-sensitive and TGF-β1-resistant CLL cells contained normal amounts of both type 1 and type 2 receptor mRNAs. Specific loss of type 1 receptor expression represents a new mechanism by which cells acquire resistance to TGF-β1-mediated growth inhibition in the development and progression of human lymphoproliferative malignancies.     

RIZ1 repression is associated with insulin-like growth factor-1 signaling activation in chronic myeloid leukemia cell lines

RIZ1 is a histone methyltransferase whose expression and activity are reduced in many cancers. In chronic myelogenous leukemia (CML), blastic transformation is associated with loss of heterozygosity in the region where RIZ1 is located and with decreased RIZ1 expression. Forced RIZ1 expression in model CML blast crisis (BC) cell lines decreases proliferation, increases apoptosis and enhances differentiation. We characterized molecular mechanisms that may contribute to potential CML tumor suppressor properties of RIZ1. Several RIZ1-regulated genes involved in insulin-like growth factor-1 (IGF-1) signaling were identified using cDNA microarrays. RIZ1 was shown to associate with promoter regions of IGF-1 and to increase histone H3 lysine 9 methylation using chromatin immunoprecipitation assays. IGF-1-blocking antibody was used to demonstrate the importance of autocrine IGF-1 signaling in CML-BC cell line viability. Forced RIZ1 expression in CML-BC cell lines decreases IGF-1 receptor activation and activation of downstream signaling components extracellular signal-regulated kinase 1/2 and AKT. These results highlight the therapeutic potential of inhibiting IGF-1 pathway in the acute phase of CML.