Citations

PurposeAlthough rare overall, marginal zone B-cell lymphoma (MZBCL) is the most common primary low-grade CNS lymphoma reported in the literature. The aim of this study is to elucidate the biology and genetic features of this unusual tumor.Patients and MethodsFifteen CNS MZBCLs were studied clinically, pathologically, and genetically, including fluorescent in situ hybridization analyses with commercially available MALT1 and IgH break-apart and centromere 3, 7, 12, and 18 probes.ResultsCNS MZBCLs preferentially affect middle-aged women (female-to-male ratio, 4:1), with 93% presenting as dural-based masses mimicking meningioma. Ten patients with 1 to 7.6 years of follow-up after diagnosis showed no evidence of disease after radiation and/or chemotherapy. Like MZBCLs outside of the CNS, they consisted of CD20+, CD3−small B lymphocytes with varying degrees of plasmacytic differentiation and predominantly κ light-chain restriction (78%). Lymphoid follicles with follicular colonization were seen in three patients and deposition of amyloid was noted in samples from two patients, one of which was tumefactive. Neither Bcl-6 protein nor Epstein-Barr virus–encoded RNA was expressed. Trisomy 3 was detected in six of 12 patients, with no rearrangements of MALT1 or IgH and no trisomies of 7, 12, or 18 detected.ConclusionOur data suggest that intracranial MZBCL is an indolent primary CNS lymphoma that typically presents as a meningioma-like dural-based mass. Trisomy 3, but not MALT1 or IgH translocation, is a common genetic abnormality that may contribute to the pathogenesis of this CNS lymphoma.

ABSTRACT Niemann‐Pick disease type C (NPC) is a genetic disorder in which patient cells exhibit lysosomal accumulation of cholesterol and sphingolipids (SLs) caused by defects in either NPC1 or NPC2 proteins. We previously demonstrated that NPC1 human skin fibroblasts overexpressing endosomal Rab proteins (Rab7 or Rab9) showed a correction in the storage disease phenotype. In the current study, we used protein transduction to further investigate Rab9‐mediated reduction of stored lipids in NPC cells. Recombinant human Rab9 fused with the herpes simplex virus VP22 protein fragment was overexpressed, purified, and added to culture medium to induce protein transduction. When VP22‐Rab9 was transduced into NPC1 fibroblasts, nearly all cells showed significant reduction in cellular free cholesterol levels, with no cytotoxicity up to 5 µM. A fraction of the VP22‐Rab9 that was transduced into the cells was shown to bind to rab GDP dissociation inhibitor, suggesting that this pool of VP22‐Rab9 had become prenylated. The reduction in cellular free cholesterol was associated with correction of abnormal intracellular trafficking of BODIPY‐lactosylceramide and an increase of sterols in the culture media. The clearance of lysosomal free cholesterol was also associated with a decrease in LDL‐receptor levels. In addition, we demonstrated reduction of intracellular cholesterol by VP22‐Rab9 transduction in NPC2 fibroblasts and in cultured mouse NPC1 neurons. These observations provide important new information about the correction of membrane traffic in NPC cells by Rab9 overexpression and may lead to new therapeutic approaches for treatment of this disease.

Thiopurine S -methyltransferase (TPMT) catalyzes the S-methylation of thiopurine drugs. TPMT genetic polymorphisms represent a striking example of the potential clinical value of pharmacogenetics. Subjects homozygous for TPMT * 3A , the most common variant allele for low activity, an allele that encodes a protein with two changes in amino acid sequence, are at greatly increased risk for life-threatening toxicity when treated with standard doses of thiopurines. These subjects have virtually undetectable levels of TPMT protein. In this study, we tested the hypothesis that TPMT * 3A might result in protein misfolding and aggregation. We observed that TPMT * 3A forms aggresomes in cultured cells and that it aggregates in vitro , functional mechanisms not previously described in pharmacogenetics. Furthermore, there was a correlation among TPMT half-life values in rabbit reticulocyte lysate, aggresome formation in COS-1 cells, and protein aggregation in vitro for the three variant allozymes encoded by alleles that include the two TPMT * 3A single-nucleotide polymorphisms. These observations were compatible with a common structural explanation for all of these effects, a conclusion supported by size-exclusion chromatography and CD spectroscopy. The results of these experiments provide insight into a unique pharmacogenetic mechanism by which common polymorphisms affect TPMT protein function and, as a result, therapeutic response to thiopurine drugs.

12 adult cadaver wrists were dissected to identify the regions of origin of the four palmar radio-carpal ligaments. A non-dimensionalized value, called the radio-carpal ligament ratio (RLR), was defined as the width of ligament origin from the radius divided by the length of the capitate. Both values were measured directly from radiographs of the cadaver specimens. The RLRs for the four palmar radio-carpal ligaments were found to be statistically consistent. We applied the RLR concept retrospectively to 20 wrists with intraarticular distal radius fractures requiring open reduction. It was found that those fracture patterns in which the fracture fragment ratios (FFR: widths of the fracture fragments divided by the length of the capitate) were outside the limits of corresponding RLRs had clear intra-operative evidence of palmar radio-carpal ligament disruption, while those with FFRs within the limits of corresponding RLRs were noted to have no ligament disruption.

Patients with Alzheimer's disease (AD) have abnormally low positron emission tomography (PET) measurements of the cerebral metabolic rate for glucose (CMRgl) in regions of the precuneus and the posterior cingulate, parietotemporal, and frontal cortex. Apolipoprotein E (APOE) ε4 gene dose (i.e., the number of ε4 alleles in a person's APOE genotype) is associated with a higher risk of AD and a younger age at dementia onset. We previously found that cognitively normal late-middle-aged APOE ε4 carriers have abnormally low CMRgl in the same brain regions as patients with probable Alzheimer's dementia. In a PET study of 160 cognitively normal subjects 47–68 years of age, including 36 ε4 homozygotes, 46 heterozygotes, and 78 ε4 noncarriers who were individually matched for their gender, age, and educational level, we now find that ε4 gene dose is correlated with lower CMRgl in each of these brain regions. This study raises the possibility of using PET as a quantitative presymptomatic endophenotype to help evaluate the individual and aggregate effects of putative genetic and nongenetic modifiers of AD risk.

An instrument has been developed to acquire polarized attenuated total internal reflection (ATIR) mid-IR spectra of supported monomolecular films in situ at the lipid/water (L/W) interface. The monolayer film is applied to the treated surface of a trapezoidal germanium crystal as it is immersed into the subphase of a specially designed Langmuir-Blodgett trough. This approach offers several advantages over the study of monolayer films at the air/water (A/W) interface by external reflection techniques, including (1) an improved signal throughput and multiple reflections, both contributing to an improved signal-to-noise (S/N) ratio; (2) versatility with respect to the chemical nature of the surface; and (3) the ability to use standard spectral subtraction methods to compensate for absorption of the aqueous subphase. The enhanced sensitivity of this approach facilitates the study of in situ interactions of peptides with fully hydrated lipid membrane surfaces.

AbstractAt the Mayo Clinic, 103 patients with primary malignant lymphoma of the thyroid have been diagnosed and treated through 1978. This study examines the clinical findings in the 57 new cases seen since the last review in 1966; pathology and survival are evaluated for the series as a whole, including the 46 patients reported previously. Age and sex patterns were unchanged since the earlier review; thyroid lymphoma tended to occur in middle‐ to older‐aged women, and patients typically presented with a fairly rapidly enlarging, painless, and firm thyroid mass. The most common histologic subtype of lymphoma encountered was diffuse large cell (diffuse histiocytic). Hashimoto's disease was found in 36% of the pathologic specimens available for review. Follow‐up was completed for all patients up to 1979. Age, sex, and histologic subtype of tumor did not appear to be significant determinants of prognosis. Patients in whom the lymphoma was confined to the thyroid (intrathyroidal type) had a better overall 5‐year survival rate (86%) than those in whom tumor invaded soft tissues surrounding the hyroid or involved regional cervical nodes (38% for the extrathyroidal type). Almost all of the patients who had intrathyroidal tumors underwent surgical resection before irradiation. However, 3 of the 5 patients in this group who were treated by radiotherapy alone survived more than 5 years. There were approximately equal numbers of patients with the extrathyroidal type of lymphoma who were treated either by radiotherapy combined with surgical resection or by radiotherapy alone. The one form of therapy was just as effective as the other.