Dissimilar background genes control susceptibility to autoimmune disease in the context of different MHC haplotypes: NOD.H-2(s) congenic mice are relatively resistant to both experimental autoimmune encephalomyelitis and type I diabetes

Nonobese diabetic (NOD) mice develop multi-organ autoimmune diseases, including type 1 diabetes. We hypothesized that backcrossing the MHC region from SJL (H-2(s)) mice, which have an endogenous PLP(139-151)-reactive repertoire, onto the background of autoimmune-prone NOD mice would result in a mouse strain that is highly susceptible to experimental autoimmune encephalomyelitis (EAE). Unexpectedly, although we detected an endogenous PLP(139-151) repertoire in the NOD.S mice, they did not develop spontaneous EAE and were relatively resistant to PLP(139-151)-induced EAE when compared to SJL mice. This resistance was associated with lower production of proinflammatory cytokines and a decreased expansion of PLP(139-151)-specific CD4(+) T cells after immunization and restimulation with PLP peptide in vitro. V(beta) chain usage among PLP(139-151)-reactive T cells differed between SJL and NOD.S mice. Furthermore, NOD.S mice were resistant to the development of insulitis and cyclophosphamide-induced diabetes, but not sialadenitis. Altogether, even though NOD mice develop spontaneous autoimmune diseases, they become relatively resistant to induction of EAE even when they express the EAE-permissive class II molecule I-A(s). Our data show that certain combinations of otherwise susceptibility-conferring MHC and non-MHC genes can mediate autoimmune-disease resistance when they are paired together. These findings do not support the "shared autoimmune gene" hypothesis.     

Rhabdoid tumor of the kidney with primitive neuroectodermal tumor of the central nervous system: Associated tumors with different histologic,cytogenetic, and molecular findings

Rhabdoid tumor of the kidney (RTK) is associated with tumors of the central nevous system (CNS) in approximately 15% of cases. We describe the clinical features, histologic and cytogenetic findings, and molecular analysis of renal and CNS tumors from the same patient. The histology of the renal tumor was consistent with rhabdoid tumor. The CNS tumor was a primitive neuroectodermal tumor (PNET). The karyotype of the RTK was normal male. The PNET of the brain demonstrated monosomy 22 as the only cytogenetic abnormality, similar to reported cases of malignant rhabdoid tumor of the brain, but dissimilar to nonrandom cytogenetic findings in other CNS PNETs. Molecular cytogenetic and DNA marker studies confirmed loss of chromosome 22 in this patient's brain tumor. DNA allelotyping showed retention of both parental chromosome 22 alleles in the RTK and loss of the maternal allele in the PNET. Evaluation of additional RTKs and brain tumors occurring in the same patient may provide insight into the origins and relationships of these enigmatic tumors.     

Trisomy 2, trisomy 20, and del(17p) as sole chromosomal abnormalities in three cases of hepatoblastoma

Short-term cultures of three hepatoblastomas were analyzed cytogenetically. Trisomy 2, trisomy 20, and a deletion of 17p were found as the sole abnormalities, yielding the karyotypes 47,XY, + 2; 47,XX, + 20; and 46,XX,del(17)(p12)/46,XX. This is the first reported case of deletion of 17p as the sole chromosomal abnormality in a hepatoblastoma and the first reported case of trisomy 20 without double minute chromosomes as a sole chromosomal abnormality in hepatoblastoma.     

A chimeric T cell receptor with super-signaling properties

A key question yet to be resolved concerns the structure and function relationship of the TCR complex. How does antigen recognition by the TCR-alphabeta chains result in the activation of distinct signal transduction pathways by the CD3-gammadeltaepsilon/zeta complex? To investigate which part of the TCR-beta chain is involved in TCR signaling, we exchanged different domains of the constant regions of the TCR-beta chain with the corresponding TCR-gamma chain domains. We show here that hybridoma cells expressing a chimeric TCR-beta chain (betaIII) containing intracellular and transmembrane TCR-gamma amino acids, together with a wild-type TCR-alpha (alphawt) chain, were 10 times more sensitive to antigenic stimulation compared to cells expressing TCR-alphawt/betawt chains. This super-signaling phenotype of the betaIII chain was observed in two different TCRs. One specific for an alloantigen (I-A(bm12)) and one for an autoantigen (I-A(b)/MOG(35-55)). We found that this chimeric alphawt/betaIII TCR had normal association with CD3-gammadeltaepsilon and zeta chains. To investigate the effect of the chimeric betaIII chain in transgenic T cells, we made MOG(35-55)-specific TCR transgenic mice expressing either the alphawt/betawt or chimeric alphawt/betaIII TCR. Similar to what was observed in hybridoma cells, transgenic alphawt/betaIII T cells showed a super-signaling phenotype upon antigenic stimulation. Further studies may help us understand the effect of increased TCR signaling on autoimmunity and may lead to the identification of signaling molecules that can be targeted to stop the progression of autoimmune disorders such as multiple sclerosis.     

Studies on Alternaria allergens. I. Isolation of allergens from Alternaria tenuis and Alternaria solani.

Extracts of Alternaria tenuis and Alternaria solani were separated into dialyzable (molecular weight less than 10,000) and non-dialyzable forms. The latter was further fractionated by gel filtration through Sephadex G-100 followed by ion-exchange chromatography on DEAE-cellulose. The dialyzable material was fractionated by gel filtration through Sephadex G-50. The allergenic activities of the fractions obtained from the A. tenuis extract was measured in vitro by the radioallergosorbent test assay and the allergenic potency was measured by radioallergosorbent test inhibition assay. Allergenic activity was detected in most of the non-dialyzable fractions, the majority of the activity being in the last G-100 fraction (MW approximately 20,000) which was predominantly protein in nature. The same component may be responsible for the activity found in the dialyzate and its first G-50 fraction since the immunodiffusion studies indicated that the last G-100 fraction has antigenic components in common with those of the first G-50 fraction. In addition, cross-reactions between A. tenuis and A. solani extracts show that the two species share common antigenic determinants.     

Fast Adaptive Unsharp Masking with Programmable Mediaprocessors

Unsharp masking is a widely used image-enhancement method in medical imaging. Hardware-based solutions can be developed to support high computational demand for unsharp masking, but they suffer from limited flexibility. Software solutions can easily incorporate new features and modify key parameters, such as filtering kernel size, but they have not been able to meet the fast computing requirement. Modern programmable mediaprocessors can meet both fast computing and flexibility requirements, which will benefit medical image computing. In this article, we present fast adaptive unsharp masking on two leading mediaprocessors or high-end digital signal processors, Hitachi/Equator Technologies MAP-CA and Texas Instruments TMS320C64x. For a 2k × 2k 16-bit image, our adaptive unsharp masking with a 201 × 201 boxcar kernel takes 225 ms on a 300-MHz MAP-CA and 74 ms on a 600-MHz TMS320C64x. This fast unsharp masking enables technologists and/or physicians to adjust parameters interactively for optimal quality assurance and image viewing.     

Somatic spectrum of cancer-associated single basepair substitutions in the TP53 gene is determined mainly by endogenous mechanisms of mutation and by selection

The spectrum of somatic TP53 single basepair substitutions detected in 955 cancers was compared with that of 2,224 different germline mutations in 279 different human genes (other than TP53), reported as the cause of inherited disease. This comparison reveals that, disregarding a relatively small subset (12%) of TP53 mutations that probably result from the action of exogenous mutagens, both the relative rates and the nearest-neighbor spectra of single basepair substitutions are similar in the two datasets. This spectral resemblance suggests that a substantial proportion of cancer-associated somatic TP53 mutations result from endogenous cellular mechanisms. The likelihood of clinical observation of a particular mutation type differs, however, between tumors and genetic diseases, when the chemical properties of the resulting amino acid substitutions are considered. Together with a sixfold higher observation likelihood for mutations at evolutionary conserved residues, this finding argues that selection is a critical factor in determining which TP53 mutations are found to be associated with human cancer. © 1995 Wiley-Liss, Inc.     

Interstitial deletion of 20q in a patient with Waldenström macroglobulinemia following chemotherapy

A 76-year-old male with a history of renal insufficiency was found to have anemia, an IgM kappa paraprotein on serum immunofixation studies, absence of lytic bone lesions, and findings in the bone marrow consistent with Waldenstr?m macroglobulinemia (WM). Cytogenetic studies including fluorescence in situ hybridization (FISH) on the post-treatment bone marrow revealed the karyotype 46,XY,del(20)(q13.1q13.3). Less than 70 cases of karyotypic abnormalities in patients with WM have been reported, which have shown no abnormalities specific to WM. Monosomy or trisomy of chromosome 20 has been reported in approximately eight cases, but to our knowledge this is the first case report of an interstitial deletion of 20q, confirmed by FISH using chromosome 20 subtelomeric specific probes. Interstitial deletions of 20q are known to occur in polycythemia vera and other hematological malignancies, especially those of myeloid origin.     

Agreement between CBNAAT,liquid culture and line probe assay for detection of Mycobacterium tuberculosis and anti-tubercular drug resistance in extrapulmonary samples

PurposeCartridge based nucleic acid amplification test (CBNAAT) has been endorsed by the WHO as the screening test for diagnosing extrapulmonary tuberculosis (EPTB). In the present study we report the agreement between CBNAAT (Xpert MTB/RIF), liquid culture (LC) and line probe assay (LPA) for diagnosis of Mycobacterium tuberculosis and detection of drug resistance among EPTB cases.MethodsThe EP samples were subjected to CBNAAT (Xpert MTB/RIF, Cepheid, USA) and wherever possible, to LC (MGIT 960, Becton Dickinson, USA) followed sequentially by first line and second line-LPA (FL-LPA, SL-LPA, Hain Lifescience, Germany) on the isolates.ResultsTotal 566/4080 (13.9%) EP samples were detected positive for M. tuberculosis on CBNAAT. Aspirates from lymph nodes were most often positive (11/30; 36.6%), followed by pus (240/873; 27.5%) and CSF samples (166/104; 15.8%). The detection of M. tuberculosis was more in adults than children except in tissue biopsy samples. Rifampicin resistance was also higher among adults except CSF in which resistance was more in children. Total 185 of 566 (32.7%) CBNAAT positive and 770 of 3510 (21.9%) CBNAAT negative samples could be cultured of which 110/185 (59.4%) and 33/770 (4.3%) respectively turned positive. FL-LPA and SL-LPA of 143 culture isolates showed that 27 isolates had drug resistance, of which 3 (2.1%) were XDR, 11 (7.7%) were Pre-XDR (FQ) and 13 (9.1%) were MDR. Of these 27 resistant isolates, 12 were negative by CBNAAT and two were mislabeled as Rifampicin sensitive or indeterminate based on the unique RpoB gene mutation patterns on LPA. The positive and negative agreements between LC and CBNAAT for detection of M. tuberculosis were 67.1% and 92.7% respectively and between LPA and CBNAAT for rifampicin resistance detection were 98.9% and 92.9% respectively.ConclusionsFor EPTB, CBNAAT should be accompanied with LC wherever possible irrespective of the CBNAAT result.     

Checkpoint Blockade Immunotherapy Induces Dynamic Changes in PD-1−CD8+ Tumor-Infiltrating T Cells

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