Molecular characterization of mar,a multiple aberration region on human chromosome segment 12q13-q15 implicated in various solid tumors

Chromosome arm 12q breakpoints in seven cell lines derived from primary pleomorphic salivary gland adenomas were mapped by FISH analysis relative to nine DNA probes. These probes all reside in a 2.8 Mb genomic DNA region of chromosome segment 12q13-q15 and correspond to previously published sequence-tagged sites (STS). Their relative positions were established on the basis of YAC cloning and long range physical and STS content mapping. The 12q breakpoints of five of the cell lines were found to be mapping within three different subregions of the 445 kb DNA interval that was recently defined as the uterine leiomyoma cluster region of chromosome 12 breakpoints (ULCR12) between STS RM33 and RM98. All seven breakpoints appeared to map within the 1.7 Mb DNA region between STS RM36 and RM103. Furthermore, the chromosome 12 breakpoints of three primary pleomorphic salivary gland adenomas were also found to be mapping between RM36 and RM103. Finally, FISH analysis of two lipoma cell lines with 12q13-q15 aberrations pinpointed the breakpoints of these to relatively small and adjacent DNA segments which, as well as those of two primary lipomas, appeared to be located also between RM36 and RM103. We conclude from the observed clustering of the 12q breakpoints of the three distinct solid tumor types that the 1.7 Mb DNA region of the long arm of chromosome 12 between RM36 and RM103 is a multiple aberration region which we designate MAR.     

Clonally expanded CD4+CD28null T cells in rheumatoid arthritis use distinct combinations of T cell receptor BV and BJ elements

Clonally expanded, autoreactive CD4(+)CD28(null) cells can be found in the peripheral blood of patients with rheumatoid arthritis and have been shown to be associated with severeextra-articular disease manifestations. We investigated the size of the CD4(+)CD28(null) compartment and the TCR beta chain repertoire of expanded CD4(+) clonotypes in 94 rheumatoid arthritis patients by complementarity-determining region 3 (CDR3) length analysis (spectratyping) in the BV6 and BV14 TCR families, with primers specific for three arbitrarily chosen beta chain joining elements (BJ1S2, BJ2S3 and BJ2S7). The spectratyping results showed a strong correlation of the size of the CD4(+)CD28(null) compartment with the detected number of BV14 clonotypes, whereas no association with BV6 oligoclonality was found. Only clones using the BV14-BJ1S2 and BV14-BJ2S3 combinations contributed to this correlation, however, whereas BV14-BJ2S7 clones did not. This preferential correlation implies a role for the TCR beta chain in stimulating clonal outgrowth and argues against the previously suggested superantigenic stimulation of in-vivo-expanded clones. Instead, since no evidence for shared antigen specificity could be detected, clonal expansion of T cells in rheumatoid arthritis might be influenced by the BJ elements because of changes in the flexibility of the protein backbone of the beta-chain.     

Peripheral snap-fit locking mechanisms and smooth surface finish of tibial trays reduce backside wear in fixed-bearing total knee arthroplasty

Background and purpose — Severe backside wear, observed in older generations of total knee replacements (TKRs), led to redesign of locking mechanisms to reduce micromotions between tibial tray and inlay. Since little is known about whether this effectively reduces backside wear in modern designs, we examined backside damage in retrievals of various contemporary fixed-bearing TKRs.

Patients and methods — A consecutive series of 102 inlays with a peripheral (Stryker Triathlon, Stryker Scorpio, DePuy PFC Sigma, Aesculap Search Evolution) or dovetail locking mechanism (Zimmer NexGen, Smith and Nephew Genesis II) was examined. Articular and backside surface damage was evaluated using the semiquantitative Hood scale. Inlays were examined using scanning electron microscopy (SEM) to determine backside wear mechanisms.

Results — Mean Hood scores for articular (A) and backside (B) surfaces were similar in most implants—Triathlon (A: 46, B: 22), Genesis II (A: 55, B: 24), Scorpio (A: 57, B: 24), PFC (A: 52, B: 20); Search (A: 56, B: 24)—except the NexGen knee (A: 57, B: 60), which had statistically significantly higher backside wear scores. SEM studies showed backside damage caused by abrasion related to micromotion in designs with dovetail locking mechanisms, especially in the unpolished NexGen trays. In implants with peripheral liner locking mechanism, there were no signs of micromotion or abrasion. Instead, “tray transfer” of polyethylene and flattening of machining was observed.

Interpretation — Although this retrieval study may not represent well-functioning TKRs, we found that a smooth surface finish and a peripheral locking mechanism reduce backside wear in vivo, but further studies are required to determine whether this actually leads to reduced osteolysis and lower failure rates.     

Neurocognitive,symptom, and health-related quality of life outcomes of a randomized trial of bevacizumab for newly diagnosed glioblastoma (NRG/RTOG 0825)

BackgroundResults of NRG Oncology RTOG 0825 reported adding bevacizumab to standard chemoradiation did not significantly improve survival endpoints and resulted in greater decline in neurocognitive function (NCF) and patient-reported outcomes (PRO) over time in bevacizumab-treated patients. The present report provides additional results of patient-centered outcomes over time and their prognostic association with survival endpoints.MethodsNCF tests, MD Anderson Symptom Inventory - Brain Tumor Module (MDASI-BT), and European Organization for Research and Treatment of Cancer (EORTC) quality of life (QOL) questionnaire with brain cancer module (QLQ-C30/BN20) were completed in a subset of progression-free patients at baseline and longitudinally. The prognostic value of baseline and early changes in NCF and PROs and differences between treatments from baseline to follow-up assessments were evaluated.ResultsA total of 508 randomized patients participated. Baseline/early changes in NCF and PROs were prognostic for OS and PFS. No between-arm differences in time to deterioration were found. At week 6, patients treated with bevacizumab evidenced greater improvement on NCF tests of executive function and the MDASI-BT Cognitive Function scale, but simultaneously reported greater decline on the EORTC Cognitive Function Scale. At later time points (weeks 22, 34, and 46), patients treated with bevacizumab had greater worsening on NCF tests as well as PRO measures of cognitive, communication, social function, motor symptoms, general symptoms, and interference.ConclusionThe collection of patient-centered clinical outcome assessments in this phase III trial revealed greater deterioration in NCF, symptoms, and QOL in patients treated with bevacizumab. Baseline and early change in NCF and PROs were prognostic for survival endpoints.     

Early detection of regional cerebral ischemia in cats: comparison of diffusion- and T2-weighted MRI and spectroscopy

Diffusion-weighted MR images were compared with T2-weighted MR images and correlated with 1H spin-echo and 31P MR spectroscopy for 6-8 h following a unilateral middle cerebral and bilateral carotid artery occlusion in eight cats. Diffusion-weighted images using strong gradient strengths (b values of 1413 s/mm2) displayed a significant relative hyperintensity in ischemic regions as early as 45 min after onset of ischemia whereas T2-weighted spin-echo images failed to clearly demonstrate brain injury up to 2-3 h postocclusion. Signal intensity ratios (SIR) of ischemic to normal tissues were greater in the diffusion-weighted images at all times than in either TE 80 or TE 160 ms T2-weighted MR images. Diffusion- and T2-weighted SIR did not correlate for the first 1-2 h postocclusion. Good correlation was found between diffusion-weighted SIR and ischemic disturbances of energy metabolism as detected by 31P and 1H MR spectroscopy. Diffusion-weighted hyperintensity in ischemic tissues may be temperature-related, due to rapid accumulation of diffusion-restricted water in the intracellular space (cytotoxic edema) resulting from the breakdown of the transmembrane pump and/or to microscopic brain pulsations.