Citations

The contribution of axial arm rotation to translation of the humeral head with the arm in the hanging position was examined using nine fresh-frozen cadaveric shoulders. Three standard clinical tests were simulated: anterior and posterior translation and sulcus tests. In both the anterior translation and sulcus tests, anterior and infe rior displacements were significantly restricted in inter nal rotation but not in neutral and external rotation. In the posterior translation test, no significant differences in displacement could be observed in internal, neutral, or external rotation. Since anterior and inferior translations of the humeral head were significantly affected by the rotation of the arm, we recommend that the anterior translation and sulcus tests be performed in various rotations.

The purpose of this study was to investigate the rela tionship of isometric and isokinetic endurance of the forearm complex under maximum effort in a healthy population. Isometric and isokinetic endurance meas urements of elbow flexion and extension of the domi nant and nondominant sides were made in 32 healthy male subjects (age range, 21 to 39 years). Both fatigue rates and the amount of time elapsed in reaching fatigue were determined. Analysis of these data reveals that 1) isometric endurance of the forearm complex cannot be used as a predictor of isokinetic endurance, as there is no relationship between the two, 2) dominant and non dominant endurance are related, a result that supports the belief that in the assessment of the endurance of a single diseased upper extremity, the best available comparison is with the contralateral healthy extremity, and 3) healthy males in the age range tested have greater endurance in elbow extension than in flexion.

Abstract Chronic lymphocytic leukemia (CLL) is commonly defined as a disease of failed apoptosis of B cells and remains an incurable disease. The mechanism of resistance to apoptosis in CLL is complex and influenced by numerous factors, including nuclear factor κB (NFκB)-mediated expression of antiapoptotic molecules. Recent evidence indicates that glycogen synthase kinase-3β (GSK-3β) positively regulates NFκB-mediated gene transcription and cell survival. Using malignant B cells collected from patients with CLL, we find that both GSK-3β and NFκB accumulate in the nucleus of CLL B cells, and pharmacologic inhibition of GSK-3 results in decreased expression of two NFκB target genes Bcl-2 and XIAP and a subsequent increase in CLL B-cell apoptosis ex vivo. Furthermore, we observed that inhibition of GSK-3 leads to a decrease in NFκB-mediated gene transcription but does not affect the nuclear accumulation of NFκB in CLL B cells. Last, using chromatin immunoprecipitation, we show that GSK-3 inhibition abrogates NFκB binding to its target gene promoters (XIAP, Bcl-2), in part through epigenetic modification of histones. Our results establish that inhibition of GSK-3 abrogates NFκB binding to its target gene promoters through an epigenetic mechanism, enhances apoptosis in CLL B cells ex vivo and identifies GSK-3 as a potential therapeutic target in the treatment of CLL.

AbstractBuilding on the prior work of use of pentostatin in chronic lymphocytic leukemia (CLL), we initiated a trial of combined pentostatin (2 mg/m2), cyclophosphamide (600 mg/m2), and rituximab (375 mg/m2) for 65 symptomatic, previously untreated patients. Of 64 evaluable patients, 34 (53%) were high Rai risk, 71% were nonmutated for the immunoglobulin heavy-chain variable region gene, 34% were CD38+, and 34% were ZAP-70+. Thirty patients (52%) had one anomaly detected by fluorescence in situ (FISH) hybridization, and 21 (36%) had complex FISH defects. Thirty-eight patients (58%) had grade 3+ hematologic toxicity but minimal transfusion needs and no major infections. Responses occurred in 58 patients (91%), with 26 (41%) complete responses (CRs), 14 (22%) nodular partial responses (nodular PRs), and 18 (28%) partial responses (PRs). Many patients with a CR also lacked evidence of minimal residual disease by 2-color flow cytometry. Examination of prognostic factors demonstrated poor response in the 3 patients with del(17p). In contrast, we found this regimen was equally effective in young versus older (> 70 years) patients and in del(11q22.3) versus other favorable prognostic factors. Thus, this novel regimen of pentostatin, cyclophosphamide, and rituximab for previously untreated patients with CLL demonstrated significant clinical activity despite poor risk-based prognoses, achievement of minimal residual disease in some, and modest toxicity.

Purpose Retrospective studies suggest cytogenetic abnormalities detected by interphase fluorescent in situ hybridization (FISH) can identify patients with chronic lymphocytic leukemia (CLL) who will experience a more aggressive disease course. Other studies suggest that patients may acquire chromosome abnormalities during the course of their disease. There are minimal prospective data on the clinical utility of the widely used hierarchical FISH prognostic categories in patients with newly diagnosed early-stage CLL or the frequency of clonal evolution as determined by interphase FISH. Patients and Methods Between 1994 and 2002, we enrolled 159 patients with previously untreated CLL (83% Rai stage 0/I) on a prospective trial evaluating clonal evolution by FISH. Patients provided baseline and follow-up specimens for FISH testing during 2 to 12 years. Results Chromosomal abnormalities detected by FISH at study entry predicted overall survival. Eighteen patients experienced clonal evolution during follow-up. The rate of clonal evolution increased with duration of follow-up with only one occurrence in the first 2 years (n = 71; 1.4%) but 17 occurrences (n = 63; 27%) among patients tested after 5+ years. Clonal evolution occurred among 10% of ZAP-70–negative and 42% of ZAP-70–positive patients at 5+ years (P = .008). Conclusion This clinical trial confirms prospectively that cytogenetic abnormalities detected by FISH can predict overall survival for CLL patients at the time of diagnosis, but also suggests that many patients acquire new abnormalities during the course of their disease. Patients with higher ZAP-70 expression may be more likely to experience such clonal evolution. These findings have important implications for both clinical management and trials of early treatment for patients with high-risk, early-stage CLL.

Abstract This study was undertaken to characterize preclinical cytotoxic interactions for human malignancies between the multikinase inhibitor sorafenib (BAY 43-9006) and proteasome inhibitors bortezomib or MG132. Multiple tumor cell lines of varying histiotypes, including A549 (lung adenocarcinoma), 786-O (renal cell carcinoma), HeLa (cervical carcinoma), MDA-MB-231 (breast), K562 (chronic myelogenous leukemia), Jurkat (acute T-cell leukemia), MEC-2 (B-chronic lymphocytic leukemia), and U251 and D37 (glioma), as well as cells derived from primary human glioma tumors that are likely a more clinically relevant model were treated with sorafenib or bortezomib alone or in combination. Sorafenib and bortezomib synergistically induced a marked increase in mitochondrial injury and apoptosis, reflected by cytochrome c release, caspase-3 cleavage, and poly(ADP-ribose) polymerase degradation in a broad range of solid tumor and leukemia cell lines. These findings were accompanied by several biochemical changes, including decreased phosphorylation of vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor-β, and Akt and increased phosphorylation of stress-related c-Jun NH2-terminal kinase (JNK). Inhibition of Akt was required for synergism, as a constitutively active Akt protected cells against apoptosis induced by the combination. Alternatively, the JNK inhibitor SP600125 could also protect cells from apoptosis induced by the combination, indicating that both inhibition of Akt and activation of JNK were required for the synergism. These findings show that sorafenib interacts synergistically with bortezomib to induce apoptosis in a broad spectrum of neoplastic cell lines and show an important role for the Akt and JNK pathways in mediating synergism. Further clinical development of this combination seems warranted. [Mol Cancer Ther 2006;5(9):2378–87]

Summary Nine fresh frozen cadaveric shoulders were used to examine the changes in intraarticular pressure (IAP) of the shoulder joint and the position of the humeral head under various loads to determine the relationship between these parameters. All the soft tissues superficial to the rotator cuff were removed. The position of the humerus relative to the scapula was monitored using an electromagnetic tracking system before and after venting the capsule with 0, 0.5, and 1.0 kg of load applied to the humerus inferiorly in addition to the weight of the arm. Simultaneously, the IAP was monitored using a pressure transducer before venting the capsule. Venting had a significant effect on the position of the humeral head: the positions of the head after venting were significantly lowered in all loading conditions. The average IAP was −76 cm H 2 O without load, and the value decreased in a linear fashion with increased load; the correlations were significant in four of six shoulders without dislocation. The correlations were less significant between the pressure and the position, and there were no significant correlations between the load and the position. IAP, which is determined primarily by the load applied, is important to stabilize the shoulder inferiorly. Because IAP is intimately related to the external load and the response is specific to individuals, examination of IAP response to external load may be helpful in characterizing various instabilities of the shoulder.