Novel approaches to modulate apoptosis resistance: basic and clinical implications in the treatment of chronic lymphocytic leukemia (CLL)

Chronic lymphocytic leukemia (CLL) is an archetype of malignancy resulting from defects in apoptosis. CLL is an exclusive accumulative disorder marked by low proliferative activity and gradual accumulation of clonal B-lymphocytes blocked in the early (G0, G1) phases of the cell cycle. The heterogeneous clinical course indicates diverse in vivo biology of the leukemic cell and suggests that CLL represents diverse behavior. Understanding the molecular biology of the disease has provided insight into the mechanisms that promote tumorigenesis, specifically defective apoptotic signaling pathways. In this review we attempt to provide a comprehensive discussion of CLL including the origin of malignant lymphocytes, the apoptotic defects and the mechanisms leading to disease progression. We further discuss the therapeutic options, focusing mainly on targeted therapy using novel agents. Finally, we suggest future directions for treatment that utilize the understanding of the disease biology.     

Human leukocyte antigen (HLA) class II association with rheumatic heart disease in Pakistan

BACKGROUND AND AIM of the study: Rheumatic heart disease (RHD) is widespread in Pakistan. Specific alleles of the human leukocyte antigen (HLA) system are associated with RHD in various world populations. The study aim was to investigate the involvement of HLA class II alleles in genetic susceptibility to RHD in patients with relatively homogeneous clinical manifestations, in Pakistan. METHODS: Blood samples were collected from 114 unrelated patients (94 females, 20 males) with rheumatic mitral valve disease, predominantly mitral stenosis, as assessed by echocardiography. The control group comprised 109 unrelated, ethnically matched, healthy individuals (60 females, 49 males) with normal echocardiograms. Genomic DNA was extracted from venous blood using a standard phenol/chloroform extraction procedure. HLA-DRB, -DQA1, and -DQB1 alleles were typed using polymerase chain reaction with sequence-specific primers. HLA allele and haplotypes frequencies were then calculated. RESULTS: A significantly higher frequency of DRB1*07 was observed in patients as compared to controls (one-way parametric analysis of variance, F = 4.84, p = 0.028; OR = 1.76, p = 0.039). No alleles for the HLA-DQA1 or -DQB1 loci were associated with the disease. HLA-DRB1*07-DQA1*0501-DQB1*02, the only haplotype that differed significantly between patients and controls (one-way parametric Anova, F = 4.866, p = 0.028; OR = 7.33, p = 0.06), did not exhibit significant linkage disequilibrium. CONCLUSION: These results show that HLA-DRB1*07, associated with RHD in various world populations, is also associated with RHD in the Pakistani population. The validation of HLA associations with RHD, which is observed in different world populations, may lead to the development of a cost-effective strategy in the primary prevention of this disease.     

Palliative surgery for advanced stage (stage IV) gastric adenocarcinoma

BACKGROUND/AIMS: The factors that effect resectability, major morbidity, early mortality, and survival in advanced stage gastric adenocarcinoma patients are evaluated. METHODOLOGY: Records of 74 patients that underwent surgery for stage IV gastric adenocarcinoma in the Third Surgical Clinic of Izmir Atatürk Training Hospital between January 1997 and January 2004 were reviewed retrospectively. Two groups (the patients with resectable disease and those with unresectable disease) were compared with regard to age, gender, primary complaint, symptoms, site of the tumor, involvement of adjacent organs, lymph node involvement, distant metastases, differentiation of tumor, surgical procedure, perioperative blood transfusions, and postoperative hospital stay. RESULTS: Mean age of the 74 patients was 58.4 years. Forty-five cases (60.8%) were considered as unresectable and 29 (39.2%) patients underwent a palliative resection. There was a significant relation between resectability and site of the tumor, and severity of invasion. As the number of perioperative blood transfusions increased, morbidity and mortality increased significantly. Although early mortality was high in the palliative resection group, survival (mean 10.4 months, longest 25 months) was better compared to that of the unresectable gastric cancer group (mean 3.5 months, longest eight months). CONCLUSIONS: A palliative gastric surgery may be applied to improve prognosis of advanced gastric cancer patients, even at the presence of peritoneal dissemination, hepatic metastases, N3 lymph node involvement, adjacent organ invasion, or poor differentiation of the tumor.     

The Time Interval from the Initiation of the P‐Wave to the Start of Left Atrial Appendage Ejection Flow: Does It Reflect İnteratrial Conduction Time?

Recurrence of atrial fibrillation is more common in patients with atrial conduction delay. In the present study, we evaluated whether findings obtained from transesophageal echocardiography (TEE), a semi-invasive method, correlate with those from an invasive method, electrophysiologic study (EPS), in measuring interatrial conduction time. METHODS AND RESULTS: We compared two methods of calculating interatrial conduction time in a group of 33 patients. The origin of the P-wave on the surface electrocardiogram (ECG) was taken as the onset of atrial activation. The time interval from this point to the commencement of the left atrial appendage ejection flow (P-LAA) was measured by TEE. Meanwhile, simultaneous recordings of the left atrial appendage were obtained with a catheter positioned in the LAA, and an invasive interatrial conduction time was measured from the origin of the surface's earliest P-wave (I-IACT). The mean I-IACT (46.27 +/- 13.25 ms) correlated strongly with the mean P-LAA (49.91 +/- 12.72 ms; r = 0.839, P < 0.0001). CONCLUSION: The interatrial conduction time can be estimated with a relatively noninvasive method using P-LAA measurements. This technique can be applied widely in predicting AF recurrence, and appropriate therapy may be applied.     

Inhibition of ovarian cancer cell metastasis by a fusion polypeptide Tat-ELP

Tumor cell metastasis is a complex, multi-step process that is a major cause of death and morbidity amongst cancer patients. Cell adhesion plays a critical role in the development of metastatic cancer, and it is mediated by interactions between receptors on the cell surface and ligands of the extracellular matrix or other surfaces. Therefore, inhibition of the cell adhesion process appears to be an effective method of preventing metastasis. This work describes a genetically engineered polypeptide with the potential to prevent cell adhesion and inhibit metastasis. We have found that the cell penetrating peptide Tat, fused with elastin-like polypeptide (ELP) inhibited adhesion, spreading, invasion and migration of SKOV-3 ovarian cancer cells in cell culture. Furthermore, we have also confirmed that Tat-ELP has anti-metastatic potential in an experimental ovarian cancer metastasis model in vivo, causing approximately 80% reduction in the tumor burden. Since cell attachment is an important step in tumor cell invasion and metastasis, these results suggest a novel role of Tat-ELP as a therapeutic intervention in cancer metastasis. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.