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Abstract: During the last decade, the extracellular molecular chaperone HSP90 (eHSP90) has been identified as a critical effector in cancer cell invasion and metastasis by virtue of its interaction with a diverse cohort of molecules that serve as key nodal points in oncogenic pathways. Thus eHSP90 has most recently emerged as a novel target in cancer therapeutics, subsequently becoming the focus of several drug development efforts. This review highlights recent studies on the mechanisms through which eHSP90 exhibits its tumor cell invasion action. It also presents latest efforts to translate this cumulative knowledge into clinical practice to disable eHSP90-driven metastasis. Keywords: Cancer therapeutics, wound healing, cell impermeable antibodies, signal transduction, pro-motility factors, extracellular.Download Full Article |
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Abstract: Background: Colorectal cancer (CRC) is a significant healthcare burden worldwide and in the Middle East (ME). KRAS mutation confers resistance to epidermal growth factor receptor (EGFR) inhibitors in the treatment of advanced CRC. Data regarding the rate of KRAS mutation from the ME are scattered and scarce. We aim to collect and review all sizable studies evaluating the frequency of KRAS mutations in CRC patients from the ME. Method: A Pubmed and Google Scholar search was conducted using keywords including KRAS, K-ras, colorectal cancer and Middle East, along with names of each ME country. Studies including over 90 patients were included in the review. Result: Eleven studies containing more than 90 patients were identified. Among all eleven studies, KRAS mutation rate ranged from 13 to 56%. Five studies reported KRAS mutation rate in M1 stage either exclusively or as part of subgroup analysis. In these studies, mutations were found in 8-45% of cases. KRAS mutations were associated with female gender, M1 stage and high CEA in 3, 2, and 1 studies respectively. Conclusion: There is a broad range of variability in KRAS mutation rate reported in different studies from the ME. This may have been due to small number of patients in the studies and lack of centralized testing for KRAS mutations. Larger and more coordinated studies from the ME population are required to ascertain the accuracy of KRAS mutation rate. Keywords: KRAS mutation, colorectal cancer, Middle East, EGFR Inhibitors.Download Full Article |
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Abstract: Objective:Gleason scores, as determined by 18-gauge core needle biopsies (NB), were compared with both Gleason scores and the pathological staging of corresponding radical prostatectomy( RP) specimens. The goal was to evaluate the clinical implication and the prognostic impact of these discrepancies. Methods: Records of 234 consecutive patients undergoing a radical retro pubic prostatectomy between 2001 and 2012 were reviewed. In total, all our patients were enrolled, al1 of whom had been diagnosed with adenocarcinoma by transrectal needle biopsies using an 18-gauge automated spring-loaded biopsy gun. Results: Grading errors were greatest with wel1-differentiated tumors. The accuracy was 18 (23%) for Gleason scores of 2-4 on needle biopsy. Of the 108 evaluable patients with Gleason scores of 5-7 on needle biopsy, 84 (78%) were graded correctly. All of the Gleason scores of 8-10 on needle biopsy were graded correctly. 54 of 162 patients (33%), with a biopsy Gleason score of < 7 had their cancer upgraded to above 7. Tumors in 18 patients (60%) with both a Gleason score < 7 on the needle biopsy and a Gleason score of 7 for the prostatectomy specimen were confined to the prostate. Conclusion: The potential for grading errors is greatest with well-differentiated tumors and in patients with a Gleason score of < 7 on the needle biopsy. Predictions using Gleason scores are sufficiently accurate to warrant its use with all needle biopsies, recognizing that the potential for grading errors is greatest with well-differentiated tumors. Keywords: Prostate adenocarcinoma, needle biopsy, radical prostatectomy, Gleason score correlation, prognostic significance.Download Full Article |
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Abstract: GHK (glycyl-L-histidyl-L-lysine) is a human plasma copper-binding peptide that declines during aging. Numerous studies have established many biological actions of GHK: it improves tissue regeneration, possesses anti-oxidant and anti-inflammatory effects, increases cellular stemness; increases decorin, angiogenesis, and nerve outgrowth. In recent studies, GHK was found to switch gene expression from a diseased state to a healthier state for certain cancers and for chronic obstructive pulmonary disease. In studies of aggressive, metastatic human colon cancer, the Broad Institute's Connectivity Map indicated that GHK, out of 1,309 bioactive molecules studied, reversed the expression of 70% of 54 genes over-expressed genes. GHK also reactivates programmed cell death in several cultured human cancer lines. To determine GHK's potential as a cancer treatment, we analyzed the molecule's effect on the human gene expression using the Connectivity Map. GHK induces a 50% or greater change of expression in 31.2% of human genes. GHK increased gene expression in 6 of the 12 human caspase genes that activate programmed cell death. In 28 other genes, GHK altered the pattern of gene expression in a manner that would be expected to inhibit cancer growth. For DNA repair genes, there was a one-sided increase in the expression of such genes (47 UP, 5 DOWN). A previous study found that a copper peptide plus ascorbic acid inhibited Ehrlich ascites cancer in mice. Using this method with GHK-copper gave a strong suppression of Sarcoma 180 in mice. These results support the idea that GHK may help to impede or suppress cancer growth. Keywords: Copper peptides, cancer therapy, cancer inhibition, sarcoma, connectivity map. Download Full Article |
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Abstract: Hepatocellular carcinoma (HCC) has a progression considered to be dependent on angiogenesis. Intratumoral microvessel density (MVD) has been associated with metastasis and recurrence risk; however, selection bias, counting errors, and lack of standardized assessment criteria have limited the clinical utility of angiogenesis quantitation. Therefore, we analyzed HCC angiogenesis with image cytometry using different methods and determined the correlation to prognosis. Tissue microarrays with 135 HCCs were CD31 and CD34 immunostained and quantitated with the Dako ACIS III Image Cytometer labeling index (LI) and Aperio Scanscope XT and MVD algorithm. LI and MVD were compared to each other and to pathologic features and prognosis (recurrence free survival). Using median cutoffs of microvesselquantitation, survival curve analysis showed a statistically significant difference between CD31 MVD algorithm measurement and prognosis (low MVD mean survival = 56.6 months and high MVD mean = 26.5 months; Log-Rank P = 0.0076). Survival was not significantly related to CD31 LI, CD34 LI or CD34 MVD. By linear regression, a direct correlation was observed between CD31 and CD34 using MVD (r = 0.45, P <0.0001), between CD31 MVD and CD31 LI (r = 0.55, P < 0.0001), and between CD31 LI and CD34 LI (r = 0.51, P < 0.0001). In addition, there was a weak but statistically significant relationship between CD31 MVD and CD34 LI (r = 0.25, P = 0.0050). Together, this data confirms previous studies linking angiogenesis to disease prognosis and suggests the utility of MVD image analysis algorithms. Keywords: Hepatocellular carcinoma, microvessel density, immunohistochemistry, prognosis.Download Full Article |