Abstract: The TP73 gene is a member of the TP53 family with high structural homology to p53 and capable of transactivating p53 target genes. The TP73 gene locus which is highly conserved and complex, encodes for two classes of isoforms TAp73 (tumor suppressor isoforms containing the transactivation domain) and ΔNp73 (oncogenic isoforms, truncated and lacking the transactivation domain) with opposing effects. The balance between TAp73 and ΔNp73 isoforms and their harmony with other members of the TP73 family regulate various cellular responses such as apoptosis, autophagy, proliferation, and differentiation. The transcriptionally active isoforms of p73 are capable of inducing apoptosis in cancer cells independent of p53 status. Unlike p53, p73 is rarely mutated in cancers, however, the ratio of ΔNp73:TAp73 is frequently up-regulated in many carcinomas and is indicative of poor prognosis. Moreover, p73 is an important determinant of chemosensitivity and radiosensitivity, the two major treatment modalities for lymphoma. In the current review, we will provide an overview of recent progress discussing the role of TP73 in cancer, specifically addressing its relevance to lymphomagenesis, progression, therapy resistance, and its potential as a novel therapeutic target.

The TP73 gene is located at the chromosome 1p36 locus that is commonly disrupted or deleted in follicular lymphoma (FL) with poor prognosis. Therefore, we analyzed the expression of the pro-apoptotic TAp73 and anti-apoptotic ΔNp73 isoforms in cases of FL with normal or abnormal 1p36. We observed a significant increase in ΔNp73 expression and ΔNp73:TAp73 ratio, lower expression of cleaved caspase-3 and a higher frequency of Ki-67 and proliferating cell nuclear antigen (PCNA) positive cells in cases of FL with abnormal 1p36. A negative correlation between the ΔNp73:TAp73 ratio and cleaved caspase-3 expression, and a positive correlation between ΔNp73 expression and Ki-67 or PCNA, were observed. The expression of TAp73 and its pro-apoptotic transcriptional targets BIM. PUMA and NOXA were significantly lower in FL compared to reactive follicular hyperplasia. Together, our data demonstrate that 1p36 disruption is associated with increased ΔNp73 expression, decreased apoptosis and increased proliferation in FL. Read More: http://informahealthcare.com/doi/abs/10.3109/10428194.2014.900759

Background KIAA1199 is a recently identified novel gene that is up-regulated in human cancer with poor survival. Our proteomic study on signaling polarity in chemotactic cells revealed KIAA1199 as a novel protein target that may be involved in cellular chemotaxis and motility. In the present study, we examined the functional significance of KIAA1199 expression in breast cancer growth, motility and invasiveness. Methods We validated the previous microarray observation by tissue microarray immunohistochemistry using a TMA slide containing 12 breast tumor tissue cores and 12 corresponding normal tissues. We performed the shRNA-mediated knockdown of KIAA1199 in MDA-MB-231 and HS578T cells to study the role of this protein in cell proliferation, migration and apoptosis in vitro. We studied the effects of KIAA1199 knockdown in vivo in two groups of mice (n = 5). We carried out the SILAC LC-MS/MS based proteomic studies on the involvement of KIAA1199 in breast cancer. Results KIAA1199 mRNA and protein was significantly overexpressed in breast tumor specimens and cell lines as compared with non-neoplastic breast tissues from large-scale microarray and studies of breast cancer cell lines and tumors. To gain deeper insights into the novel role of KIAA1199 in breast cancer, we modulated KIAA1199 expression using shRNA-mediated knockdown in two breast cancer cell lines (MDA-MB-231 and HS578T), expressing higher levels of KIAA1199. The KIAA1199 knockdown cells showed reduced motility and cell proliferation in vitro. Moreover, when the knockdown cells were injected into the mammary fat pads of female athymic nude mice, there was a significant decrease in tumor incidence and growth. In addition, quantitative proteomic analysis revealed that knockdown of KIAA1199 in breast cancer (MDA-MB-231) cells affected a broad range of cellular functions including apoptosis, metabolism and cell motility. Conclusions Our findings indicate that KIAA1199 may play an important role in breast tumor growth and invasiveness, and that it may represent a novel target for biomarker development and a novel therapeutic target for breast cancer.

Objectives:I-123 is considered an ideal isotope for diagnostic studies. A significant advantage of I-123 over I-131 is that, the radiation dose delivered is about 100-fold less. Consequently, potential ‘‘stunning’’ because of the dosimetry procedure prior to treatment would be less concerning. However, its relatively short half-life makes it impractical for a prolonged biokinetic study. The aim of the current study was to assess the relationship between actual I-131 retention and the success rate of I-131 ablation in differentiated thyroid carcinoma (DTC) following I-123 whole body scan (WBS). Patients and methods: 23 consecutive patients with newly diagnosed DTC (21 papillary, and 2 Follicular), underwent total or near total thyroidectomy, followed by I-123 WBS, and subsequent I-131 ablation were enrolled in current study. The whole body external exposure rate from the patient at 1 meter was measured immediately after ingestion of I-131, after 24 and 48 hours, using a calibrated Victoreen 451P ionization chamber survey meter (Fluke Biomedical, USA). The retained activity at 48h, and the whole body effective half-life for each patient were then calculated. Patients were classified according to their follow up data after 6 months into two groups; those who have successful ablation (Negative WBS and an undetectable serum thyroglobulin level in the absence of antithyroglobulin antibodies), and those who need reablation (Positive WBS and/ or elevated serum Thyroglobulin). Results: Of the 23 patients studied, 15 were considered to have successful ablation and 8 still need reablation. No significant difference regarding age, gender, histopathology, and activity of I-131 ablation dose between both groups. The retained I-131 activity at 48 hours was 13.50±3.87% of the administered dose, and the effective half life was 16.37±2.43 hours for patients who have successful ablation compared to 7.79±3.28% (p0.05), and 12.64±2.27 hours (p0.05) respectively for patients who need reablation. Conclusions:We found a significantly higher retained I-131 activity at 48 hours and longer effective half-life among patients successfully ablated compared to those who need reablation, and recommend dosimetric adjusted I-131 ablation dose whenever feasible accordingly.