Virtual colonoscopy an alternative to fecal occult blood test and colonoscopy for colorectal cancer screening?

from Cancer via ola Kala on Inoreader http://ift.tt/1R0bLDn
via IFTTT

Reduced and Full-Preparation CT Colonography, Fecal Immunochemical Test, and Colonoscopy for Population Screening of Colorectal Cancer: A Randomized Trial

Background:

Population screening for colorectal cancer (CRC) is widely adopted, but the preferred strategy is still under debate. We aimed to compare reduced (r-CTC) and full cathartic preparation CT colonography (f-CTC), fecal immunochemical test (FIT), and optical colonoscopy (OC) as primary screening tests for CRC.

Methods:

Citizens of a district of Florence, Italy, age 54 to 65 years, were allocated (8:2.5:2.5:1) with simple randomization to be invited by mail to one of four screening interventions: 1) biennial FIT for three rounds, 2) r-CTC, 3) f-CTC, 4) OC. Patients tested positive to FIT or CTC (at least one polyp ≥6mm) were referred to OC work-up. The primary outcomes were participation rate and detection rate (DR) for cancer or advanced adenoma (advanced neoplasia). All statistical tests were two-sided.

Results:

Sixteen thousand eighty-seven randomly assigned subjects were invited to the assigned screening test. Participation rates were 50.4% (4677/9288) for first-round FIT, 28.1% (674/2395) for r-CTC, 25.2% (612/2430) for f-CTC, and 14.8% (153/1036) for OC. All differences between groups were statistically significant (P = .047 for r-CTC vs f-CTC; P < .001 for all others). DRs for advanced neoplasia were 1.7% (79/4677) for first-round FIT, 5.5% (37/674) for r-CTC, 4.9% (30/612) for f-CTC, and 7.2% (11/153) for OC. Differences in DR between CTC groups and FIT were statistically significant (P < .001), but not between r-CTC and f-CTC (P = .65).

Conclusions:

Reduced preparation increases participation in CTC. Lower attendance and higher DR of CTC as compared with FIT are key factors for the optimization of its role in population screening of CRC.

from Cancer via ola Kala on Inoreader http://ift.tt/1JKLQaA
via IFTTT

Human Leukocyte Antigen-Presented Macrophage Migration Inhibitory Factor is a Surface Biomarker and Potential Therapeutic Target for Ovarian Cancer

T cells recognize cancer cells via human leukocyte antigen (HLA)/peptide complexes and, when disease overtakes these immune mechanisms, immunotherapy can exogenously target these same HLA/peptide surface markers. We previously identified an HLA-A2-presented peptide derived from macrophage migration inhibitory factor (MIF) and generated antibody RL21A against this HLA-A2/MIF complex. The objective of the current study was to assess the potential for targeting the HLA-A2/MIF complex in ovarian cancer. First, MIF peptide FLSELTQQL was eluted from the HLA-A2 of the human cancerous ovarian cell lines SKOV3, A2780, OV90, and FHIOSE118hi and detected by mass spectrometry. By flow cytometry, RL21A was shown to specifically stain these four cell lines in the context of HLA-A2. Next, partially matched HLA-A*02:01+ ovarian cancer (n=27) and normal fallopian tube (n=24) tissues were stained with RL21A by immunohistochemistry to assess differential HLA-A2/MIF complex expression. Ovarian tumor tissues revealed significantly increased RL21A staining compared to normal fallopian tube epithelium (p<0.0001), with minimal staining of normal stroma and blood vessels (p<0.0001 and p<0.001 compared to tumor cells) suggesting a therapeutic window. We then demonstrated the anti-cancer activity of toxin-bound RL21A via the dose-dependent killing of ovarian cancer cells. In summary, MIF-derived peptide FLSELTQQL is HLA-A2-presented and recognized by RL21A on ovarian cancer cell lines and patient tumor tissues, and targeting of this HLA-A2/MIF complex with toxin-bound RL21A can induce ovarian cancer cell death. These results suggest that the HLA-A2/MIF complex should be further explored as a cell-surface target for ovarian cancer immunotherapy.

from Cancer via ola Kala on Inoreader http://ift.tt/1R9KQmI
via IFTTT

A cyclin-dependent kinase inhibitor, dinaciclib, impairs homologous recombination and sensitizes multiple myeloma cells to PARP inhibition

Poly(ADP-ribose) polymerases 1 and 2 (PARP1/2) are required for single-strand break repair, and their inhibition causes DNA replication-fork collapse and double-strand break (DSB) formation. These DSBs are primarily repaired via homologous recombination (HR), a high-fidelity repair pathway. Should HR be deficient, DSBs may be repaired via error-prone nonhomologous end-joining mechanisms, or may persist, ultimately resulting in cell death. Synthetic lethality thus exists between PARP and HR functions. Multiple myeloma (MM) cells are characterized by chromosomal instability and pervasive DNA damage, implicating aberrant DNA repair. Cyclin-dependent kinases (CDKs), upstream modulators of HR, are dysregulated in MM. Here we show that a CDK inhibitor, dinaciclib, impairs HR repair and sensitizes MM cells to the PARP1/2 inhibitor ABT-888. Dinaciclib abolishes ABT-888-induced BRCA1 and RAD51 foci and potentiates DNA damage, indicated by increased H2AX foci. Dinaciclib treatment reduces expression of HR-repair genes, including Rad51, and blocks BRCA1 phosphorylation, a modification required for HR repair, thus inhibiting HR repair of chromosomal DSBs. Co-treatment with dinaciclib and ABT-888 in vitro resulted in synthetic lethality of MM cells, but not normal CD19⁺ B cells, and slowed growth of MM xenografts in SCID mice almost two-fold. These findings support combining dinaciclib with PARP inhibitors for MM therapy.

from Cancer via ola Kala on Inoreader http://ift.tt/1R9KQ6e
via IFTTT

The role of HMGB1 in radio-resistance of bladder cancer.

Although radical cystectomy surgery is the standard of care for muscle-invasive bladder cancer, it entails complete removal of the bladder and surrounding organs which leads to substantial loss in patient quality of life. Radiation therapy, which spares the bladder, would be a more appropriate treatment modality if we can utilize molecular markers to select patients with better response to radiation. In this study we investigate a protein called HMGB1 (High Mobility Group Box protein 1) as a predictive marker for radiation therapy response in bladder cancer. Our in vitro results indicate a positive correlation between higher levels of HMGB1 protein and resistance to radiation in various cell lines. Upon HMGB1 protein knockdown highly significant (more than 1.5 fold) sensitization to radiation therapy was achieved. We saw that loss of HMGB1 was associated with atleast 2 times higher (P<0.001) DNA damage in cell lines post radiation. Our results also depicted that autophagy was inhibited more than 3 fold (P<0.001) upon HMGB1 knockdown implicating its role in autophagy as another cause of bladder cancer radioresistance. Further validation was done in vivo by conducting mice tumor xenograft experiments, where HMGB1 knockdown tumors showed a significantly better (P<0.001) response to radiation therapy and decreased autophagy (shown by P62 staining) as compared to controls. The cumulative findings of our in vitro and in vivo studies highlight the significance of HMGB1 as a radiation response marker as well as its utility in radio-sensitization of bladder cancer.

from Cancer via ola Kala on Inoreader http://ift.tt/1R9KSuS
via IFTTT

Optimization of RGD containing cyclic peptides against {alpha}v{beta}3 integrin

We have previously reported the use of one-bead-one-compound (OBOC) combinatorial technology to develop a disulfide cyclic, Arg-Gly-Asp containing octapeptide LXW7 (cGRGDdvc), that targets αvβ3 integrin with high affinity and specificity (Mol Cancer Ther, 9:2714-23, 2010). αvβ3 integrin is known to be over-expressed in many cancers and in tumor vasculature, and it has been established as a cancer therapeutic target. To further optimize LXW7, we have performed systematic structure activity relationship (SAR) studies. Based on the results, two highly focused OBOC peptide libraries were designed, synthesized and screened against αvβ3 integrin transfected K562 cells. One of the best ligands, LXW64 was found to have 6.6-fold higher binding affinity than LXW7, and showed preferential binding to cells expressing αvβ3 integrin. In addition to binding strongly to U-87MG glioblastoma cells in vitro, LXW64 also targets U-87MG xenografts implanted in nude mice, indicating that it is an excellent vehicle for delivery of cytotoxic payload to tumors and tumor blood vessels that overexpress αvβ3 integrin.

from Cancer via ola Kala on Inoreader http://ift.tt/1R9KSuM
via IFTTT

An HRE-binding Py-Im polyamide impairs hypoxic signaling in tumors.

Hypoxic gene expression contributes to the pathogenesis of many diseases, including organ fibrosis, age-related macular degeneration and cancer. HIF-1, a transcription factor central to the hypoxic gene expression, mediates multiple processes including neovascularization, cancer metastasis and cell survival. Py-Im polyamide 1 has been shown to inhibit HIF-1-mediated gene expression in cell culture but its activity in vivo was unknown. This study reports activity of polyamide 1 in subcutaneous tumors capable of mounting a hypoxic response and showing neovascularization. We show that 1 distributes into subcutaneous tumor xenografts and normal tissues, reduces the expression of proangiogenic and prometastatic factors, inhibits the formation of new tumor blood vessels and suppresses tumor growth. Tumors treated with 1 show no increase in HIF-1a and have reduced ability to adapt to the hypoxic conditions, as evidenced by increased apoptosis in HIF-1a positive regions and the increased proximity of necrotic regions to vasculature. Overall, these results show that a molecule designed to block the transcriptional activity of HIF-1 has potent anti-tumor activity in vivo, consistent with partial inhibition of the tumor hypoxic response.

from Cancer via ola Kala on Inoreader http://ift.tt/1P1ao0T
via IFTTT