Prostate cancer: status of current treatments and emerging antisense-based therapies

Prostate cancer, like most other solid tumors, represents a heterogeneous entity consisting of a mixture of androgen-dependent and androgen-independent cells. Although proliferation of prostate tumor cells is often initially androgen-dependent, the inevitable development of androgen-insensitivity in late-stage prostate cancer renders androgen-suppressing treatments ultimately ineffective. Non-hormonal chemotherapy induces apoptosis in actively proliferating cells and is typically of little value, since prostate cancer demonstrates very slow growth kinetics. Objective response rates of < 10% and no improved survival rates have been observed in several hundred clinical studies using both experimental and approved chemotherapeutic agents. An improved understanding of the molecular mechanisms responsible for the onset of the disease, as well as the factors that control the proliferation of prostate cancer cells, have identified key changes in gene expression during cancer progression, especially from androgen-dependent to androgen-independent status. Manipulation of the genes implicated in disease progression represent an important approach for therapeutic intervention. This review summarizes recent progress that has been made with the use of antisense technology with various chemistries to modify gene expression, a strategy that seems to hold great promise for prostate cancer therapy.     

End-group effects on the properties of PEG-co-PGA hydrogels

A series of resorbable poly(ethylene glycol)-co-poly(glycolic acid) (PEG-co-PGA, 4KG5) macromonomers have been synthesized with the chemistries from three different photopolymerizable end-groups (acrylates, methacrylates and urethane methacrylates). The aim of the study is to examine the effects of the chemistry of the cross-linker group on the properties of photocross-linked hydrogels. 4KG5 hydrogels were prepared by photopolymerization with high vinyl group conversion as confirmed by ¹H nuclear magnetic resonance spectrometry using a 1D diffusion-ordered spectrometry pulse sequence. Our study reveals that the nature of end-groups in a moderately amphiphilic polymer can adjust the distribution and size of the micellar configuration in water, leading to changes in the macroscopic structure of hydrogels. By varying the chemistry of the cross-linker group (diacrylates (DA), dimethacrylates (DM) and urethane dimethacrylates (UDM)), we determined that the hydrophobicity of a single core polymer consisting of poly(glycolic acid) could be fine-tuned, leading to significant variations in the mechanical, swelling and degradation properties of the gels. In addition, the effects of cross-linker chemistry on cytotoxicity and proliferation were examined. Cytotoxicity assays showed that the three types of hydrogels (4KG5 DA, DM and UDM) were biocompatible and the introduction of RGD ligand enhanced cell adhesion. However, differences in gel properties and stability differentially affected the spreading and proliferation of myoblast C2C12 cells.     

Functional Impression Technique for an Ocular Prosthesis

The loss of an eye is the most devastating, psychologically damaging experience for a patient. All hope to bring such patients back to their accustomed and comfortable life-style rests on a cosmetically acceptable prosthesis. An intra-orbital ocular prosthesis serves the purpose in those defects where the orbital margins are intact. Though the stock eye may match the natural eye’s iris and sclera in color, the fit of the prosthesis to the tissue bed may not be as good as desired. Herein, a functional ocular impression technique is presented to achieve a better fit of the prosthesis to the defect area. This technique aims to combine cosmetic excellence with comfort for greater benefit to the patient.     

Association between family history of cancers and risk of prostate cancer

IntroductionFamily history of prostate cancer is an established risk factor for prostate cancer. However, the relationship between family history of cancers other than prostate cancer and prostate cancer risk is inconclusive. This study sought to examine the association between family history of cancers and prostate cancer.MethodsA case–control study was conducted in which cases and controls were randomly selected from a large urology clinic in Central Virginia. Cases were 600 histologically confirmed prostate cancer patients who were diagnosed between January 2000 and December 2005, and controls were 686 patients who visited the clinic during the same period and were diagnosed with urological illnesses other than cancers and prostate-related problems. Data on family history of cancers, lifestyle and demographic factors were collected through mail survey utilizing the method suggested by Dillman. Unconditional logistic regression analysis was used to estimate the odds ratios (OR) and the corresponding 95% confidence intervals (CI) after adjustment for potential confounding factors including body mass index (BMI), alcohol intake, physical activity, smoking, diet, history of vasectomy and sexually transmitted disease (STD), age, race, marital history, education, and income. Multiple comparisons adjustments were made using the Bonferroni adjustment.ResultsMen with a family history of any cancer in first-degree relatives including parents (OR = 2.42, 95% CI = 1.53–3.84) and parents only (OR = 1.90, 95% CI = 1.23– 2.94) were at increased risk of developing prostate cancer. Significant increased risk was also observed with family history of prostate cancer in first-degree relatives (OR = 2.68, 95% CI = 1.53–4.69) and parents only (OR = 3.26, 95% CI = 1.71–6.24). Even after adjustments for multiple comparisons, the significance persisted both in first-degree relatives (OR = 2.68, 95% CI = 1.16–6.21) and parents alone (OR = 3.26, 95% CI = 1.24– 8.63).ConclusionThis study demonstrated an increased prostate cancer risk for men with a family history of any cancer or prostate cancer in first-degree relatives and parents alone. Health care providers need to be aware of the potential risk of family history of cancers on prostate cancer.     

Smac mimetic Birinapant induces apoptosis and enhances TRAIL potency in inflammatory breast cancer cells in an IAP-dependent and TNF-α-independent mechanism

X-linked inhibitor of apoptosis protein (XIAP), the most potent mammalian caspase inhibitor, has been associated with acquired therapeutic resistance in inflammatory breast cancer (IBC), an aggressive subset of breast cancer with an extremely poor survival rate. The second mitochondria-derived activator of caspases (Smac) protein is a potent antagonist of IAP proteins and the basis for the development of Smac mimetic drugs. Here, we report for the first time that bivalent Smac mimetic Birinapant induces cell death as a single agent in TRAIL-insensitive SUM190 (ErbB2-overexpressing) cells and significantly increases potency of TRAIL-induced apoptosis in TRAIL-sensitive SUM149 (triple-negative, EGFR-activated) cells, two patient tumor-derived IBC models. Birinapant has high binding affinity (nM range) for cIAP1/2 and XIAP. Using isogenic SUM149- and SUM190-derived cells with differential XIAP expression (SUM149 wtXIAP, SUM190 shXIAP) and another bivalent Smac mimetic (GT13402) with high cIAP1/2 but low XIAP binding affinity (K _d > 1 μM), we show that XIAP inhibition is necessary for increasing TRAIL potency. In contrast, single agent efficacy of Birinapant is due to pan-IAP antagonism. Birinapant caused rapid cIAP1 degradation, caspase activation, PARP cleavage, and NF-κB activation. A modest increase in TNF-α production was seen in SUM190 cells following Birinapant treatment, but no increase occurred in SUM149 cells. Exogenous TNF-α addition did not increase Birinapant efficacy. Neutralizing antibodies against TNF-α or TNFR1 knockdown did not reverse cell death. However, pan-caspase inhibitor Q-VD-OPh reversed Birinapant-mediated cell death. In addition, Birinapant in combination or as a single agent decreased colony formation and anchorage-independent growth potential of IBC cells. By demonstrating that Birinapant primes cancer cells for death in an IAP-dependent manner, these findings support the development of Smac mimetics for IBC treatment.     

Nutrition‐sensitive agriculture programme impacts on time use and associations with nutrition outcomes

Success of nutrition‐sensitive agriculture programmes targeted to women may be influenced by increased demands on women''s and other household members'' time and by time‐related trade‐offs to accommodate programme participation. However, evidence of how such programmes impact time use and whether changes in time‐related demands negatively influence maternal or child health and nutrition outcomes is limited. This paper examines the impact of Helen Keller International''s Enhanced Homestead Food Production programme in Burkina Faso (2010–2012) on women''s and men''s time use and associations between changes in women''s time use and maternal and child health and nutrition outcomes. We used quantitative data from a cluster‐randomized controlled trial (baseline 2010, endline 2012) and qualitative data from two rounds of process evaluation (2011, 2012). Two‐stage analyses were used to first assess programme impacts on women''s and men''s time use using difference‐in‐difference impact estimates and second to evaluate whether programme impacts on women''s time use were associated with changes in women''s and children''s health and nutrition outcomes. Programme impacts were considered significant if corrected P < 0.01, and associations were considered significant if p < 0.05 and p < 0.01. Qualitative data were analysed through manual coding and by calculating the means and standard deviations for the time spent by women and men on activities in intervention and control groups. Findings show that the programme significantly increased the amount of time women spent on agriculture in the intervention compared to the control group, but this was not associated with changes in maternal or child health or nutrition outcomes. Process evaluation data supported these findings.     

Crystal structure of the serine protease domain of Sesbania mosaic virus polyprotein and mutational analysis of residues forming the S1-binding pocket

Sesbania mosaic virus (SeMV) polyprotein is processed by its N-terminal serine protease domain. The crystal structure of the protease domain was determined to a resolution of 2.4 A using multiple isomorphous replacement and anomalous scattering. The SeMV protease domain exhibited the characteristic trypsin fold and was found to be closer to cellular serine proteases than to other viral proteases. The residues of the S1-binding pocket, H298, T279 and N308 were mutated to alanine in the DeltaN70-Protease-VPg polyprotein, and the cis-cleavage activity was examined. The H298A and T279A mutants were inactive, while the N308A mutant was partially active, suggesting that the interactions of H298 and T279 with P1-glutamate are crucial for the E-T/S cleavage. A region of exposed aromatic amino acids, probably essential for interaction with VPg, was identified on the protease domain, and this interaction could play a major role in modulating the function of the protease.