Design of selective nuclear receptor modulators: RAR and RXR as a case study

Retinoic acid receptors (RARs) and retinoid X receptors (RXRs) are members of the nuclear receptor superfamily whose effects on cell growth and survival can be modulated therapeutically by small-molecule ligands. Although compounds that target these receptors are powerful anticancer drugs, their use is limited by toxicity. An improved understanding of the structural biology of RXRs and RARs and recent advances in the chemical synthesis of modified retinoid and rexinoid ligands should enable the rational design of more selective agents that might overcome such problems. Here, we review structural data for RXRs and RARs, discuss strategies in the design of selective RXR and RAR modulators, and consider lessons that can be learned for the design of selective nuclear-receptor modulators in general.     

Urban air pollution and respiratory emergency visits at pediatric unit, Reggio Emilia, Italy

Short-term effects of air pollution on daily mortality and hospital admissions for respiratory causes are well documented. Few studies, however, explore the association between exposure to air pollution and daily emergency room visits for respiratory disorders, particularly in Italy and particularly among children as a susceptible population. A time-series analysis was conducted to explore the short-term association between air pollutants (PM10, total suspended particulates [TSP], NO2, SO2, CO, O3) and pediatric emergency room (ER) visits in a small city of northern Italy, Reggio Emilia, during the period 03/01/2001-03/31/2002. There were 1051 ER visits included in the study. Data were analyzed using generalized additive models (GAM), adjusting for various confounding variables, including temperature, humidity, and pollens (Graminaceae). The analyses were also stratified according to the nationality of children (Italians and foreigners). In single-pollutant models, the strongest associations were observed at lag 3 for a 10-microg/m3 increase of TSP (2.7% increase in ER, 95% CI 0.7-4.6) and PM10 (3.0% increase, 95% CI 0.4-5.7), and at lag 4 for a 10-microg/m3 increase of NO2 (11.0% increase in ER, 95% CI 3.6-18.8). At lag 3, the percentage increase in ER visits is similar for the 2 groups of children (Italians and foreigners) for TSP and PM10. The results of the study support the findings that air pollution is a relevant determinant of deterioration of respiratory health among children.     

Solid-state chemistry of ambroxol theophylline-7-acetate

Ambroxol theophylline-7-acetate (ACE) is the salt obtained by reaction of equimolar amounts of ambroxol (AMB), a drug showing mucolytic and expectorant properties, and theophylline-7-acetic acid (TAA), a xanthine derivative with specific bronchodilator activity. ACE is used for the treatment of bronchial and pulmonary diseases (bronchitis, asthma, emphysema, chronic obstructive disease). Recrystallization experiments of ACE resulted in the isolation of two polymorphs (monotropically related) and four solvated forms. X-ray diffractometry, DSC, TGA, and HSM techniques were used to investigate the forms that are obtained by thermal desolvation of the solvates. The phase diagram of the TAA-AMB binary system was constructed by performing thermal analyses on mixtures of TAA-AMB and of each component plus the interaction compound (TAA-ACE and ACE-AMB). The Schroeder-Van Laar equation proved to be a very useful tool for checking the consistency between the experimental data and the theoretical model related to the general system, showing complete miscibility in the liquid phase and complete immiscibility in the solid phase.     

Extremity Soft Tissue Sarcoma: Adding to the Prognostic Meaning of Local Failure

Background We explored the prognostic meaning of local relapse and surgical margins in adult soft tissue sarcoma of the extremities. Methods Out of a series of 1017 patients with extremity soft tissue sarcoma treated over 20 years, we picked a group of 238 patients operated on at our institution for their first local relapse: 88 after their primary operation performed at the same center and 150 elsewhere. At operation for relapse, margins were microscopically negative in 77% and 75% of patients, respectively. Median follow-up was 107 months. Results The 10-year mortality rate was 22% in the absence of local relapse, whereas in locally relapsing patients it was 54% and 43%, respectively, for patients first operated on at our institute and for those who were not. The hazard ratio of positive versus negative surgical margins was 1.7 for cause-specific death and 2.1 for distant metastases in patients first operated on at our institute, as opposed to 1.2 and 1.3 for the others. Conclusions Local relapse was an unfavorable prognostic factor. In the face of a consistent surgical policy for local relapse in a single-institution setting, patients relapsing after the first operation performed at our institution received rescue treatment less frequently than those previously operated on outside a referral center. This is likely due to an inherently higher tumor aggressiveness. In the presence of such a higher aggressiveness, the adequacy of surgical margins at operation for first relapse seemed more critical prognostically. This may have clinical and speculative implications. Presented at the Annual Meeting of the American Society of Clinical Oncology, June 2–6, 2006, Atlanta, GA (USA) (abstract 9565).     

Biomechanical analysis of screw-augmented intramedullary fixation for tibiotalocalcaneal arthrodesis

BACKGROUND: This study compared intramedullary (IM) fixation for tibiotalocalcaneal arthrodesis with and without a tibiotalocalcaneal augmentation screw. METHODS: Each specimen in six matched pairs of fresh frozen cadavers underwent tibiotalocalcaneal arthrodesis with an IM nail. One specimen from each pair also received a tibiotalocalcaneal augmentation screw. Initial and final stiffness, load to failure, and construct deformation at failure were calculated with dorsiflexion loading. Bone mineral density of each pair was determined. Statistical analysis was done using a paired Student t-test and a Pearson correlation. RESULTS: Initial and final stiffness and load to failure were significantly higher for the tibiotalocalcaneal screw augmented fixation group as compared with the specimens with no additional screw (initial stiffness, 128.0 versus 78.4 N/mm, p = 0.04; final stiffness, 230.9 versus 164.7 N/mm, p = 0.04; load to failure, 875.5 versus 660.2 N, p = 0.03). There was a significant negative correlation between bone mineral density and average construct deformation in the samples without the added tibiotalocalcaneal screw (r = -0.90, p = 0.02). CONCLUSIONS: In tibiotalocalcaneal arthrodesis with intramedullary nail fixation, a tibiotalocalcaneal augmentation screw provides more stable fixation. CLINICAL RELEVANCE: Use of an augmentation screw as described in this study may lead to lower complication rates, particularly in patients with osteopenic bone.     

Adipose tissue-derived human mesenchymal stem cells mediated prodrug cancer gene therapy

Human adipose tissue-derived mesenchymal stem cells (AT-MSC) are considered to be a promising source of autologous stem cells in personalized cell-based therapies. Tumor tracking properties of MSC provide an attractive opportunity for targeted transgene delivery into the sites of tumor formation. In the present study, we addressed whether the suicide gene introduction into human AT-MSC could produce a tumor-specific prodrug converting cellular vehicle for targeted chemotherapy. We prepared yeast fusion cytosine deaminase::uracil phosphoribosyltransferase gene-expressing cells [cytosine deaminase (CD)-expressing AT-MSC (CD-AT-MSC)] by retrovirus transduction. We explored their therapeutic potential on a model of human colon cancer in the presence of prodrug 5-fluorocytosine (5-FC). Gene manipulation of human AT-MSC did not sensitize CD-AT-MSC to 5-FC, thus overcoming the inherent disadvantage of suicide effect on cellular vehicle. CD-AT-MSC in combination with 5-FC augmented the bystander effect and selective cytotoxicity on target tumor cells HT-29 in direct coculture in vitro. We confirmed directed migration ability of AT-MSC and CD-AT-MSC toward tumor cells HT-29 in vitro. Moreover, we achieved significant inhibition of s.c. tumor xenograft growth by s.c. or i.v. administered CD-AT-MSC in immunocompromised mice treated with 5-FC. We confirmed the ability of CD-AT-MSC to deliver the CD transgene to the site of tumor formation and mediate strong antitumor effect in vivo. Taken together, these data characterize MSC derived from adipose tissue as suitable delivery vehicles for prodrug converting gene and show their utility for a personalized cell-based targeted cancer gene therapy.     

Alcohol consumption and risk of leukemia: A multicenter case-control study

A population-based case-control study of 649 leukemia cases and 1771 controls carried out in 11 Italian areas, offered the opportunity to evaluate the relationship between alcohol consumption and leukemia risk. For all leukemias, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), and chronic lymphocytic leukemia (CLL), we found a non-significantly inverse association for moderate levels of total alcohol and wine intake, but increased risks at high levels, with, in most cases, significant trend effects (odd ratios (OR) for all leukemias in the lowest quartile of total alcohol consumption [0.1-9.0 g/day of ethanol] versus never-drinker = 0.73; 95% confidence intervals (95% CI) = 0.51-1.03; OR in the highest quartile [> 31.7 g/day] = 1.15; 95% CI = 0.82-1.63; p of the linear trend test = 0.007). For chronic myeloid leukemia (CML), we found a non-significantly positive association for all levels of total alcohol and wine intake, and a significant positive linear trend effect (p = 0.03) for wine intake (OR for 0.1-9.0 g/day of ethanol intake from wine = 1.34; 95% CI = 0.61-2.94; OR in the highest quartile of wine intake [> 27.7 g/day] = 2.13; 95% CI = 1.01-4.50). No consistent dose-response was detected analysing duration of alcohol consumption for any leukemia subtypes. In conclusion, even though our study did not show a clear association between alcohol intake and leukemia risk, some of the patterns of the risk estimates (a possible J-shaped dose-response curve between alcohol intake and ALL, AML, and CLL risks, and the positive association between alcohol and CML), may be suggestive.     

Postoperative radiotherapy for synovial sarcoma of the head and neck during pregnancy: clinical and technical management and fetal dose estimates

AIMS AND BACKGROUND: In vivo and phantom dosimetry is reported to estimate the fetal dose and evaluate the effectiveness of a special shielding device to reduce fetal exposure in a woman undergoing postoperative radiation therapy for synovial oral cavity sarcoma at the 30th week of pregnancy. METHODS: In vivo measurements were performed by placing thermoluminescent dosimeters on 3 points for fetal dose estimation: uterine fundus, umbilicus and pubis. A Rando anthropomorphic phantom was used to simulate radiotherapy. We also performed off-axis dose measurements for wedged beams to estimate the dose contribution of this accessory used in the treatment. RESULTS: The special shielding device reduced the fetal dose by 70% on average, despite the presence of wedges, which increased the dose by a factor of about 2.5. Before delivery the patient received 48 Gy, and from the in vivo measurements a fetal dose of 8.5, 1.7 and 0.7 cGy was estimated to the uterine fundus, umbilicus and pubis, respectively. CONCLUSIONS: Pre-treatment simulation in the same irradiation conditions is the only reliable approach to predict the fetal dose. By using a special shielding device, radiotherapy can be optimized while keeping the fetal exposure below the risk of deterministic damage.