Fragment-based discovery of hydroxy-indazole-carboxamides as novel small molecule inhibitors of Hsp90.

Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe the identification of novel small molecular weight inhibitors of Hsp90 using a fragment based approach. Fragments were selected by docking, tested in a biochemical assay and the confirmed hits were crystallized. Information gained from X-ray structures of these fragments and other chemotypes was used to drive the fragment evolution process. Optimization of these high µM binders resulted in 3-benzylindazole derivatives with significantly improved affinity and anti-proliferative effects in different human cancer cell lines.

Distraction osteogenesis for temporomandibular joint reconstruction.

PURPOSE: This clinical study evaluated the use of transport distraction osteogenesis in reconstruction of the ramus-condyle unit (RCU) of the temporomandibular joint (TMJ). PATIENTS AND METHODS: Thirteen TMJ reconstructions were carried out in 12 patients. Diagnoses included tumors, trauma, ankylosis, and degenerative joint disease. The follow-up period has ranged from 7 to 59 months. RESULTS: Successful distraction was carried out in all cases, with development of solid regenerate bone and an effective new articulation. There were no complications. A good functional level was achieved in all cases. One patient with bilateral rheumatoid arthritis has experienced ongoing degenerative changes in the reconstructed condyles, with reappearance of an anterior open bite. The occlusion has remained stable in all other cases. CONCLUSIONS: Distraction osteogenesis is a promising treatment option in reconstruction of the RCU of the TMJ.

Wound healing and perioperative care.

Wounding or injury unleashes a tightly choreographed array of cellular, physiologic, biochemical, and molecular processes that restore the integrity and functional capacity of damaged tissue. Healing in the orofacial region usually is taken for granted, yet local and systemic factors can hinder the process of tissue restitution and set the stage for adverse outcomes. Although surgical attention focuses on local wound care, consideration of systemic factors is equally important. An understanding of the biologic underpinnings of the wound healing continuum provides surgeons with a framework for developing the skills required to care for wounds and facilitate healing.

CpG oligonucleotides: novel regulators of osteoclast differentiation.

The macrophage capability to recognize bacterial DNA is mimicked by oligodeoxynucleotides containing unmethylated CG dinucleotides ('CpG' motifs) in specific sequence contexts (CpG ODN). CpG ODN stimulates NF-kappaB activation in murine macrophages. In light of the pivotal role played by NF-kappaB in osteoclast differentiation, we examined the ability of CpG ODN to modulate osteoclastogenesis. CpG ODN alone induced TRAP-positive cells in bone marrow macrophage (BMM) cultures, but not multinucleation or calcitonin receptor expression. CpG ODN inhibited RANKL-induced osteoclastogenesis when present from the beginning of BMM culture, but strongly increased RANKL-induced osteoclastogenesis in RANKL-pretreated BMMs. CpG ODN enhanced the expression of interleukin 1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha). Antibodies to TNF-alpha and the TNF type 1 receptor, but not the addition of IL-1 receptor antagonist, blocked CpG ODN-induced osteoclastogenesis in RANKL-pretreated cultures. On the other hand, CpG ODN reduced expression of the M-CSF receptor, which is critical during the initiation of osteoclast differentiation. These results suggest that CpG ODN, via the induction of TNF-alpha, support osteoclastogenesis in cells that are committed to the osteoclast differentiation pathway but, due to down-modulation of M-CSF receptor, inhibit early steps of osteoclast differentiation. Thus, CpG ODN represents a potential therapeutic tool for treating bone diseases.

Characteristics and prognostic factors of osteosarcoma of the jaws: a retrospective cohort study.

IMPORTANCE: Osteosarcoma of the jaws is rare and clinically distinct from osteosarcoma of the long bones of the body with different treatment and outcomes. The literature on these tumors is limited to case reports and small case series mostly from single institutions. We used data from the population-based national Surveillance, Epidemiology and End Results (SEER) cancer registry to determine the epidemiology and prognostic factors associated with osteosarcoma of the jaws. OBJECTIVE: To investigate the epidemiologic characteristics and prognostic factors for survival in patients diagnosed with osteosarcoma of the jaws. DESIGN, SETTING, AND PARTICIPANTS: A retrospective, population-based cohort study of 541 patients in the SEER tumor registry diagnosed with osteosarcoma of the jaws from 1973 through 2011 were reviewed. EXPOSURES: Patients had been treated with surgery, radiation, both, or neither. MAIN OUTCOMES AND MEASURES: Overall and disease-specific survival. RESULTS: A total of 541 patients diagnosed with osteosarcoma of the jaws were identified (49.9% male and 50.1% female, with a mean age of 41.3 years). Kaplan-Meier analysis demonstrated an overall survival (OS) and disease-specific survival (DSS) of 53% and 62%, respectively, at 5 years and 35% and 54%, respectively, at 10 years. Multivariate Cox regression analysis revealed that independent predictors of OS and DSS included age at diagnosis (hazard ratio [HR], 1.03; 95% CI, 1.02-1.04 [P < .001] for OS; and HR, 1.03; 95% CI, 1.02-1.05 [P < .001] for DSS); stage at presentation (HR, 1.37; 95% CI, 1.10-1.71 [P = .006] for OS; and HR, 1.34; 95% CI, 1.01-1.76 [P = .04] for DSS); and surgical resection (HR, 0.31; 95% CI, 0.16-0.60 [P < .001] for OS; and HR, 0.22; 95% CI, 0.09-0.56 [P = .001] for DSS). Tumor size was not significant for OS (HR, 1.00; 95% CI, 1.00-1.01 [P = .11] but significant for DSS (HR, 1.01; 95% CI, 1.00-1.01 [P = .003]). CONCLUSIONS AND RELEVANCE: To our knowledge, this is the largest study to date investigating prognostic factors for survival in patients diagnosed with osteosarcoma of the jaws. Determinants of survival include age at diagnosis, stage at presentation, tumor size, and surgical therapy. Radiation therapy was not associated with improved survival, reflecting the controversy surrounding its use in clinical literature.

Osteoradionecrosis of the mandible: scientific basis for clinical staging.

Osteoradionecrosis of the mandible can be a serious complication of radiotherapy for head and neck cancer. The disorder generally presents in one of several distinct clinical variations. This is probably because of a complex interaction of etiologic factors. A clinical staging system for the disorder is described. Such a system is necessary for the conduct of clinical research, and for the development and assessment of treatment regimens.

A novel strategy for ADME screening of prodrugs: combined use of serum and hepatocytes to integrate bioactivation and clearance, and predict exposure to both active and prodrug to the systemic circulation.

Common strategies to optimize prodrugs use either in vitro or rodent in vivo approaches, which do not consider elimination pathways that do not result in the generation of the desired product or might be misleading because of species differences, respectively. As a step forward, we have incorporated a novel application of hepatocytes into our prodrug optimization strategy to increase the bioavailability of a poorly soluble drug candidate by attaching a charged ester linker. The model involves the incubation of hepatocytes from multiple species in serum-containing medium to mimic formation as well as simultaneous metabolism of both prodrug and active drug. Using this strategy, a correlation between the in vitro AUC and the AUC after intravenous administration was obtained for active drug formation in several species. Moreover, hepatocytes correctly predicted the likelihood of undesired exposure with nonhydrolyzed prodrug. This novel approach enabled us to identify several prodrugs, which showed improved exposure over a wide dose range. Furthermore, a strategy was developed resulting in a decision tree that can be used to determine the applicability of the hepatocyte model in the screening process.

Subcutaneous methylnaltrexone for treatment of acute opioid-induced constipation: phase 2 study in rehabilitation after orthopedic surgery.

BACKGROUND: Methylnaltrexone has been shown to be effective for treating opioid-induced constipation (OIC) in chronic settings, but its effects on acute OIC have not been studied. OBJECTIVE: To assess safety and efficacy of subcutaneous methylnaltrexone in patients with acute OIC after orthopedic procedures. DESIGN: Double-blind, randomized, parallel-group, placebo-controlled, hypothesis-generating phase 2 study. SETTING: Sixteen US hospitals and rehabilitation facilities. PATIENTS: Adult patients with acute OIC after orthopedic surgical procedure, expected to require opioids for at least 7 days postrandomization. INTERVENTIONS: Patients received once-daily subcutaneous methylnaltrexone 12 mg or placebo for up to 4 or 7 days. MEASUREMENTS: All endpoints were exploratory and included the percentage of patients achieving laxation within 2 and 4 hours of first dose and time to laxation. RESULTS: Thirty-three patients received at least 1 dose of study drug (methylnaltrexone, n = 18; placebo, n = 15). Within 2 and 4 hours, significantly more patients receiving methylnaltrexone achieved laxation (2 hours: 33.3% vs 0%, P = 0.021; 4 hours: 38.9% vs 6.7%, P = 0.046) compared with placebo. Time to laxation was significantly shorter with methylnaltrexone (median = 15.8 hours) versus placebo (median = 50.9 hours), P = 0.0197. The most common adverse events related to the gastrointestinal tract. Pain scores remained stable and were similar to those of placebo, and signs and symptoms of opioid withdrawal did not emerge in patients receiving methylnaltrexone. CONCLUSIONS: Methylnaltrexone was generally well tolerated and was active in inducing laxation in this study of patients experiencing acute OIC following orthopedic surgery.

History, accomplishments, issues and prospects of supportive service programs in Naturally Occurring Retirement Communities in new York State: lessons learned.

Naturally Occurring Retirement Communities (NORCs) provide unique settings for the delivery of a variety of supportive services to the elderly. New York State's experience with the development of supportive service programs within NORCs provides valuable information for community planners and practitioners in terms of factors that contribute to the evolution and shaping of supportive service programs and lessons learned from existing programs.