Enhancement of the Triple Alpha Rate in a Hot Dense Medium.

In a sufficiently hot and dense astrophysical environment the rate of the triple-alpha (3α) reaction can increase greatly over the value appropriate for helium burning stars owing to hadronically induced deexcitation of the Hoyle state. In this Letter we use a statistical model to evaluate the enhancement as a function of temperature and density. For a density of 10^{6} g cm^{-3} enhancements can exceed a factor of 100. In high temperature or density situations, the enhanced 3α rate is a better estimate of this rate and should be used in these circumstances. We then examine the effect of these enhancements on production of ^{12}C in the neutrino wind following a supernova explosion and in an x-ray burster.

Using mixed methods to measure the perception of community capacity in an academic-community partnership for a walking intervention.

H.U.B. City Steps is a 5-year community-based participatory research walking intervention designed to help lower blood pressure in a majority African American population in southern Mississippi via community collaboration and capacity building, increased walking, culturally tailored health education sessions, and motivational interviewing. Building community capacity for physical activity is a key component of this intervention. Qualitative and quantitative methods have been used to assess how project stakeholders perceive the community capacity-building efforts of the project. This article illustrates the baseline results of this mixed methods approach from the perspective of three groups of stakeholders: project researchers and staff, community advisory board, and intervention walking coaches. Eight constructs were examined, including leadership, resources, external networking, visibility and recognition, personnel sustainability, ability and commitment to organize, communication with community members, and relationships with influential others. Quantitative results indicated significant differences among stakeholder groups for project leadership and personnel sustainability. Qualitative perspectives provided an opportunity to examine possible reasons for these differences. Overall findings provide direction related to improving intervention outcomes and sustainability.

Autoclaving of Poloxamer 407 hydrogel and its use as a drug delivery vehicle.

With antibiotic-resistant bacteria becoming increasingly prevalent, biomaterials capable of targeted, in situ drug delivery are urgently needed. The synthetic polymer Poloxamer 407 (P407) is of particular interest due to its thermoreversible gelation. Clinical use of P407 typically involves sterilization via autoclaving, but the effects of these extreme environmental conditions on hydrogel water content, rheological properties and efficacy as a drug delivery vehicle remain unknown. The aim of this study was to investigate the effects of autoclaving on the properties of P407 hydrogel. Autoclaving reduced hydrogel water content due to evaporation, thus increasing the polymer weight fraction of the hydrogels. In contrast, except for a reduction in gelation temperature following autoclaving, autoclaved hydrogels had similar rheological properties as nonautoclaved hydrogels. In vitro, autoclaving did not hinder the hydrogel's efficacy as a carrier for vancomycin antibiotic, and P407 (with and without vancomycin) had a bactericidal effect on planktonic Staphylococcus aureus. An in vivo pilot study using P407 to deliver bacteriophage highlighted the need for additional understanding of the functionality of the hydrogel for surgical applications. In conclusion, P407 hydrogel water content and gelation temperature were reduced by autoclave sterilization, while other rheological properties and the efficacy of the biomaterial as a delivery vehicle for vancomycin in vitro were unaffected.

CRISPR-Cas9 modified bacteriophage for treatment of Staphylococcus aureus induced osteomyelitis and soft tissue infection.

Osteomyelitis, or bone infection, is often induced by antibiotic resistant Staphylococcus aureus strains of bacteria. Although debridement and long-term administration of antibiotics are the gold standard for osteomyelitis treatment, the increase in prevalence of antibiotic resistant bacterial strains limits the ability of clinicians to effectively treat infection. Bacteriophages (phages), viruses that in a lytic state can effectively kill bacteria, have gained recent attention for their high specificity, abundance in nature, and minimal risk of host toxicity. Previously, we have shown that CRISPR-Cas9 genomic editing techniques could be utilized to expand temperate bacteriophage host range and enhance bactericidal activity through modification of the tail fiber protein. In a dermal infection study, these CRISPR-Cas9 phages reduced bacterial load relative to unmodified phage. Thus we hypothesized this temperate bacteriophage, equipped with the CRISPR-Cas9 bactericidal machinery, would be effective at mitigating infection from a biofilm forming S. aureus strain in vitro and in vivo. In vitro, qualitative fluorescent imaging demonstrated superiority of phage to conventional vancomycin and fosfomycin antibiotics against S. aureus biofilm. Quantitative antibiofilm effects increased over time, at least partially, for all fosfomycin, phage, and fosfomycin-phage (dual) therapeutics delivered via alginate hydrogel. We developed an in vivo rat model of osteomyelitis and soft tissue infection that was reproducible and challenging and enabled longitudinal monitoring of infection progression. Using this model, phage (with and without fosfomycin) delivered via alginate hydrogel were successful in reducing soft tissue infection but not bone infection, based on bacteriological, histological, and scanning electron microscopy analyses. Notably, the efficacy of phage at mitigating soft tissue infection was equal to that of high dose fosfomycin. Future research may utilize this model as a platform for evaluation of therapeutic type and dose, and alternate delivery vehicles for osteomyelitis mitigation.

Prevalence of Vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy.

PURPOSE: To evaluate serum 25-hydroxyvitamin D [25(OH)D] concentrations and factors related to vitamin D inadequacy in postmenopausal North American women receiving therapy to treat or prevent osteoporosis. METHODS: Serum 25(OH)D and PTH were obtained in 1536 community-dwelling women between November 2003 and March 2004. Multivariate logistic regression was used to assess risk factors for suboptimal (<30 ng/ml) 25(OH)D. RESULTS: Ninety-two percent of study subjects were Caucasian, with a mean age of 71 yr. Thirty-five percent resided at or above latitude 42 degrees north, and 24% resided less than 35 degrees north. Mean (sd) serum 25(OH)D was 30.4 (13.2) ng/ml: serum 25(OH)D was less than 20 ng/ml in 18%; less than 25 ng/ml in 36%; and less than 30 ng/ml in 52%. Prevalence of suboptimal 25(OH)D was significantly higher in subjects who took less than 400 vs. 400 IU/d or more vitamin D. There was a significant negative correlation between serum PTH concentrations and 25(OH)D. Risk factors related to vitamin D inadequacy included age, race, body mass index, medications known to affect vitamin D metabolism, vitamin D supplementation, exercise, education, and physician counseling regarding vitamin D. CONCLUSIONS: More than half of North American women receiving therapy to treat or prevent osteoporosis have vitamin D inadequacy, underscoring the need for improved physician and public education regarding optimization of vitamin D status in this population.

Phase II and pharmacodynamic study of the farnesyltransferase inhibitor R115777 as initial therapy in patients with metastatic pancreatic adenocarcinoma.

PURPOSE: R115777 is a selective nonpeptidomimetic inhibitor of farnesyltransferase (FTase), one of several enzymes responsible for posttranslational modification that is required for the function of p21(ras) and other proteins. Given that RAS mutations are nearly universal in pancreatic cancer and R115777 demonstrated preclinical activity against pancreatic cell lines and xenografts, this phase II study was undertaken to determine its clinical activity and effect on target proteins in patients with measurable metastatic pancreatic adenocarcinoma. PATIENTS AND METHODS: Twenty patients who had not received prior therapy for metastatic disease were treated with 300 mg of R115777 orally every 12 hours for 21 of 28 days. Inhibition of FTase activity in peripheral-blood mononuclear cells was measured using a lamin B C-terminus peptide as substrate. Western blot analysis was performed to monitor farnesylation status of the chaperone protein HDJ-2. RESULTS: No objective responses were seen. Median time to progression was 4.9 weeks, and median survival time was 19.7 weeks. The estimated 6-month survival rate was 25%, with no patients progression-free at 6 months. Grade 3/4 toxicities were liver enzyme elevation, anemia, neutropenia, thrombocytopenia, fatigue, nausea/vomiting, rash, and anorexia. FTase activity (mean +/- SD) decreased by 49.8% +/- 9.8% 4 hours after treatment on day 1 and 36.1% +/- 24.8% before treatment on day 15. HDJ-2 farnesylation (mean +/- SD) decreased by 33.4% +/- 19.8% on day 15. CONCLUSION: Although treatment with R115777 resulted in partial inhibition of FTase activity in mononuclear cells, it did not exhibit single-agent antitumor activity in patients with previously untreated metastatic pancreatic cancer.

Phase I and pharmacokinetic study of once daily oral administration of S-1 in patients with advanced cancer.

PURPOSE: To determine the maximum tolerated dose, dose-limiting toxicities(DLTs), and pharmacokinetics of S-1, a combination of tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP), and oxonic acid, administered once daily in patients with advanced cancer. EXPERIMENTAL DESIGN: Eighteen patients with refractory malignancies were treated with S-1 administered once daily for 21 consecutive days, followed by a 1-week break. Of 16 evaluable patients, 6 were treated at a dose of 50 mg/m(2)/day, and 10 were treated at 60 mg/m(2)/day. RESULTS: DLTs were observed in 1 of 6 evaluable patients treated with 50 mg/m(2)/day and in 4 of 10 evaluable patients treated with 60 mg/m(2)/day. DLTs included diarrhea, nausea/vomiting, fatigue, and hyperbilirubinemia. The maximum tolerated dose was 50 mg/m(2)/day. Pharmacokinetic data are consistent with potent modulation of 5-fluorouracil (5-FU) by CDHP, with prolonged half-life and 5-FU AUC at least 10-fold higher than reported in previous studies of equitoxic doses of tegafur modulated by uracil. Pharmacodynamic analysis demonstrated a correlation between diarrhea grade and both 5-FU C(max) (r = 0.57, P < 0.05) and 5-FU area under the curve (r = 0.74, P < 0.01). CONCLUSIONS: The recommended Phase II dose of S-1 administered once daily for 21 consecutive days of 28 is 50 mg/m(2). The pharmacokinetic data presented provide evidence of 5-FU modulation by CDHP. Pharmacodynamic analyses suggest that the utility of pharmacology-based dosing of S-1 should be explored in future trials. Evaluation of once-daily dosing of S-1 in malignancies for which fluoropyrimidines have known antitumor activity is warranted.

Survival following intensive preoperative combined modality therapy with paclitaxel, cisplatin, 5-fluorouracil, and radiation in resectable esophageal carcinoma: a phase I report.

PURPOSE: To assess the benefits of aggressive chemoradiation therapy followed by surgery in resectable esophageal carcinoma. METHOD: Twenty-nine patients with resectable carcinoma were treated with 60 Gy of radiation (2 Gy daily for 6 weeks) and concurrent chemotherapy consisting of continuous infusion of 5-fluorouracil (200-225 mg/m(2)/d), paclitaxel (25, 40, 50, or 60 mg/m(2)) weekly over 1 hour, and cisplatin (25 mg/m(2)) weekly immediately following paclitaxel throughout radiation. Patients received either 4 cycles of postoperative paclitaxel 175 mg/m(2) over 3 hours and cisplatin 75 mg/m(2) every 3 weeks or paclitaxel 175 mg/m(2) over 3 hours and cisplatin 75 mg/m(2) every 3 weeks prior to the initiation of chemoradiation. After induction therapy and restaging, esophagectomy was performed 4 to 6 weeks later. RESULTS: Twenty-seven patients were eligible for study (26 men, 23 with adenocarcinoma). Median age was 58 years (range 30-73). The maximum tolerated dose combination was paclitaxel 50 mg/m(2) over 1 hour weekly, cisplatin 25 mg/m(2) over 1 hour weekly, 5-fluorouracil 200 mg/m(2)/d by continuous infusion throughout radiotherapy and radiation to 60 Gy. Twenty-two patients completed therapy and underwent surgical resection. Four patients had complete pathological responses and 18 had partial responses with no mortality. The commonest dose-limiting toxicity was mucositis and esophagitis (n = 7). Median follow-up of 27 patients was 150 weeks (range 7-303). At 2-year follow-up 16/27 (59%) were alive and 15/27 (56%) were free of disease. At 4-year follow-up 12/27 (44%) were alive and free of disease. Median follow-up of 22 patients undergoing esophagectomy was 205 weeks (range 26-303). At 4-year follow-up 10/22 (45%) were alive and free of disease. For the 18 patients treated at or above the maximum tolerated dose, median follow-up was 151 weeks (range 35-206) and at 3-year follow-up 9/18 (50%) were alive and free of disease. CONCLUSION: Aggressive combined modality therapy of esophageal carcinoma was associated with excellent long-term survival in this phase I trial.

Bisphosphonate therapy for osteoporosis: combining optimal fracture risk reduction with patient preference.

OBJECTIVE: To review current use of bisphosphonates as first-line therapy for osteoporosis, with an emphasis on the importance of patient compliance and persistence. METHODS: The US National Library of Medicine was used to obtain the relevant information on current bisphosphonate treatment for osteoporosis management, and patient compliance and persistence with treatment. RESULTS: Bisphosphonates have demonstrated efficacy in fracture risk reduction, although differences may exist with respect to both onset of action and the site of fracture risk reduction. Good compliance and persistence with osteoporosis therapy is needed to reduce fracture risk, but currently the willingness of patients to conform to their prescribed course of treatment is suboptimal. Intermittent dosing schedules have been developed to facilitate ease of medication-taking in order to help improve rates of compliance and persistence. When primary care physicians provide patients with information about the established efficacy and safety of medications, as well as clarifying the crucial link between continued, consistent treatment and fracture risk reduction, patients are more likely to understand the importance of taking their medications consistently in order to maximize the effectiveness of the therapy. CONCLUSIONS: A therapy that provides vertebral and nonvertebral efficacy, is well-tolerated, and offers a flexible dosing regimen is likely to enhance patient compliance and persistence, and provide optimal fracture protection. Numerous studies have consistently demonstrated that medication compliance and persistence are well-correlated with fracture risk reduction.

Response to oral bisphosphonates in subgroups of younger and older postmenopausal women.

BACKGROUND: Although the effects of bisphosphonates in bone are known for postmenopausal women, it is not known if younger postmenopausal women have a similar response. Furthermore, it is not known if the effects of alendronate and risedronate differ in postmenopausal women in regard to age, specifically in women at or younger than the mean age of natural menopause. Our aim was to examine the effects of two oral bisphosphonates in postmenopausal women by age. METHODS: This was a post-hoc analysis of postmenopausal women <55 or > or =55 years old with low bone mineral density (BMD), randomized to once weekly alendronate 70 mg or risedronate 35 mg for 1 year with 1-year extensions in U.S. and International Fosamax Actonel Comparison Trials. RESULTS: In both age subgroups of postmenopausal women, alendronate produced significantly greater mean BMD increases from baseline than risedronate at hip trochanter, lumbar spine, total hip, and femoral neck. Changes in BMD were not significantly different between younger and older alendronate-treated women, although treatment differences favoring alendronate were numerically greater for younger than older postmenopausal women at all sites. Significantly greater reductions in bone turnover markers also occurred with alendronate vs. risedronate in both subgroups. Tolerability was similar between treatments. CONCLUSIONS: In this post-hoc subgroup analysis of older and younger postmenopausal women receiving alendronate or risedronate, larger treatment differences in BMD gain in younger compared with older women suggest that patient age may affect the relative efficacy of these antiresorptive drugs.

The primary care osteoporosis risk of fracture screening (POROS) study: design and baseline characteristics.

OBJECTIVE: POROS evaluates a 3-step fracture risk screening program in women 50-64 not previously diagnosed with osteoporosis. This report details the research design and baseline characteristics. METHODS: Recruiting from 6 primary care sites, baseline characteristics, including fracture risk factors, were assessed via self-administered questionnaires (SAQs). Subjects with >or=1 risk factor were randomized to Intervention or Non-Intervention. Those without any risk factors were placed in the No Risk Factors group. Bone turnover was measured in the Intervention group via urine N-telopeptide (NTx) testing. Subjects with NTx>50 had central hip and spine Dual-energy X-ray Absorptiometry (dxa). All groups were followed for 24 months, completing SAQs on osteoporosis management and fractures. At baseline, comparisons were made on demographics, health status, and prevalence of fracture risk factors. RESULTS: 2839 women were enrolled and included in baseline analyses (1464 Intervention, 372 Non-Intervention, and 1003 No Risk Factors). The mean age was 56.1 and 81.1% were postmenopausal. As expected by randomization, the Intervention and Non-Intervention groups had similar baseline characteristics. The most commonly reported fracture risk factors were body mass index <24 kg/m(2) and needing to use arms to stand from a chair. Subjects in the No Risk Factors group were more likely to be younger, heavier, Hispanic, in good health, a non-smoker, and to drink less alcohol. CONCLUSION: A stepwise screening program, utilizing data on fracture risk factors and high bone turnover prior to obtaining central bone density, can contribute significantly to fracture risk assessment in perimenopausal and younger postmenopausal women.

Phase I study of capecitabine and oxaliplatin in combination with the proteasome inhibitor bortezomib in patients with advanced solid tumors.

PURPOSE: The combination of capecitabine and oxaliplatin has clinical benefit in a variety of gastrointestinal malignancies. The proteasome inhibitor bortezomib enhances the cytotoxic activity of fluoropyrimidines and platinum agents in vivo, and targeting of NF-kappaB may overcome chemotherapy resistance. Thus, we performed this phase I study to document the safety and obtain preliminary efficacy data for the combination of capecitabine, oxaliplatin, and bortezomib. PATIENTS AND METHODS: Patients with advanced solid tumors were treated with oxaliplatin 130 mg/m(2) intravenously on day 1, capecitabine 750-900 mg/m(2) twice daily orally for 14 days, and bortezomib 1.0, 1.3, or 1.6 mg/m(2) intravenously on days 1 and 8 of 21 day cycles. CT scans were repeated every 2 cycles. RESULTS: Thirteen patients received 45 cycles of treatment (median, 2; range, 1-8). No dose-limiting toxicities were noted at all bortezomib dose levels when administered with full dose capecitabine and oxaliplatin. The most common grade 3 nonhematologic toxicities during any cycle of therapy included elevated transaminases (3), vomiting, diarrhea, and dehydration (2 each). Only one patient experienced grade 3 peripheral neuropathy in cycle 8. Three objective tumor responses were noted (squamous cell of anus, adenocarcinoma of unknown primary, adenocarcinoma of rectum). CONCLUSIONS: Weekly bortezomib can be safely combined with full doses of capecitabine and oxaliplatin. As 1.6 mg/m(2) weekly of bortezomib is the maximum tolerated dose in single-agent studies, no further dose escalation was performed in this study. Preliminary evidence of antitumor activity is demonstrated. The further evaluation of this combination in diseases for which capecitabine and oxaliplatin have efficacy should be considered.

Induction cisplatin and paclitaxel followed by combination chemoradiotherapy with 5-fluorouracil, cisplatin, and paclitaxel before resection in localized esophageal cancer: a phase II report.

BACKGROUND: Multimodality therapy for esophageal cancer holds promise for improving outcome in this lethal disease. On the basis of encouraging data from a phase I trial, we conducted a phase II study of preoperative chemotherapy, followed by concurrent chemoradiotherapy and surgery. METHODS: Patients with clinically staged resectable esophageal cancer were treated with induction cisplatin and paclitaxel, followed by 45 Gy of external beam radiation with concurrent infusional 5-fluorouracil and weekly cisplatin and paclitaxel. Four to eight weeks after multimodality induction, esophagectomy was performed in suitable patients. Study end points were survival, pathologic complete response, and toxicity. RESULTS: Twenty-one patients were enrolled with a median age of 58 years, and all patients were clinically staged II or III. Sixteen (76.2%) patients completed the trial, of whom four (25%) had a pathologic complete response. One patient died from postoperative complications. Grade 3 or 4 toxicity was observed in 76% of patients, and dose-limiting toxicity was seen in 6 of the first 14 patients, thus necessitating a planned dose reduction of paclitaxel. At a median follow-up of 30 months, 13 patients remain alive. The 2-year disease-specific survival for the study population was 78%. CONCLUSIONS: This regimen of multimodality therapy before resection resulted in an encouraging 2-year survival rate but a disappointing rate of pathologic complete response and was toxic, necessitating a predetermined paclitaxel dose reduction. The incorporation of taxanes into induction strategies for esophageal cancer seems promising, but the optimal schedule remains undefined.