Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study.

Belumosudil, an investigational oral selective inhibitor of Rho-associated coiled-coil-containing protein kinase 2 (ROCK2), reduces type 17 and follicular T helper cells via downregulation of STAT3 and enhances regulatory T cells via upregulation of STAT5. Belumosudil may effectively treat patients with chronic graft-versus-host disease (cGVHD), a major cause of morbidity and late nonrelapse mortality after an allogeneic hematopoietic cell transplant. This phase 2 randomized multicenter registration study evaluated belumosudil 200 mg daily (n = 66) and 200 mg twice daily (n = 66) in subjects with cGVHD who had received 2 to 5 prior lines of therapy. The primary end point was best overall response rate (ORR). Duration of response (DOR), changes in Lee Symptom Scale score, failure-free survival, corticosteroid dose reductions, and overall survival were also evaluated. Overall median follow-up was 14 months. The best ORR for belumosudil 200 mg daily and 200 mg twice daily was 74% (95% confidence interval [CI], 62-84) and 77% (95% CI, 65-87), respectively, with high response rates observed in all subgroups. All affected organs demonstrated complete responses. The median DOR was 54 weeks; 44% of subjects have remained on therapy for ≥1 year. Symptom reduction with belumosudil 200 mg daily and 200 mg twice daily was reported in 59% and 62% of subjects, respectively. Adverse events (AEs) were consistent with those expected in patients with cGVHD receiving corticosteroids and other immunosuppressants. Sixteen subjects (12%) discontinued belumosudil because of possible drug-related AEs. Belumosudil, a promising therapy for cGVHD, was well tolerated with clinically meaningful responses. This trial was registered at www.clinicaltrials.gov as #NCT03640481.

Enrichment in a stoichiometric model of two producers and one consumer.

We consider a stoichiometric population model of two producers and one consumer. Stoichiometry can be thought of as the tracking of food quality in addition to food quantity. Our model assumes a reduced rate of conversion of biomass from producer to consumer when food quality is low. The model is open for carbon but closed for nutrient. The introduction of the second producer, which competes with the first, leads to new equilibria, new limit cycles, and new bifurcations. The focus of this paper is on the bifurcations which are the result of enrichment. The primary parameters we vary are the growth rates of both producers. Secondary variable parameters are the total nutrients in the system, and the producer nutrient uptake rates. The possible equilibria are: no-life, one-producer, coexistence of both producers, the consumer coexisting with either producer, and the consumer coexisting with both producers. We observe limit cycles in the latter three coexistence combinations. Bifurcation diagrams along with corresponding representative time series summarize the behaviours observed for this model.

Forest patch modeling: using high performance computing to simulate aboveground interactions among individual trees.

Functional-structural plant models (FSPMs) typically integrate suites of detailed physiological and phenological processes to simulate the growth of individual plants. Recent advances in high-performance computing have allowed FSPMs to be extended to patches of interacting trees. Here, we describe a parallel modelling strategy to run simultaneous individual tree models across an 8 × 8 patch of trees. The 64 'core' trees are surrounded by multiple rings of neighbour trees to remove edge effects. A sensitivity analysis of the patch model demonstrates that computational factors such as the number of independently simulated trees (9 v. 36) or number of neighbour rings (3 v. 6) did not significantly influence model estimates of tree volume growth. Updated submodels for phenology and redistribution of overwinter carbohydrate storage allow the simulation to be more responsive to above ground competition among trees in a patch over multiple growing seasons. An 8-year patch-scale simulation of aspen clones 216 and 259 was conducted using high-resolution environmental data from the Aspen FACE Experiment, a long-term free-air carbon dioxide enrichment (FACE) study. Tree heights and volumes were comparable to 8-year growth measurements made at the Aspen FACE site.

Effect of anatomical fine structure on the dispersion of solutes in the spinal subarachnoid space.

The dispersion of a solute bolus is calculated for cerebrospinal fluid undergoing oscillatory flow in the subarachnoid space of the spine. The fine structure of the subarachnoid space (nerves and trabeculae) enhances both longitudinal and transverse dispersions five to ten times over a simple model with an open annular space. Overall, dispersion is >10(3) times simple molecular diffusion. The result of enhanced dispersion is rapid spread and dilution of the bolus, effectively stirred by fluid movement around the fine structure.

Effect of anatomical fine structure on the flow of cerebrospinal fluid in the spinal subarachnoid space.

The lattice Boltzmann method is used to model oscillatory flow in the spinal subarachnoid space. The effect of obstacles such as trabeculae, nerve bundles, and ligaments on fluid velocity profiles appears to be small, when the flow is averaged over the length of a vertebra. Averaged fluid flow in complex models is little different from flow in corresponding elliptical annular cavities. However, the obstacles stir the flow locally and may be more significant in studies of tracer dispersion.

New bone formation with teriparatide [human parathyroid hormone-(1-34)] is not retarded by long-term pretreatment with alendronate, estrogen, or raloxifene in ovariectomized rats.

With the ready availability of several osteoporosis therapies, teriparatide [human PTH-(1-34)] is likely to be prescribed to postmenopausal women with prior exposure to agents that prevent bone loss, such as bisphosphonates, estrogen, or selective estrogen receptor modulators. Therefore, we evaluated the ability of once daily teriparatide to induce bone formation in ovariectomized (Ovx) rats with extended prior exposure to various antiresorptive agents, such as alendronate (ABP), 17 alpha-ethinyl estradiol (EE), or raloxifene (Ral). Sprague Dawley rats were Ovx and treated with ABP (28 microg/kg, twice weekly), EE (0.1 mg/kg per d), or Ral (1 mg/kg per d) for 10 months before switching to teriparatide 30 microg/kg per d for another 2 months. Analysis of the proximal tibial metaphysis showed that all three antiresorptive agents prevented ovariectomy-induced bone loss after 10 months, but were mechanistically distinct, as shown by histomorphometry. Before teriparatide treatment, ABP strongly suppressed activation frequency and bone formation rate to below levels in other treatment groups, whereas these parameters were not different from sham values for EE or Ral. Trabecular area for ABP, EE, and Ral were greater than that in Ovx controls. However, the trabecular bone effects of ABP were attributed not only to effects on the secondary spongiosa, but also to the preservation of primary spongiosa, which was prevented from remodeling. After 2 months of teriparatide treatment, lumbar vertebra showed relative bone mineral density increases of 18%, 7%, 11%, and 10% for vehicle/teriparatide, ABP/teriparatide, EE/teriparatide, and Ral/teriparatide, respectively, compared with 10 month levels. Histomorphometry showed that trabecular area was increased by 105%, 113%, 36%, and 48% for vehicle/teriparatide, ABP/teriparatide, EE/teriparatide, and Ral/teriparatide, respectively, compared with 10 month levels. Teriparatide enhanced mineralizing surface, mineral apposition rate, and bone formation rate in all groups. Compression testing of vertebra showed that teriparatide improved strength (peak load) and toughness in all groups to a proportionately similar extent compared with 10 month levels. These data showed a surprising ability of the rat skeleton to respond to teriparatide despite extensive pretreatment with ABP, EE, or Ral. Therefore, the mature skeleton of Ovx rats remains highly responsive to the appositional effects of teriparatide regardless of pretreatment status in terms of cancellous bone area or rate of bone turnover.

Synthesis and biological evaluation of paclitaxel-C225 conjugate as a model for targeted drug delivery.

Tumor-targeted drug delivery is an attractive strategy in cancer treatment. We have previously reported a paclitaxel model conjugate using a bombesin receptor-recognizing peptide in which the drug cytotoxicity against H1299 human nonsmall cell lung cancer was enhanced compared to unconjugated taxol. In an effort to expand the development of tumor-recognizing taxanes, paclitaxel (PTX, taxol) was conjugated to the anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody (MAb) Erbitux (C225) to serve as a model MAb-mediated drug delivery compound. Thus, paclitaxel was derivatized at its 2'-hydroxy function by introduction of a succinate linker, and the carboxyl group of the latter was covalently attached to C225 through amide bond formation. The final product conjugate (PTXC225) was analyzed mass spectrometrically for assessment of the drug-to-antibody ratios. Cytotoxicity screening of the drug-antibody conjugate against A431, UM-SCC-1, and UM-SCC-6 cells indicated an enhancement in cytocidal effect of paclitaxel as compared to those of the free drug, the intact antibody, and a physical mixture of the two (the controls). In A431 cells, the conjugate showed 25.2% +/- 2.2% of apoptosis induction as compared to little or no apoptosis caused by the controls. Biodistribution analysis of the PTXC225 in tumor-implanted nude mice and a tyrosine-kinase assay showed that conjugation of the drug did not interfere with the immunoreactivity of the antibody. The 24-h tumor uptake of C225 and PTXC225 were 11.7% +/- 6.0% and 7.1% +/- 3.6% of the injected dose per gram of tissue (%ID/g), respectively, which were not significantly different. Also, in A431-implanted nude mice, the conjugate and C225 showed tumor growth inhibition effects of 57.2% and 41.2%, respectively, against a saline-treated control, which were not significantly different from each other. This lack of difference in the in vivo antitumor activity of the MAb-delivered drug and free PTX may be due to either a relatively low dose of the antibody-delivered drug (346 microg/kg), or an untimely release of it, or both. The tumor growth inhibition pattern of the conjugate, however, was identical to that of C225, indicating that the attachment of PTX did not affect the antigen-binding and growth inhibitory features of the MAb. These preliminary results demonstrate the potential of tumor-targeted delivery of taxol as a promising strategy in cancer treatment and warrant further work to develop more suitable drug-MAb linkers as well as improved dosage and treatment protocols.

Epidermal growth factor receptor as a therapeutic target in head and neck cancer.

Epidermal growth factor receptor (EGFR) is a cell membrane protein that is overexpressed in almost all head and neck squamous cell carcinomas. Overexpression of EGFR has been associated with a poor prognosis in head and neck tumors as well as many other malignancies. This cell membrane protein has been considered an excellent choice as an antitumor therapeutic target. Preclinical and clinical investigations are currently underway to determine the most appropriate use of anti-EGFR therapies. IMC-C225 is a monoclonal antibody that blocks EGFR function and has shown promising radiosensitizing and chemosensitizing properties in preclinical studies. Additionally, initial phase I/II clinical studies of IMC-C225 in combination with radiotherapy or chemotherapy have suggested that the preclinical findings may translate into promising clinical results in squamous cell carcinoma of the head and neck. Therefore, patients with head and neck carcinomas are being evaluated in phase III studies exploring the combination of IMC-C225 and radiation as well as the combination of IMC-C225 and cisplatin in locally advanced and recurrent disease.

Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMC-C225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts.

Colon carcinomas frequently express the epidermal growth factor receptor (EGFR), and this expression correlates with more aggressive disease and poor prognosis. Previous studies have shown that EGFR blockade by monoclonal antibody IMC-C225 can inhibit the growth of human colon carcinoma tumor cells in vitro and xenografts of these tumors in athymic mice. In this report, we have studied the in vivo activity of IMC-C225 combined with the topoisomerase I inhibitor irinotecan (CPT-11) using two models of human colorectal carcinoma in nude mice. IMC-C225 was tested at a dose of 1 or 0.5 mg administered q3d. CPT-11 was administered at a dose of 100 mg/kg/week or a maximum tolerated dose of 150 mg/kg/week. Treatment with the combination of IMC-C225 (1 and 0.5 mg) and CPT-11 (100 mg/kg) significantly inhibited the growth of established DLD-1 and HT-29 tumors compared with either CPT-11 or IMC-C225 monotherapy (P < 0.05). Combination therapy with IMC-C225 (1 mg) and the MTD of CPT-11 (150 mg/kg) resulted in a regression rate of 100 and 60% of established DLD-1 and HT-29 tumors, respectively. In a refractory tumor model, combined treatment with IMC-C225 and CPT-11 significantly inhibited the growth of CPT-11 refractory DLD-1 and HT-29 tumors, whereas either agent alone did not control tumor growth. Histological examination of treated tumors showed extensive tumor necrosis, decreased tumor cell proliferation, increased tumor cell apoptosis, and a marked decrease in tumor vasculature. These results suggest that EGFR blockade by IMC-C225 combined with topoisomerase I inhibitors may be an effective therapy against chemorefractory colorectal carcinoma tumors.

Research on complementary and alternative medicine using randomized controlled trials.

In 1998, the National Institutes of Health (NIH) formed the National Center for Complementary and Alternative Medicine (NCCAM) from what had formerly been the Office of Alternative Medicine. This presentation opens with a brief discussion on the history of the NIH and the development of CAM at the NIH before moving on to the work of the NCCAM. The NCCAM is moving toward an integration of CAM therapies into conventional medicine, when there is evidence for the value of CAM. One of twenty-five institutes or centers at the NIH, the NCCAM looks at evidence-based medicine and public health. In this context, "public health" means educating the public about its health. The NCCAM supports training to conduct research and plays an important role in disseminating information to the public and to health providers about what works and what is safe. This evolves into the concept of evidence-based medical and public-health practices, that is, making decisions on the basis of evidence from scientifically rigorous studies that are sufficiently large to provide a confident estimate of biologically and medically important benefits and risks. In the hierarchy of generating scientific evidence, randomized controlled trials are considered the "gold standard." The NCCAM entertains proposals for studies that come spontaneously from investigators, or, upon identifying an existing need that is not being met by the investigative community, the NCCAM can initiate a request for proposals. Every proposal is subjected to a rigorous application and review process. Another possible step in the assessment of the evidence from clinical trials is to do a systematic analysis of several studies to bring together all the information that is available. Systematic reviews of smaller studies that individually might have an insufficient sample size can assist in making treatment decisions, but, importantly, they can lead the NCCAM in the development of future, definitive studies. Training to conduct research is especially important to CAM. This presentation outlines several approaches the NCCAM has to training (see http://nccam.nih.gov).

New opportunities and proven approaches in complementary and alternative medicine research at the National Institutes of Health.

This presentation describes some of the issues that arise when applying the clinical-trial approach of conventional medicine to complementary and alternative medicine (CAM) modalities. Conventional medicine has been making the evolution to using an evidence base and to making recommendations only when the evidence is strong. The National Center for Complementary Medicine (NCCAM), one of twenty-five Institutes or Centers of the National Institutes of Health (NIH), is working to hold CAM to the same high standards, not by rejecting previous CAM research, but by building on that strong evidence base of what works and what is safe. The process for conventional drug and device development follows an orderly process of preclinical studies (usually on animals), phase I, phase II, and phase III studies (with the large human clinical trial phase taking place in phase III). Today, the randomized controlled trial is recognized as providing the highest level of scientific evidence. This conventional medicine approach to development is now being used to develop complementary and alternative therapies. For instance, the discovery and development of Taxol (Bristol-Meyers Squibb, New York, NY), an extract from the bark of the Pacific yew tree that is now a widely used chemotherapeutic agent, followed the conventional pathway to approval and marketing. But for most CAM products, the pathway is not so straightforward. Most CAM therapies are traditional therapies or new products that are already available to the public. Most of what is known about these therapies is of an anecdotal nature. There has been little isolation of the active principals from the crude product and there has usually been no preclinical testing. This presentation details various approaches and programs that address how to plan and conduct a rigorous clinical trial of a CAM product. And, while it takes a good deal of persistence and a strong focus on what are the critical principals in a trial, I conclude that it is possible to apply randomized controlled trials to most of the CAM modalities.

Hyoscyamine as a pharmacological adjunct in colonoscopy: a randomized, double blinded, placebo-controlled trial.

OBJECTIVE: Investigators have assessed the utility of antispasmodic agents in colonoscopy, with conflicting results. The aim of this study is to determine the effects of premedication with hyoscyamine, an anticholinergic antispasmodic, on outcomes in colonoscopy. METHODS: A total of 165 patients undergoing elective colonoscopy were randomized in a double blinded fashion to one of three arms: intravenous hyoscyamine (0.25 mg), oral hyoscyamine (0.25 mg), or placebo, administered 20-40 min before colonoscopy. Primary outcome measures included insertion time to cecum, patient's assessment of pain, and physician assessment of spasm. Secondary outcome measures included amount of analgesic medications used, total procedure time, amount and type of pathology visualized, and physician assessment of patient's pain. RESULTS: Bivariate analysis showed no difference between the three groups in insertion time (13.8 min, 14.8 min, and 13.8 min for placebo, intravenous hyoscyamine, and oral hyocyamine, respectively), analgesic medication necessary, or any other primary or secondary outcome variable. Multivariate analysis controlling for potential confounders also failed to demonstrate any differences between the groups. Women had higher procedure duration and analgesic requirement, and reported more pain than did men. CONCLUSIONS: This randomized, double blinded, placebo-controlled trial did not demonstrate efficacy of either intravenous or oral hyoscyamine as a premedication for colonoscopy.

Research on physical activity and health among people with disabilities: a consensus statement.

Research is required to advance the understanding of issues related to the effect of physical activity on health and disease prevention among people with disabilities. This report is the result of a consensus process using selected experts in health and exercise. The purpose of the consensus conference was to identify research priorities for physical activity and health among people with disabilities. Priorities were established by 30 participants, who were selected by the principal investigators to achieve balance in the areas of engineering, epidemiology, medicine, nutrition, exercise physiology, and psychology. Experts summarized relevant data from their research and from comprehensive review of the scientific literature on the topic areas chosen for the conference. Public commentary was provided by participants in the 1996 Paralympic Congress. Panel members discussed openly all material presented to them in executive session. Commentary from open discussion periods were recorded and transcribed. Selected panelists prepared first drafts of the consensus statements for each research priority question. All of these drafts were distributed to the panelists and pertinent experts. The documents were edited by the drafting committee to obtain consensus. This research priority setting process revealed that greater emphasis must be placed on determining the risks and benefits of exercise among people with disabilities. Exercise must be studied from the perspective of disease prevention while mitigating risk for injury. Five areas were identified as focal points for future work: epidemiological studies; effects of nutrition on health and ability to exercise; cardiovascular and pulmonary health; children with disabilities; and accessibility and safety of exercise programs. As people with disabilities live longer, the need for addressing long-term health issues and risk for secondary disability must receive greater attention. As a consequence of the consensus process, specific recommendations for future research regarding the impact of exercise on the health and quality of life of persons with disabilities were defined.

Prevention research at the National Institutes of Health.

Prevention of disease and disability and preservation of health are compelling strategies that are endorsed by the public, health care providers, and researchers. Despite this general acceptance of the concept, the "devil is in the details." What can and should be recommended with confidence to the public and health care providers regarding prevention and how can these recommendations be implemented? Prevention programs should be based on durable evidence of efficacy and should assure that the benefits of interventions and changes exceed the risks. The latter is particularly important for population-based primary prevention because many are influenced but fewer may benefit. Prevention research must provide the evidence of benefit and risk. The responsibility of the National Institutes of Health (NIH) is to develop the scientific basis for prevention and to train prevention scientists who are responsible for creating this science base. The interpretation and dissemination of information from research studies are important and necessary aspects to assure translation of the science into personal and public health practices. The components of prevention research are investigation of the factors that place individuals and groups at risk of disease and disability; trials of the interventions that can modify this risk; and testing the approaches that can effectively implement beneficial changes. NIH is committed to addressing these endeavors, and its individual Institutes and Centers support a broad portfolio of prevention research. This paper will provide an overview of NIH support, the functional relationships of prevention research within NIH, and background information that can be useful to those interested in research.

Importance of baseline functional and socioeconomic factors for participation in cardiac rehabilitation.

Enrollment in cardiac rehabilitation has been reported to improve exercise capacity, psychological well-being, and survival. However, participation rates are low and the reasons for nonparticipation have not been adequately defined. The purpose of this study was to evaluate the major correlates of nonparticipation and to examine the level of participation of patients who stand to benefit most on the basis of preenrollment functional status and health behaviors. Three hundred ninety-three patients undergoing coronary artery bypass surgery (1) had baseline functional status and quality-of-life data collected, and (2) were recruited for participation in the Duke Center for Living comprehensive 3-week post-coronary bypass surgery rehabilitation program. Baseline demographic, clinical, catheterization, functional status, psychological status, and health behavior descriptors were analyzed to identify univariate and multivariable correlates of a patient's decision to participate in the program. At baseline, most clinical factors were similar in participants (n = 52) and nonparticipants (n = 341), but the nonparticipants were more often women (26% vs 12%, p = 0.02). Participants were also more likely to be employed (63% vs 45%, p = 0.02) and had a higher education and income distribution than nonparticipants (both p = 0.001). On 2 separate scales, nonparticipants had significantly more baseline functional impairment than participants (both p = 0.001). In multivariable analysis, the independent correlates of higher participation rates were: higher education (college graduates 71% more likely to participate than high school graduates) and better baseline Duke Activity Status Index (patients with mild functional impairment were at least 42% more likely to participate than patients with moderate impairment).(ABSTRACT TRUNCATED AT 250 WORDS)