An experimental investigation into a dual taper acoustic black hole termination.

Acoustic black holes (ABHs) can provide effective damping of the reflected wave component when used to terminate a beam. The behaviour of an ABH is characterised by its local modes, which produce narrow frequency bands of high absorption. To enhance the performance of ABH terminations, a multi-taper ABH has previously been proposed and analytical results demonstrate that the use of two or more tapers produces a compound effect on the reflection coefficient, resulting in more bands of low reflection. This paper extends this work and presents an experimental realisation of a multi-taper ABH confirming the previous analytical results.

TB stigma and its correlates among HIV-positive people who inject drugs in Ukraine.

BACKGROUND: TB is commonly stigmatized. Correlates of perceived TB stigma have not been assessed specifically among HIV-positive people who inject drugs (PWIDs). It is also unclear how perceived TB stigma intersects with other forms of stigma affecting this population. We aimed to evaluate perceived TB stigma, its correlates and its intersection with HIV and substance use stigma among HIV-positive PWIDs in Ukraine.METHODS: Among 191 participants at three sites across Ukraine, we assessed stigma scores, socio-demographic, behavioral and health-related variables by TB status (history of active TB infection, history of treatment for latent TB infection LTBI, no history of TB infection). We used self-reported history of LTBI treatment as a proxy for LTBI status. We used ordinary least squares to estimate factors associated with perceived TB stigma.RESULTS: Lower perceived TB stigma scores were associated with LTBI status (adjusted beta (aß) -0.2, 95% CI -0.3 to 0.0; P = 0.032). Higher perceived TB stigma scores were associated with higher substance use stigma scores (aß 0.1, 95% CI 0.0 to 0.2; P = 0.004). Depressive symptoms were common in this sample, although not significantly associated with TB status.CONCLUSION: History of LTBI treatment appears to impact beliefs about perceived TB stigma. Individuals who endorse higher substance use stigma are more likely to hold stigmatizing perceptions about people with TB. HIV-positive PWIDs with history of active TB infection or LTBI treatment commonly experience mental health distress. This stigma intersection needs further exploration in this population, including of its relation with mental health, to provide further insights for targeted interventions.

A parametric study of an acoustic black hole on a beam.

Acoustic black holes (ABHs) are geometric structural features that provide a potential lightweight damping solution for flexural vibrations. In this article, a parametric study of an ABH on a beam has been carried out to assess how practical design constraints affect its behaviour, thus providing detailed insight into design trade-offs. The reflection coefficient of the ABH has been calculated for each taper profile, parameterised via the tip-height, taper-length, and power-law, and it has been shown to exhibit spectral bands of low reflection. These bands have been related to the modes of the ABH cell and become more closely spaced in frequency as the ABH parameters are suitably varied. This suggests that ABH design should maximise the modal density to minimise the broadband reflection coefficient; however, the minimum level of reflection is also dependent on the power-law and tip-height. Consequently, broadband reflection values have been used to show that optimum power-law and tip-height settings exist that achieve a balance between maximum modal density and minimum level of reflection. Additionally, at discrete frequencies, in cases where tip-height and taper-length are practically constrained, the power law can be tuned to maximise performance. Finally, an experimental study is used to validate the results.

Bone marrow transplant with post-transplant cyclophosphamide for recessive dystrophic epidermolysis bullosa expands the related donor pool and permits tolerance of nonhaematopoietic cellular grafts.

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is a severe systemic genodermatosis lacking therapies beyond supportive care for its extensive, life-limiting manifestations. OBJECTIVES: To report the safety and preliminary responses of 10 patients with RDEB to bone marrow transplant (BMT) with post-transplant cyclophosphamide (PTCy BMT) after reduced-intensity conditioning with infusions of immunomodulatory donor-derived mesenchymal stromal cells (median follow-up 16 months). METHODS: BMT toxicities, donor blood and skin engraftment, skin biopsies, photographic and dynamic assessments of RDEB disease activity were obtained at intervals from pre-BMT to 1 year post-BMT. RESULTS: Related donors varied from haploidentical (n = 6) to human leucocyte antigen (HLA)-matched (n = 3), with one HLA-matched unrelated donor. Transplant complications included graft failure (n = 3; two pursued a second PTCy BMT), veno-occlusive disease (n = 2), posterior reversible encephalopathy (n = 1) and chronic graft-versus-host disease (n = 1; this patient died). In the nine ultimately engrafted patients, median donor chimerism at 180 days after transplant was 100% in peripheral blood and 27% in skin. Skin biopsies showed stable (n = 7) to improved (n = 2) type VII collagen protein expression by immunofluorescence and gain of anchoring fibril components (n = 3) by transmission electron microscopy. Early signs of clinical response include trends toward reduced body surface area of blisters/erosions from a median of 49·5% to 27·5% at 100 days after BMT (P = 0·05), with parental measures indicating stable quality of life. CONCLUSIONS: PTCy BMT in RDEB provides a means of attaining immunotolerance for future donor-derived cellular grafts (ClinicalTrials.gov identifier NCT02582775). What's already known about this topic? Severe, generalized recessive dystrophic epidermolysis bullosa (RDEB) is marked by great morbidity and early death. No cure currently exists for RDEB. Bone marrow transplant (BMT) is the only described systemic therapy for RDEB. What does this study add? The first description of post-transplant cyclophosphamide (PTCy) BMT for RDEB. PTCy was well tolerated and provided excellent graft-versus-host disease prophylaxis, replacing long courses of calcineurin inhibitors in patients receiving human leucocyte antigen-matched sibling BMT. What is the translational message? The PTCy BMT platform permits identification of a suitable related donor for most patients and for subsequent adoptive transfer of donor nonhaematopoietic cells after establishment of immunological tolerance.

Cellular geometry controls the efficiency of motile sperm aggregates.

Sperm that swim collectively to the fertilization site have been observed across several vertebrate and invertebrate species, with groups ranging in size from sperm pairs to massive aggregates containing hundreds of cells. Although the molecular mechanisms that regulate sperm-sperm adhesion are still unclear, aggregation can enhance sperm motility and thus offer a fertilization advantage. Here, we report a thorough computational investigation on the role of cellular geometry in the performance of sperm aggregates. The sperm head is modelled as a persistent random walker characterized by a non-trivial three-dimensional shape and equipped with an adhesive region where cell-cell binding occurs. By considering both, a simple parametric head shape and a computer reconstruction of a real head shape based on morphometric data, we demonstrate that the geometry of the head and the structure of the adhesive region crucially affects both the stability and motility of the aggregates. Our analysis further suggests that the apical hook commonly found in the sperm of muroid rodents might serve to shield portions of the adhesive region and promote efficient alignment of the velocities of the interacting cells.

A platform for high-throughput screening of DNA-encoded catalyst libraries in organic solvents.

We have developed a novel high-throughput screening platform for the discovery of small-molecules catalysts for bond-forming reactions. The method employs an in vitro selection for bond-formation using amphiphilic DNA-encoded small molecules charged with reaction substrate, which enables selections to be conducted in a variety of organic or aqueous solvents. Using the amine-catalysed aldol reaction as a catalytic model and high-throughput DNA sequencing as a selection read-out, we demonstrate the 1200-fold enrichment of a known aldol catalyst from a library of 16.7-million uncompetitive library members.

Systemic gene delivery transduces the enteric nervous system of guinea pigs and cynomolgus macaques.

Characterization of adeno-associated viral vector (AAV) mediated gene delivery to the enteric nervous system (ENS) was recently described in mice and rats. In these proof-of-concept experiments, we show that intravenous injections of clinically relevant AAVs can transduce the ENS in guinea pigs and non-human primates. Neonatal guinea pigs were given intravenous injections of either AAV8 or AAV9 vectors that contained a green fluorescent protein (GFP) expression cassette or phosphate-buffered saline. Piglets were euthanized three weeks post injection and tissues were harvested for immunofluorescent analysis. GFP expression was detected in myenteric and submucosal neurons along the length of the gastrointestinal tract in AAV8 injected guinea pigs. GFP-positive neurons were found in dorsal motor nucleus of the vagus and dorsal root ganglia. Less transduction occurred in AAV9-treated tissues. Gastrointestinal tissues were analyzed from young cynomolgus macaques that received systemic injection of AAV9 GFP. GFP expression was detected in myenteric neurons of the stomach, small and large intestine. These data demonstrate that ENS gene delivery translates to larger species. This work develops tools for the field of neurogastroenterology to explore gut physiology and anatomy using emerging technologies such as optogenetics and gene editing. It also provides a basis to develop novel therapies for chronic gut disorders.

The HIT Expert Probability (HEP) Score: a novel pre-test probability model for heparin-induced thrombocytopenia based on broad expert opinion.

BACKGROUND: The diagnosis of heparin-induced thrombocytopenia (HIT) is challenging. Over-diagnosis and over-treatment are common. OBJECTIVES: To develop a pre-test clinical scoring model for HIT based on broad expert opinion that may be useful in guiding clinical decisions regarding therapy. PATIENTS/METHODS: A pre-test model, the HIT Expert Probability (HEP) Score, was constructed based on the opinions of 26 HIT experts. Fifty patients referred to a reference laboratory for HIT testing comprised the validation cohort. Two hematology trainees scored each patient using the HEP Score and a previously published clinical scoring system (4 T's). A panel of three independent experts adjudicated the 50 patients and rendered a diagnosis of HIT likely or unlikely. All subjects underwent HIT laboratory testing with a polyspecific HIT ELISA and serotonin release assay (SRA). RESULTS: The HEP Score exhibited significantly greater interobserver agreement [intraclass correlation coefficient: 0.88 (95% CI 0.80-0.93) vs. 0.71 (0.54-0.83)], correlation with the results of HIT laboratory testing and concordance with the diagnosis of the expert panel (area under receiver-operating curve: 0.91 vs. 0.74, P = 0.017) than the 4 T's. The model was 100% sensitive and 60% specific for determining the presence of HIT as defined by the expert panel and would have allowed for a 41% reduction in the number of patients receiving a direct thrombin inhibitor (DTI). CONCLUSION: The HEP Score is the first pre-test clinical scoring model for HIT based on broad expert opinion, exhibited favorable operating characteristics and may permit clinicians to confidently reduce use of alternative anticoagulants. Prospective multicenter validation is warranted.

Surgically induced osteoarthritis in the rat results in the development of both osteoarthritis-like joint pain and secondary hyperalgesia.

OBJECTIVE: In the present study, we sought to develop/characterize the pain profile of a rat model of surgically induced osteoarthritis (OA). METHODS: OA was surgically induced in male Lewis rats (200-225 g) by transection of the medial collateral ligament and medial meniscus of the femoro-tibial joint. In order to characterize the pain profile, animals were assessed for a change in hind paw weight distribution (HPWD), development of mechanical allodynia, and the presence of thermal and mechanical hyperalgesia. Rofecoxib and gabapentin were examined for their ability to decrease change in weight distribution and tactile allodynia. RESULTS: Transection of the medial collateral ligament and medial meniscus of male Lewis rats resulted in rapid (<3 days) changes in hind paw weight bearing and the development of tactile allodynia (secondary hyperalgesia). There was, however, no appreciable effect on thermal hyperalgesia or mechanical hyperalgesia. Treatment with a single dose of rofecoxib (10 mg/kg, PO, day 21 post surgery) or gabapentin (100mg/kg, PO, day 21 post surgery) significantly attenuated the change in HPWD, however, only gabapentin significantly decreased tactile allodynia. CONCLUSION: The rat medial meniscal tear (MMT) model mimics both nociceptive and neuropathic OA pain and is responsive to both a selective cylooxygenase-2 (COX-2) inhibitor commonly utilized for OA pain (rofecoxib) and a widely prescribed drug for neuropathic pain (gabapentin). The rat MMT model may therefore represent a predictive tool for the development of pharmacologic interventions for the treatment of the symptoms associated with OA.

Binding of 14-3-3beta to the carboxyl terminus of Wee1 increases Wee1 stability, kinase activity, and G2-M cell population.

Wee1 protein kinase plays an important regulatory role in cell cycle progression. It inhibits Cdc-2 activity by phosphorylating Tyr15 and arrests cells at G2-M phase. In an attempt to understand Wee1 regulation during cell cycle, yeast two-hybrid screening was used to identify Wee1-binding protein(s). Five of the eight positive clones identified encode 14-3-3beta. In vivo binding assay in 293 cells showed that both full-length and NH2-terminal truncated Wee1 bind with 14-3-3beta. The 14-3-3beta binding site was mapped to a COOH-terminal consensus motif, RSVSLT (codons 639 to 646). Binding with 14-3-3beta increases the protein level of full-length Wee1 but not of the truncated Wee1. Accompanying the protein level increases, the kinase activity of Wee1 also increases when coexpressed with 14-3-3beta. Increased Wee1 protein level/enzymatic activity is accountable, at least in part, to an increased Wee1 protein half-life when coexpressed with 14-3-3beta. The protein half-life of the NH2-terminal truncated Wee1 is much longer than that of the full-length protein and is not affected by 14-3-3beta cotransfection. Biologically, 14-3-3beta/Wee1 coexpression increases the cell population at G2-M phase. Thus, Wee1 binding with 14-3-3beta increases its biochemical activity as well as its biological function. The finding reveals a novel mechanism by which 14-3-3 regulates G2-M arrest and suggests that the NH2-terminal domain of Wee1 contains a negative regulatory sequence that determines Wee1 stability.

Human cytomegalovirus infection in a retinoblastoma cell line in vitro.

BACKGROUND: The focus of these studies was to determine whether the Y79 human retinoblastoma cell line could function as a good in vitro model system for studying human cytomegalovirus (HCMV) infection. METHODS: Y79 cells were exposed to an HCMV mutant carrying a LacZ gene, and the resulting beta-galactosidase expression in infected cells was assessed by flow cytometry. The extent to which the three classes of viral gene products immediate early, early, and late proteins - were expressed was analyzed by immunohistochemical staining and Western blotting. Infected Y79 cells were also co-cultivated on human foreskin fibroblast (SF cell) cultures to recover virus. RESULTS: Infection of Y79 cells with the virus resulted in beta-galactosidase expression as detected by flow-cytometric analysis. Immunohistochemical staining revealed that a portion of Y79 cells expressed antigens reactive to monoclonal antibodies against immediate early, early, and late HCMV proteins. The 43-kDa early gene product was also detected by Western blotting. Infected Y79 cells co-cultivated on SF cell cultures yielded infectious foci, which turned blue following X-gal staining, demonstrating productive HCMV infection in the Y79 cells. CONCLUSION: These results demonstrate that while HCMV can productively infect Y79 cultures, it does so in a highly inefficient manner, leading these authors to conclude that this cell line does not provide a particularly good model system to study HCMV infection.

Specific, irreversible inactivation of the epidermal growth factor receptor and erbB2, by a new class of tyrosine kinase inhibitor.

A class of high-affinity inhibitors is disclosed that selectively target and irreversibly inactivate the epidermal growth factor receptor tyrosine kinase through specific, covalent modification of a cysteine residue present in the ATP binding pocket. A series of experiments employing MS, molecular modeling, site-directed mutagenesis, and 14C-labeling studies in viable cells unequivocally demonstrate that these compounds selectively bind to the catalytic domain of the epidermal growth factor receptor with a 1:1 stoichiometry and alkylate Cys-773. While the compounds are essentially nonreactive in solution, they are subject to rapid nucleophilic attack by this particular amino acid when bound in the ATP pocket. The molecular orientation and positioning of the acrylamide group in these inhibitors in relation to Cys-773 entirely support these results as determined from docking experiments in a homology-built molecular model of the ATP site. Evidence is also presented to indicate that the compounds interact in an analogous fashion with erbB2 but have no activity against the other receptor tyrosine kinases or intracellular tyrosine kinases that were tested in this study. Finally, a direct comparison between 6-acrylamido-4-anilinoquinazoline and an equally potent but reversible analog shows that the irreversible inhibitor has far superior in vivo antitumor activity in a human epidermoid carcinoma xenograft model with no overt toxicity at therapeutically active doses. The activity profile for this compound is prototypical of a generation of tyrosine kinase inhibitors with great promise for therapeutic significance in the treatment of proliferative disease.

An in vivo model of human cytomegalovirus retinal infection.

PURPOSE: To develop an animal model system in which human retina implanted in the anterior chamber of the eyes of rats would support human cytomegalovirus replication. Cytomegalovirus retinitis currently represents the most common cause of posterior uveitis in many urban areas in North America. Despite the tremendous interest in cytomegalovirus retinitis as a result of the acquired immunodeficiency syndrome (AIDS) epidemic, human cytomegalovirus infection has been difficult to model in vivo because of its extreme species-specificity. METHODS: Human retina was introduced into the anterior chamber of athymic rats and allowed to attach to the rat iris. A human cytomegalovirus mutant carrying a beta-galactosidase indicator gene was then injected into the anterior chamber to infect the implanted tissue. After 4 weeks, the eyes were removed, sectioned, and developed with a chromogenic substrate to demonstrate the presence and location of beta-galactosidase expression. RESULTS: Multiple spreading foci of beta-galactosidase expression were found in the retinal implants, indicating that human cytomegalovirus replication had occurred within the human tissue. There was no infection of rat tissue. CONCLUSIONS: This model allows human cytomegalovirus infection of human retina to be established in vivo and sustained long enough to permit multiple cycles of viral replication to occur. The model thus has potential for evaluating antiviral therapies directed against human cytomegalovirus retinal disease.

Efficacy of a recombinant glycoprotein D subunit vaccine on the development of primary and recurrent ocular infection with herpes simplex virus type 1 in mice.

The protective efficacy of a glycoprotein D subunit vaccine (gD2 SB AS4) was evaluated in a mouse model of human recurrent herpetic stromal keratitis (HSK). When administered before primary infection, gD2 SB AS4 protected mice against corneal pathology, mortality, and latency resulting from ocular viral challenge with herpes simplex virus type 1 (HSV-1) McKrae strain. In addition, gD2 SB AS4 significantly decreased postreactivation corneal disease. A control vaccine, gD2 alum, protected against acute ocular infection only. When administered after primary infection, gD2 SB AS4 vaccination decreased postreactivation ocular shedding but had no other significant effects. Vaccination with gD2 SB AS4 was associated with high anti-gD antibody responses and low delayed-type hypersensitivity responses. These results have identified a prophylactic vaccine, gD2 SB AS4, with activity against acute and recurrent HSK in mice and emphasize the need for vaccine evaluation in both primary and recurrent ocular herpetic disease models.

Clinically relevant suramin dosing regimen in mice with no effects against PC-3 prostate xenografts.

The goal of these studies was to develop a suramin dosing schedule that would maintain suramin plasma concentrations in mice in the 150-250 mu g/ml range. A high pressure liquid chromatography method was used to determine suramin plasma concentrations in mice. For pharmacokinetic studies CD2F(1) mice were treated intraperitoneally with 140 mg/kg of suramin. These pharmacokinetic data were used to develop a clinically relevant dosing regimen. To test the efficacy of this dosing regimen, athymic nude mice were implanted orthotopically with PC-3 prostate carcinoma cells, randomized, and treated intraperitoneally. The pharmacokinetically derived dosing regimen resulted in no antitumor effect against PC-3 prostate tumors. Suramin plasma concentrations ranged from 155 to 258 mu g/ml over the 14-day therapy period with tumor concentrations in the 53-241 mu g/g wet weight range.

A comparison of recurrent and primary herpes simplex keratitis in NIH inbred mice.

Herpes simplex virus (HSV) infection is one of the leading causes of corneal blindness. This study compared the clinical, virologic, and immunopathologic features of primary and recurrent murine models of herpes simplex keratitis (HSK) in the National Institutes of Health (NIH) inbred mouse strain. Primary infection resulted in multiple epithelial dendrites, followed by diffuse stromal opacification, symptoms that do not mimic what is seen in human HSK. In contrast, recurrent infection presented clinical features that included microdendrites, focal stromal opacities, disciform endotheliitis, and corneal neovascularization, which were similar to those observed in human disease. Immunohistochemical characterizations indicated that the number and duration of T cells and macrophages in recurrent HSK resemble those observed in primary disease. Results also indicated that the amount of infectious virus detected in the cornea during primary and recurrent disease was similar. However, when corneas were stained for HSV-1 antigens, mice with primary HSK displayed diffuse HSV antigen expression throughout the cornea, whereas HSV antigens were more focally distributed in recurrent disease. These data suggest that the clinical differences between the recurrent and primary herpetic keratitis may, in part, reflect the different distribution of HSV-1 antigens within the cornea.

Inhibition of the epidermal growth factor receptor tyrosine kinase by PD153035 in human A431 tumors in athymic nude mice.

PD153035 is a potent (Ki = 6 pm) and specific inhibitor of the epidermal growth factor (EGF) receptor tyrosine kinase that suppresses tyrosine phosphorylation of the EGF receptor in A431 cells at nanomolar concentrations in cell culture. We have examined the pharmacokinetics of this compound and its ability to rapidly suppress phosphorylation of the EGF receptor in A431 human epidermoid tumors grown as xenografts in immunodeficient nude mice. Following a single i.p. dose of 80 mg/kg, the drug levels in the plasma and tumor rose to 50 and 22 microM within 15 minutes. While the plasma levels of PD153035 fell below 1 microM by 3 hours, in the tumors it remained at micromolar concentrations for at least 12 hours. The tyrosine phosphorylation of the EGF receptor was rapidly suppressed by 80-90% in the tumors. However receptor phosphorylation returned to control levels after 3 hours despite the continued presence of the drug at concentrations which, based on previous in vitro results, were predicted to maintain inhibition. EGF-stimulated tyrosine kinase activity in tumor extracts was decreased and recovered in parallel with the effects of PD153035 on receptor phosphorylation though the activity had reached only about half of the control activity after three hours. These results demonstrate the potential for using small molecule inhibitors to inhibit the EGF receptor tyrosine kinase in vivo, though a fair evaluation of their potential anti-cancer activity will have to wait for solutions to problems with sustained delivery which may allow us to maintain suppression of EGF receptor phosphorylation.

Cellular transport of CI-980.

CI-980, originally synthesized as a potential folate antagonist, is a tubulin-binding mitotic inhibitor currently in pediatric phase I and adult phase II clinical trials. Because of its extensive tissue distribution in animals and its favorable activity against multidrug resistant (MDR)-cells compared with other mitotic inhibitors, such as vincristine, we examined the membrane transport properties of CI-980. CI-980 accumulated rapidly in L1210 and CHO/K1 cells, reaching intracellular levels 40- and 8-fold higher, respectively, than those in the extracellular medium. Efflux was also quite rapid, but a small fraction of drug remained associated with the cells in drug-free medium. The uptake of CI-980 was not temperature or energy dependent, nor was it saturable up to an extracellular concentration of 100 microM. Inhibitors of nucleoside transport had no effect on CI-980 uptake. A cell line deficient in the transport of reduced folate was not resistant to CI-980, nor did it exhibit reduced CI-980 uptake. A 100-fold excess of the R-enantiomer inhibited CI-980 uptake by only 50%. These results are consistent with a model of CI-980 uptake involving passive diffusion followed by significant but largely reversible binding to intracellular or membrane components.

Enhanced therapeutic effect of amsalog (CI-921) in combination with cisplatin in vitro and in vivo.

CI-921, the 5-methyl-4-carboxamide analog of amsacrine, in combination with cisplatin produced a 6-fold better cell kill in vitro than expected based on additive effects. The combination of CI-921 and cisplatin was subsequently evaluated in three in vivo model systems: intraperitoneally (TP) and intravenously (IV) implanted P388 leukemia, and advanced stage subcutaneously (SC) implanted LC-12 squamous cell carcinoma. All drug treatments were administered IP on an intermittent treatment schedule which was optimal for both agents. Combination therapy was superior to therapy with the best single agent alone, CI-921, in all three model systems. Against IP implanted P388 leukemia, combination therapy produced greater than 8 logs of net tumor cell kill with 60-day survivors (cures). This level of activity was 50-fold greater (1.7 log) than that obtained with CI-921 alone. An IV implant of P388 leukemia was used in a confirmatory study to provide a more rigorous evaluation against disseminated disease. Combination therapy against IV implanted P388 leukemia produced greater than 7.7 logs of net tumor cell kill, which was 630-fold greater (2.8 logs) than that obtained with CI-921 therapy alone. Against advanced stage LC-12 (200-1000 mg tumors at initial treatment), combination therapy improved tumor cell kill by 0.6 log (4-fold) over that obtained with CI-921 therapy alone and also produced greater numbers of 120-day survivors than did single agent therapy with CI-921. The combination of carboplatin and CI-921 was also evaluated against IV implanted P388 leukemia to determine if the enhanced therapeutic effect of CI-921 and cisplatin could be extended to include CI-921 and carboplatin. Combination therapy with CI-921 and carboplatin increased net log tumor cell kill by 0.8 and 1.5 log in two separate tests (6- and 32-fold, respectively) over that obtained with CI-921 therapy alone. The data indicate that combination therapy with CI-921 and platinum containing anticancer agents may have clinical application.