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We discuss the prospects for improving the precision on the hadronic corrections to the anomalous magnetic moment of the muon, and the plans of the Muon $g-2$ Theory Initiative to update the Standard Model prediction., Contribution to the US Community Study on the Future of Particle Physics (Snowmass 2021)

OBJECTIVES:Following a perinatal death, a standardised multidisciplinary review should take place. Learning from these deaths and engaging parents in this process could help prevent future perinatal deaths in line with United Kingdom (UK) national and international targets to reduce the number of such deaths by 2020. Moreover, it would support parents in understanding events around the death of their baby. An earlier study (Parents' Active Role and ENgagement in The review of their Stillbirth/perinatal death - PARENTS 1 study) found that parents would endorse the opportunity to give feedback into the perinatal mortality review process (PNMR). In subsequent focus groups, healthcare professionals were positive about parental engagement, although they considered there may be significant challenges. The objective of this study was to develop core principles and recommendations for parental engagement in PNMR in the UK.METHODS:We followed a two-round Delphi technique to reach a consensus on core principles; including a national consensus workshop and an online questionnaire. The consensus meeting was attended by a national panel of stakeholders (clinical and academic experts, parent support groups, managers and commissioners) in stillbirth, neonatal and bereavement care (n=22). To develop recommendations for parental engagement, participants discussed four key areas including: receiving feedback from parents; format of the PNMR meeting; the parental pathway; and challenging aspects of engaging with parents in reviews. Content analysis was conducted to generate recommendations from the meeting for a subsequent, anonymous web-based survey. Attendees of the consensus workshop and members of the PARENTS 2 Project Advisory Board were asked to rank recommendations using a 9-point Likert scale from 1 (not important) to 9 (critical). It had been agreed a priori, in compliance with established Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria, that 'Consensus' would be achieved if over 70% scored the principle as 'critical' (score 7 to 9) and less than 15% scored the principle as 'not important' (score 1 to 3). Principles where Consensus was achieved would be included in the core recommendations.RESULTS:Twenty-five of the 29 invited stakeholders participated in the consensus meeting and the subsequent online questionnaire in June 2017 (86.2% response rate). Consensus was agreed on 12 core principles. Ninety-six percent agreed that it was of critical importance that there should be a face-to-face explanation of the PNMR process; 72% considered parents should be offered the opportunity to nominate a suitable advocate; 92% believed responses to parents' comments should be formally documented; 96% indicated that it was vital for action plans to be translated into lessons learnt and that this process is monitored; and 100% of stakeholders voted that a plain English summary should be produced for the parents following the meeting. There was good agreement on a further seven principles.CONCLUSIONS:Key national stakeholders were unanimously supportive of parental engagement and agreed on core principles to make it feasible, meaningful and robust process. A six-month pilot of parental engagement in the perinatal mortality review process (PARENTS 2 Study) in two UK units took place after the consensus on core principles. In collaboration with the National Perinatal Epidemiology Unit, findings will inform the national standardised perinatal mortality review tool (PMRT).

The Malaria Policy Advisory Committee to the World Health Organization held its fourth meeting in Geneva, Switzerland from 11 to 13 September, 2013. This article provides a summary of the discussions, conclusions and recommendations from that meeting. Meeting sessions included: recommendations for achieving universal coverage of long-lasting insecticide-treated nets; guidance on estimating the longevity of insecticide-treated nets; improving capacity in entomology and vector control; a review of the latest evidence on intermittent preventive treatment in pregnancy; improving dissemination of Malaria Policy Advisory Committee guidance; updates on the development of the global technical strategy for malaria control and elimination (2016–2025) and the global strategy for control and elimination of Plasmodium vivax; updates from the drug resistance and containment technical expert group, the evidence review group on malaria burden estimation, a consultation on malaria case management indicators, and the constitution of the surveillance, monitoring and evaluation technical expert group; subnational elimination criteria; and consideration for future evidence review groups, including diagnosis in low transmission settings and testing for Glucose-6-Phosphate Dehydrogenase Deficiency. Policy statements, position statements and guidelines that arise from the Malaria Policy Advisory Committee meeting conclusions and recommendations will be formally issued and disseminated to World Health Organization Member States by the World Health Organization Global Malaria Programme.

Contains fulltext : 135410.pdf (Publisher’s version ) (Open Access)

In this proof-of-concept, open-label, phase 2 study, patients with relapsed/refractory multiple myeloma (RRMM) received elotuzumab with bortezomib and dexamethasone (EBd) or bortezomib and dexamethasone (Bd) until disease progression/unacceptable toxicity. Primary endpoint was progression-free survival (PFS); secondary/exploratory endpoints included overall response rate (ORR) and overall survival (OS). Two-sided 0.30 significance level was specified (80% power, 103 events) to detect hazard ratio (HR) of 0.69. Efficacy and safety analyses were performed on all randomized patients and all treated patients, respectively. Of 152 randomized patients (77 EBd, 75 Bd), 150 were treated (75 EBd, 75 Bd). PFS was greater with EBd vs Bd (HR, 0.72; 70% confidence interval [CI], 0.59-0.88; stratified log-rank P = .09); median PFS was longer with EBd (9.7 months) vs Bd (6.9 months). In an updated analysis, EBd-treated patients homozygous for the high-affinity Fc?RIIIa allele had median PFS of 22.3 months vs 9.8 months in EBd-treated patients homozygous for the low-affinity allele. ORR was 66% (EBd) vs 63% (Bd). Very good partial response or better occurred in 36% of patients (EBd) vs 27% (Bd). Early OS results, based on 40 deaths, revealed an HR of 0.61 (70% CI, 0.43-0.85). To date, 60 deaths have occurred (28 EBd, 32 Bd). No additional clinically significant adverse events occurred with EBd vs Bd. Grade 1/2 infusion reaction rate was low (5% EBd) and mitigated with premedication. In patients with RRMM, elotuzumab, an immunostimulatory antibody, appears to provide clinical benefit without added clinically significant toxicity when combined with Bd vs Bd alone. Registered to ClinicalTrials.gov as NCT01478048.

© 2016 Lynch and Salikhova.Educational practice should be based on the developmental needs of the student, but teacher training rarely focuses on the link between those needs and practice. The aim of the present study was to investigate what teachers think about the needs of students. In this initial report of research on teachers’ beliefs, 247 practicing teachers from the Republic of Tatarstan, recruited from continuing education/recertification classes conducted in Kazan, Russia, responded to a list of 26 statements drawn from Self-determination theory (SDT), Maslow’s hierarchical theory of needs, and several other sources, rank-ordering them in terms of their importance for the child’s healthy psychological development. The article presents the rank-ordering of teachers’ beliefs about student needs as well as the factor structure of those needs. Two needs from SDT (relatedness, competence) ranked more highly than Maslow’s needs, but, unexpectedly, teachers ranked the need for meaning most highly. Results indicated that autonomy was valued less than most other candidate needs, and, additionally, an unexpected factor structure emerged. The paper, which suggests caution when testing and utilizing existing constructs in new cultural contexts, will be of interest to researchers and educators alike as they work to strengthen the link between student needs and educational practice.

Ageing is a complex multifactorial process that results in many changes in physiological changes processes that ultimately increase susceptibility to a wide range of diseases. As such an ageing population is resulting in a pressing need for more and improved treatments across an assortment of diseases. Such treatments can come from a better understanding of the pathogenic pathways which, in turn, can be derived from models of disease. Therefore the more closely the model resembles the disease situation the more likely relevant the data will be that is generated from them. Here we review the state of knowledge of mouse models of a range of diseases and aspects of an ageing physiology that are all germane to ageing. We also give recommendations on the most common mouse models on their relevance to the clinical situations occurring in aged patients and look forward as to how research in ageing models can be carried out. As we continue to elucidate the pathophysiology of disease, often through mouse models, we also learn what is needed to refine these models. Such factors can include better models, reflecting the ageing patient population, or a better phenotypic understanding of existing models. (C) 2016 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license.

Background: Advantages offered by canine population substructure, combined with clinical presentations similar to human disorders, makes the dog an attractive system for studies of cancer genetics. Cancers that have been difficult to study in human families or populations are of particular interest. Histiocytic sarcoma is a rare and poorly understood neoplasm in humans that occurs in 15% to 25% of Bernese Mountain Dogs (BMD). Methods: Genomic DNA was collected from affected and unaffected BMD in North America and Europe. Both independent and combined genome-wide association studies (GWAS) were used to identify cancer-associated loci. Fine mapping and sequencing narrowed the primary locus to a single gene region. Results: Both populations shared the same primary locus, which features a single haplotype spanning MTAP and part of CDKN2A and is present in 96% of affected BMD. The haplotype is within the region homologous to human chromosome 9p21, which has been implicated in several types of cancer. Conclusions: We present the first GWAS for histiocytic sarcoma in any species. The data identify an associated haplotype in the highly cited tumor suppressor locus near CDKN2A. These data show the power of studying distinctive malignancies in highly predisposed dog breeds. Impact: Here, we establish a naturally occurring model of cancer susceptibility due to CDKN2 dysregulation, thus providing insight about this cancer-associated, complex, and poorly understood genomic region. Cancer Epidemiol Biomarkers Prev; 21(7); 1019–27. ©2012 AACR.

We describe the draft genome of the microcrustacean Daphnia pulex, which is only 200 megabases and contains at least 30,907 genes. The high gene count is a consequence of an elevated rate of gene duplication resulting in tandem gene clusters. More than a third of Daphnia's genes have no detectable homologs in any other available proteome, and the most amplified gene families are specific to the Daphnia lineage. The coexpansion of gene families interacting within metabolic pathways suggests that the maintenance of duplicated genes is not random, and the analysis of gene expression under different environmental conditions reveals that numerous paralogs acquire divergent expression patterns soon after duplication. Daphnia-specific genes, including many additional loci within sequenced regions that are otherwise devoid of annotations, are the most responsive genes to ecological challenges.

We have carried out multiwavelength observations of the near-by ($z=0.046$) rich, merging galaxy cluster Abell 3376 with the Murchison Widefield Array (MWA). As a part of the GaLactic and Extragalactic All-sky MWA survey (GLEAM), this cluster was observed at 88, 118, 154, 188 and 215 MHz. The known radio relics, towards the eastern and western peripheries of the cluster, were detected at all the frequencies. The relics, with a linear extent of $\sim$ 1 Mpc each, are separated by $\sim$ 2 Mpc. Combining the current observations with those in the literature, we have obtained the spectra of these relics over the frequency range 80 -- 1400 MHz. The spectra follow power laws, with $\alpha$ = $-1.17\pm0.06$ and $-1.37\pm0.08$ for the west and east relics, respectively ($S \propto \nu^{\alpha}$). Assuming the break frequency to be near the lower end of the spectrum we estimate the age of the relics to be $\sim$ 0.4 Gyr. No diffuse radio emission from the central regions of the cluster (halo) was detected. The upper limit on the radio power of any possible halo that might be present in the cluster is a factor of 35 lower than that expected from the radio power and X-ray luminosity correlation for cluster halos. From this we conclude that the cluster halo is very extended ($>$ 500 kpc) and/or most of the radio emission from the halo has decayed. The current limit on the halo radio power is a factor of ten lower than the existing upper limits with possible implications for models of halo formation., Comment: 10 pages, 6 figures

The Malaria Policy Advisory Committee to the World Health Organization met in Geneva, Switzerland from 13 to 15 March, 2013. This article provides a summary of the discussions, conclusions and recommendations from that meeting. Meeting sessions included: a review of the efficacy of artemisinin-based combination therapy in Guyana and Suriname; the outcomes from a consultation on non-malaria febrile illness; the outcomes from the second meeting of the Evidence Review Group on malaria burden estimation; an update on the review of the WHO Guidelines for the Treatment of Malaria; an update regarding progress on the constitution of the vector control Technical Expert Group; updates on the RTS, S/AS01 vaccine and the malaria vaccine technology roadmap; financing and resource allocation for malaria control; malaria surveillance and the need for a surveillance, monitoring and evaluation Technical Expert Group; criteria and classification related to malaria elimination; the next meeting of the Evidence Review Group on Intermittent Preventive Treatment in pregnancy; an update on the soon-to-be launched Elimination Scenario Planning Tool; and an update on the process for the Global Technical Strategy for Malaria Control and Elimination (2016–2025). Policy statements, position statements, and guidelines that arise from the MPAC meeting conclusions and recommendations will be formally issued and disseminated to World Health Organization Member States by the World Health Organization Global Malaria Programme.

Antenna layout is an important design consideration for radio interferometers because it determines the quality of the snapshot point spread function (PSF, or array beam). This is particularly true for experiments targeting the 21-cm Epoch of Reionization signal as the quality of the foreground subtraction depends directly on the spatial dynamic range and thus the smoothness of the baseline distribution. Nearly all sites have constraints on where antennas can be placed - even at the remote Australian location of the Murchison Widefield Array (MWA) there are rock outcrops, flood zones, heritages areas, emergency runways and trees. These exclusion areas can introduce spatial structure into the baseline distribution that enhances the PSF sidelobes and reduces the angular dynamic range. In this paper we present a new method of constrained antenna placement that reduces the spatial structure in the baseline distribution. This method not only outperforms random placement algorithms that avoid exclusion zones, but surprisingly outperforms random placement algorithms without constraints to provide what we believe are the smoothest constrained baseline distributions developed to date. We use our new algorithm to determine antenna placements for the originally planned MWA, and present the antenna locations, baseline distribution and snapshot PSF for this array choice., U.S. National Science Foundation (grants AST CAREER-0847753, AST-0457585, AST-0908884 and PHY-0835713), Australian Research Council (grants LE0775621 and LE0882938), U.S. Air Force Office of Scientific Research (grant FA9550-0510247)

When bovine aortic endothelial (BAE) cells are superfused with a solution containing low calcium (approximately 10 nM) and subsequently exposed to a solution containing normal Ca2+ (2 mM) a large transient increase in intracellular calcium is seen. This elevation in [Ca2+]i is similar to that described as the calcium paradox in cardiac cells. If the cells are exposed to the agonist, ATP, during the period in low-Ca2+ solution the paradoxical rise in [Ca2+]i is increased. Removal of external Na+ from the low-Ca2+ solution reduces the rise in [Ca2+]i on returning to 2mM-Ca2+ solution. These data are consistent with the presence of a calcium paradox in these cells and with the hypothesis that the underlying mechanism involves the loading of the cell with Na+ during the period in low Ca2+. This process may occur as a result of the altered selectivity of the ATP-activated Ca2+ influx mechanism.

International audience; Due to the continued demand for bandwidth, network operators have to increase the data rates at which individual wavelengths operate at. As these data rates will exceed 100 Gbit/s in the next 5 – 10 years, it will be crucial to be able to monitor and compensate for the amount of chromatic dispersion encountered by individual wavelength channels. This paper will focus on the use of the novel nonlinear optical-to-electrical conversion process of Two-Photon Absorption (TPA) for dispersion monitoring. By incorporating a specially designed semiconductor microcavity, the TPA response becomes wavelength dependent, thus allowing simultaneous channel selection and monitoring without the need for external wavelength filtering.

One of the most significant challenges in neuroscience is to identify the cellular and molecular processes that underlie learning and memory formation. The past decade has seen remarkable progress in understanding changes that accompany certain forms of acquisition and recall, particularly those forms which require activation of afferent pathways in the hippocampus. This progress can be attributed to a number of factors including well-characterized animal models, well-defined probes for analysis of cell signaling events and changes in gene transcription, and technology which has allowed gene knockout and overexpression in cells and animals. Of the several animal models used in identifying the changes which accompany plasticity in synaptic connections, long-term potentiation (LTP) has received most attention, and although it is not yet clear whether the changes that underlie maintenance of LTP also underlie memory consolidation, significant advances have been made in understanding cell signaling events that contribute to this form of synaptic plasticity. In this review, emphasis is focused on analysis of changes that occur after learning, especially spatial learning, and LTP and the value of assessing these changes in parallel is discussed. The effect of different stressors on spatial learning/memory and LTP is emphasized, and the review concludes with a brief analysis of the contribution of studies, in which transgenic animals were used, to the literature on memory/learning and LTP.

The rapid internationalization of capital markets in recent times has manifested itself in mobility of equity investment as well as in a growing number of foreign cross-listings. We study a fairly complete sample of all Dutch foreign crosslistings since 1973. By measuring the stock market reaction on the announcement date of the foreign listing we can conclude that shareholders look forward to an increase in value. The approximate increase in value on the announcement day is 0.68 % for all companies and the cumulative return is 1,38 %. The stock price increase seems to be permanent. This evidence is consistent with various potential explanations. A foreign listing may decrease barriers to capital flows and thus reduce the costs of capital for firms listed in segmented domestic markets. Alternatively, they may represent positive signals of higher firm value, either because the listing is a sign of the capacity of the firm to expand its international activities or its willingness to undergo greater scrutiny by international investors. On average, companies that got listed on the NYSE experience a higher increase of value (AR=1,21% ; CAR 1,48). The result that the listings on the NYSE appear to result in a greater increase in value may be associated with both interpretations. A NYSE listing may result in greater internationalization of the shareholder base; it may result in an increased amount of transparency and disclosure; or it may enhance visibility of corporate strategy for both US and international investors.

Agonist induced increases in intracellular free calcium, [Ca2+]i, were measured in single Fura-2 loaded bovine aortic endothelial (BAE) cells by dual wavelength microspectrofluorimetry. Low doses of ATP (less than 10 microM) induced complex changes in [Ca2+]i. These changes usually consisted of a large initial transient peak with subsequent fluctuations superimposed upon a maintained rise in [Ca2+]i. Higher doses of ATP (greater than 50 microM) produced much simpler biphasic increases in [Ca2+]i in individual cells. Acetylcholine and bradykinin also elicited increases in [Ca2+]i in single cells in confluent monolayers of endothelial cells. However, only acetylcholine produced complex fluctuations. High doses of acetylcholine evoked simple rises in [Ca2+]i similar to those seen with high doses of ATP. In contrast, bradykinin evoked relatively simple rises in [Ca2+]i at all doses used. These results indicate that the mechanisms responsible for generating agonist induced increases in [Ca2+]i in BAE cells are not homogeneous. ATP and acetylcholine produced more complex Ca2+ changes or 'signatures' in single confluent bovine aortic endothelial cells than bradykinin. All three agonists appeared to release Ca2+ from intracellular stores as well as stimulating Ca2+ influx. The possible mechanisms underlying these phenomena are discussed.

A theory for the expression of a population's response to density-independent gradients of environmental factors is derived for the case of asexuality. It is shown that the environmental tolerance of a genotype is a function of at least four parameters: g$_1$ and V$_{E1}$, the environmental optimum and its developmental variance between individuals, and g$_2$ and V$_{E2}$, the expected genetic contribution to the breadth of adaptation and its developmental variance. The realized breadth of adaptation of a genotype (V$^{1/2}$) is a complex function of g$_2$, V$_{E1}$, and V$_{E2}$, but we argue that, with an appropriate scale transformation, the tolerance curve of a genotype is approximately normal, with mean g$_1$ and standard deviation V$^{1/2}$. It is shown that temporal heterogeneity in the environment selects for more-broadly-adapted genotypes but that the within-generation component (V$_{\phitw}$) plays a more prominent role than the between-generation component (V$_{\phitb}$). Spatial heterogeneity selects for higher V$^{1/2}$ only when it occurs in conjunction with temporal variance within generations and only if V$_{\phitb}$ is small relative to V$_{\phitw}$. We argue that since g$_2$ is expected to evolve subject to the constraint that V$^{1/2}$ is optimized, species exposed to conditions favoring identical V$^{1/2}$ may evolve different g$_2$ if pronounced interspecific differences exist for V$_{E1}$ and V$_{E2}$. A maximum-likelihood method is shown to be capable of generating accurate estimates of the genotypic parameters g$_1$, g$_2$, V$_{E1}$, and V$_{E2}$ with moderately large samples. We suggest how this procedure may be used to estimate analogous parameters for a population of mixed genotypes and to obtain estimates of the genetic variance for the environmental optimum and breadth of adaptation. The potential utility of this methodology for the analysis of data routinely generated in programs for environmental assessment and plant breeding is pointed out.

We discuss the prospects for improving the precision on the hadronic corrections to the anomalous magnetic moment of the muon, and the plans of the Muon $g-2$ Theory Initiative to update the Standard Model prediction., Comment: Contribution to the US Community Study on the Future of Particle Physics (Snowmass 2021)

Summary: We have demonstrated that the inherent inefficiency of the TPA process in semiconductors can be overcome by incorporating the semiconductor in a microcavity structure. Proof of concept devices with a 0.27μm Ga0.7Al0.3As active region and two Bragg reflectors with the cavity resonance of 890 nm were fabricated. We measured the TPA photocurrent of these devices and have demonstrated a factor of 12000 enhancement over a nonmicrocavity device at 890 nm. Our active length of 0.27 nm is as efficient as 5.4 mm without a microcavity, overcoming the very long detector lengths limiting the use of TPA in practical autocorrelators, optical switches and sampling devices for real telecommunication systems. The effect of the cavity is to enhance the intra-cavity optical intensity, which leads to an increase in the nonlinear response of the active region. We studied, theoretically and experimentally, the impact of the cavity on the temporal response and the sensitivity of the device, which are critical considerations for commercial applications. This cavity design has a 3 pico-second response time and the autocorrelation trace is comparable with the BBO crystal response for an input 1.6 ps pulse. Devices designed for 1550 nm have also been realised and our measurements indicate these two-photon absorption based detectors are potential candidates for optical autocorrelation of short optical pulses, and for optical switching and sampling in optical time division multiplexed (OTDM) communications systems.

The fragile site at Xq27.3 is an unstable microsatellite repeat, p(CCG)n. In fragile-X syndrome pedigrees, this sequence exhibits variable amplification, the length of which correlates with fragile-site expression. There is a direct relationship between increased p(CCG)n copy number and propensity for instability: individuals having large amplifications exhibit somatic variation due to increased instability. The instability of the p(CCG)n repeat, when transmitted through affected pedigrees, explains the unusual segregation patterns of fragile-X phenotype, referred to as the Sherman paradox. All individuals of fragile-X genotype were found (where testing was possible) to have a parent with amplified p(CCG)n repeat, indicating that few, if any, cases of fragile-X syndrome are not familial.

Neurofibromatosis type 1 (NF1) is caused by deletions, insertions, translocations, and point mutations in the NF1 gene, which spans 350 kb on the long arm of human chromosome 17. Although several point mutations have been described, large molecular abnormalities have rarely been characterized in detail. We describe here the molecular breakpoints of a 12-kb deletion of the NF1 gene, which is responsible for the NF1 phenotype in a kindred with two children affected because of germline mosaicism in the unaffected father, who has the mutation in 10% of his spermatozoa. The mutation spans introns 31-39, removing 12,021 nt and inserting 30 bp, of which 19 bp are a direct repetition of a sequence located in intron 31, just 4 bp before the 5' breakpoint. The 5' and 3' breakpoints contain the sequence TATTTTA, which could be involved in the generation of the deletion. The most plausible explanation for the mechanism involved in the generation of this 12-kb deletion is homologous/nonhomologous recombination. Since sperm of the father does not contain the corresponding insertion of the 12-kb deleted sequence, this deletion could have occurred within the NF1 chromosome through loop formation. RNA from lymphocytes of one of the NF1 patients showed similar levels of the mutated and normal transcripts, suggesting that the NF1-mRNA from mutations causing frame shifts of the reading frame or stop codons in this gene is not degraded during its processing. The mutation was not detected in fresh lymphocytes from the unaffected father by PCR analysis, supporting the case for true germ-line mosaicism.

It is shown that the excellent Murchison Radio-astronomy Observatory site allows the Murchison Widefield Array to employ a simple RFI blanking scheme and still calibrate visibilities and form images in the FM radio band. The techniques described are running autonomously in our calibration and imaging software, which is currently being used to process an FM-band survey of the entire southern sky., Accepted for publication in Proceedings of Science [PoS(RFI2010)016]. 6 pages and 3 figures. Presented at RFI2010, the Third Workshop on RFI Mitigation in Radio Astronomy, 29-31 March 2010, Groningen, The Netherlands

BMS-214662 is a potent and selective inhibitor of farnesyltransferase (FTI). In rodent fibroblasts transformed by oncogenes, BMS-214662 reversed the H-Ras-transformed phenotype but not that of K-Ras or other oncogenes. In soft agar growth assays, BMS-214662 showed good potency in inhibiting H-ras-transformed rodent cells, A2780 human ovarian carcinoma tumor cells, and HCT-116 human colon carcinoma tumor cells. Inhibition of H-Ras processing in HCT-116 human colon tumor cells was more rapid than in H-Ras-transformed rodent fibroblast tumors. BMS-214662 is the most potent apoptotic FTI known and demonstrated broad spectrum yet robust cell-selective cytotoxic activity against a panel of cell lines with diverse histology. The presence of a mutant ras oncogene was not a prerequisite for sensitivity. Athymic and conventional mice were implanted s.c. with different histological types of human and murine tumors, respectively. BMS-214662 was administered both parenterally and p.o. and was active by all these routes. Curative responses were observed in mice bearing staged human tumor xenografts including HCT-116 and HT-29 colon, MiaPaCa pancreatic, Calu-1 lung, and EJ-1 bladder carcinomas. A subline of HCT-116, HCT-116/VM46, resistant to many standard cytotoxic agents by means of a multiple drug resistance mechanism, remained quite susceptible to BMS-214662, and borderline activity was achieved against N-87 human gastric carcinoma. Two murine tumors, Lewis lung carcinoma and M5076 sarcoma, were insensitive to the FTI. In a study performed using Calu-1 tumor-bearing mice, no obvious schedule dependency of BMS-214662 was observed. The FTI, BMS-214662, demonstrated broad spectrum activity against human tumors, but murine tumors were not as sensitive.