Simultaneous Combinations Research Articles

Pooling job physical exposure data from multiple independent studies in a consortium study of carpal tunnel syndrome

Pooling data from different epidemiological studies of musculoskeletal disorders (MSDs) is necessary to improve statistical power and to more precisely quantify exposure–response relationships for MSDs. The pooling process is difficult and time-consuming, and small methodological differences could lead to different exposure–response relationships. A sub-committee of a six-study research consortium studying carpal tunnel syndrome: (i) visited each study site, (ii) documented methods used to collect physical exposure data and (iii) determined compatibility of exposure variables across studies. Certain measures of force, frequency of exertion and duty cycle were collected by all studies and were largely compatible. A portion of studies had detailed data to investigate simultaneous combinations of force, frequency and duration of exertions. Limited compatibility was found for hand/wrist posture. Only two studies could calculate compatible Strain Index scores, but Threshold Limit Value for Hand Activity Level could be determined for all studies. Challenges of pooling data, resources required and recommendations for future researchers are discussed. Practitioner Summary: There is a need for standardised measures and measurement protocols of physical exposure for the upper extremity. This study may provide guidance for those planning to conduct an epidemiological study on quantified job physical exposures, or planning to merge physical exposure data from similar studies with some methodologic differences.

Quantifying Subpopulation Synergy for Antibiotic Combinations via Mechanism-Based Modeling and a Sequential Dosing Design

Quantitative modeling of combination therapy can describe the effects of each antibiotic against multiple bacterial populations. Our aim was to develop an efficient experimental and modeling strategy that evaluates different synergy mechanisms using a rapidly killing peptide antibiotic (nisin) combined with amikacin or linezolid as probe drugs. Serial viable counts over 48 h were obtained in time-kill experiments with all three antibiotics in monotherapy against a methicillin-resistant Staphylococcus aureus USA300 strain (inoculum, 10(8) CFU/ml). A sequential design (initial dosing of 8 or 32 mg/liter nisin, switched to amikacin or linezolid at 1.5 h) assessed the rate of killing by amikacin and linezolid against nisin-intermediate and nisin-resistant populations. Simultaneous combinations were additionally studied and all viable count profiles comodeled in S-ADAPT and NONMEM. A mechanism-based model with six populations (three for nisin times two for amikacin) yielded unbiased and precise (r = 0.99, slope = 1.00; S-ADAPT) individual fits. The second-order killing rate constants for nisin against the three populations were 5.67, 0.0664, and 0.00691 liter/(mg · h). For amikacin, the maximum killing rate constants were 10.1 h(-1) against its susceptible and 0.771 h(-1) against its less-susceptible populations, with 14.7 mg/liter amikacin causing half-maximal killing. After incorporating the effects of nisin and amikacin against each population, no additional synergy function was needed. Linezolid inhibited successful bacterial replication but did not efficiently kill populations less susceptible to nisin. Nisin plus amikacin achieved subpopulation synergy. The proposed sequential and simultaneous dosing design offers an efficient approach to quantitatively characterize antibiotic synergy over time and prospectively evaluate antibiotic combination dosing strategies.

Neural processing of emotional facial and semantic expressions in euthymic bipolar disorder (BD) and its association with theory of mind (ToM).

BackgroundAdults with bipolar disorder (BD) have cognitive impairments that affect face processing and social cognition. However, it remains unknown whether these deficits in euthymic BD have impaired brain markers of emotional processing.Methodology/Principal FindingsWe recruited twenty six participants, 13 controls subjects with an equal number of euthymic BD participants. We used an event-related potential (ERP) assessment of a dual valence task (DVT), in which faces (angry and happy), words (pleasant and unpleasant), and face-word simultaneous combinations are presented to test the effects of the stimulus type (face vs word) and valence (positive vs. negative). All participants received clinical, neuropsychological and social cognition evaluations. ERP analysis revealed that both groups showed N170 modulation of stimulus type effects (face > word). BD patients exhibited reduced and enhanced N170 to facial and semantic valence, respectively. The neural source estimation of N170 was a posterior section of the fusiform gyrus (FG), including the face fusiform area (FFA). Neural generators of N170 for faces (FG and FFA) were reduced in BD. In these patients, N170 modulation was associated with social cognition (theory of mind).Conclusions/SignificanceThis is the first report of euthymic BD exhibiting abnormal N170 emotional discrimination associated with theory of mind impairments.

Abstract 3838: NKP-2235 exhibits a novel pattern of cytotoxicity with synergism across a broad range of antitumor agents demonstrated in multiple tumor types

Abstract Background: NKP-2235 is a first-in-class, orally bioavailable gallium based anti-cancer compound. The intracellular targets for NKP-2235 include the endoplasmic reticulum (ER). NKP-2235 treatment of tumor cells causes ER stress, intracellular Ca2+ release and induction of pro-apoptotic factors. In single agent in vitro cytotoxicity assays, NKP-2235 has shown activity against tumor lines resistant to many standard anti-cancer agents. The aims of this study were to evaluate the anti-tumor effects of NKP-2235 in combination with standard cytotoxics or targeted agents and assess its single agent cytotoxicity pattern in the NCI 60 tumor cell line anti-cancer drug screen and COMPARE analysis. Methods: NKP-2235 testing in the NCI 60 tumor cell line anticancer drug screen was performed by the NCI. COMPARE analysis was conducted using cytotoxicity data from 170 compounds in the NCI compound library. In vitro combination studies were performed in breast, colon, glioma, lung and prostate tumor cell lines. NKP-2235 was tested in combination with 5-FU, temozolomide, gemcitabine, paclitaxel, erlotinib, temsirolimus, or docetaxel either simultaneously or sequentially. For simultaneous combinations, cells were exposed to NKP-2235 and a combination agent, at their respective ED50, for 72hrs. For sequential NKP-2235 combinations cells were exposed to different dosing sequences, all agents at their respective ED50, for a total of 96 hrs. Cytotoxicity was determined using the MTT assay and combination index (CI) values were calculated using the Chou-Talalay method. Results: Screening against the NCI 60 tumor cell line panel and COMPARE analysis show that single agent NKP-2235 has a markedly different pattern of cytotoxicity from the 170 anti-cancer agents previously tested by the NCI. In addition, the screening confirmed that the NKP-2235 cytotoxicity is distinct from that of gallium salts such as gallium nitrate. The combination studies demonstrated that NKP-2235 has synergistic activity when combined simultaneously with: 5-FU (CI 0.6), temozolomide (CI 0.8), gemcitabine (CI 0.7), temsirolimus (CI 0.7), and docetaxel (CI 0.7) in the cell lines tested. Interestingly, while simultaneous combination is synergistic with docetaxel in prostate cancer cells, the NKP-2235-paclitaxel combinations required sequential dosing for synergistic activity (CI 0.09) in lung cancer cells. Similarly, the NKP-2235-temsirolimus combination is synergistic in simultaneous setting, while NKP-2235-erlotinib combination required sequential dosing for synergistic activity (CI 0.3) in lung cancer cells. Conclusions: This study demonstrates that NKP-2235 has a novel pattern of cytotoxicity and marked synergism in combination with a broad range of anti-tumor agents in many tumor types. These data support the study of this novel agent in single agent and combination clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3838. doi:1538-7445.AM2012-3838

A Computational Model of the Development of Separate Representations of Facial Identity and Expression in the Primate Visual System

Experimental studies have provided evidence that the visual processing areas of the primate brain represent facial identity and facial expression within different subpopulations of neurons. For example, in non-human primates there is evidence that cells within the inferior temporal gyrus (TE) respond primarily to facial identity, while cells within the superior temporal sulcus (STS) respond to facial expression. More recently, it has been found that the orbitofrontal cortex (OFC) of non-human primates contains some cells that respond exclusively to changes in facial identity, while other cells respond exclusively to facial expression. How might the primate visual system develop physically separate representations of facial identity and expression given that the visual system is always exposed to simultaneous combinations of facial identity and expression during learning? In this paper, a biologically plausible neural network model, VisNet, of the ventral visual pathway is trained on a set of carefully-designed cartoon faces with different identities and expressions. The VisNet model architecture is composed of a hierarchical series of four Self-Organising Maps (SOMs), with associative learning in the feedforward synaptic connections between successive layers. During learning, the network develops separate clusters of cells that respond exclusively to either facial identity or facial expression. We interpret the performance of the network in terms of the learning properties of SOMs, which are able to exploit the statistical indendependence between facial identity and expression.

Clausewitz: The Debate Continues

Stephen L. Melton. The Clausewitz Delusion: How the American Army Screwed Up the Wars in Iraq and Afghanistan (A Way Forward). Minneapolis: Zenith Press, 2009. 309 pp. $30.00. ISBN: 978-0-7603- 371...

Extreme climatic events in the Amazon basin

During 2009 the Amazon basin was hit by a heavy flooding with a magnitude and duration few times observed in several decades. Torrential rain in northern and eastern Amazonia during the austral summer of 2008–2009 swelled the Amazon River and its tributaries. By July 2009, water levels of the Rio Negro, a major Amazon tributary, reached at Manaus harbor a new record, the highest mark of the last 107 years. During the 2008–2009 hydrological year, the rainy season on northern and northwestern Amazonia started prematurely, and was followed by a longer-than-normal rainy season. An anomalously southward migration of the ITCZ during May–June 2009, due to the warmer than normal surface waters in the tropical South Atlantic, was responsible for abundant rainfall in large regions of eastern Amazonia and Northeast Brazil from May to July 2009. We also compared the flood of 2009 with other major events recorded in 1989 and 1999. The hydrological consequences of this pattern were earlier than normal floods in Amazon northern tributaries, which peak discharges at their confluences with the main stem almost coincided with the peaks of southern tributaries. Since the time displacement of the contribution to the main stem of northern and southern Amazon tributaries is fundamental for damping flood waves in the main stem, the simultaneous combinations of peak discharges of tributaries resulted in an extreme flood.

Activities of Triazole-Echinocandin Combinations against Candida Species in Biofilms and as Planktonic Cells

Biofilm formation complicates the treatment of various infections caused by Candida species. We investigated the effects of simultaneous or sequential combinations of two triazoles, voriconazole (VRC) and posaconazole (PSC), with two echinocandins, anidulafungin (AND) and caspofungin (CAS), against Candida albicans and Candida parapsilosis biofilms in comparison to their planktonic counterparts. Antifungal activity was assessed by the 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]2H-tetrazolium-5-carboxanilide (XTT) metabolic assay. Antifungal-agent interactions were analyzed by the Bliss independence model in the simultaneous-treatment studies and by analysis of variance (ANOVA) in the sequential-treatment studies. Against C. albicans planktonic cells, the simultaneous combination of PSC (32 to 128 mg/liter) and CAS (0.008 to 0.25 mg/liter) was synergistic; the combinations of PSC (128 to 1,024 mg/liter) with AND (0.03 to 0.5 mg/liter) and VRC (32 to 512 mg/liter) with AND (0.008 to 0.03 mg/liter) were antagonistic. Against C. parapsilosis planktonic cells, the interaction between VRC (32 to 1,024 mg/liter) and CAS (1 to 16 mg/liter) was antagonistic. All simultaneous antifungal combinations demonstrated indifferent interactions against biofilms of both Candida species. Damage to biofilms of both species increased (P<0.01) in the presence of subinhibitory concentrations of echinocandins (0.008 to 0.064 mg/liter), followed by the addition of PSC (512 mg/liter for C. albicans and 64 to 512 mg/liter for C. parapsilosis) or VRC (256 to 512 mg/liter for C. albicans and 512 mg/liter for C. parapsilosis). Triazole-echinocandin combinations do not appear to produce antagonistic effects against Candida sp. biofilms, while various significant interactions occur with their planktonic counterparts.

Investigating the time resolution of a compact multidimensional gamma-spectrometer

Multidimensional gamma-spectrometry is a powerful technique for making low-level nuclear measurements. The systems typically utilise multiple sodium iodide detectors to measure coincident or anti-coincident gamma-energies. This allows significant background reduction and high selectivity of cascading radionuclides including 22Na. As events are rejected or selected based on their event time, the timing resolution of the multi-channel analyser (MCA) is important. This has been assessed for three compact MCA systems produced by Canberra and Ortec. The Canberra OspreyTM and LynxTM provided the best timing performance, capturing 88.3 and 97.9% of 22Na positron emissions within 200 ns. In comparison only 12.5% of events were measured within 200 ns by the Ortec digiBASE-ETM. However all systems captured the majority of events within 1000 ns, providing multidimensional spectra that allow the evaluation of simultaneous energy combinations.

Combining creativity and control: Understanding individual motivation in large-scale collaborative creativity

Recent research has shown that management control systems (MCS) can improve performance in contexts characterized by high levels of task uncertainty. This seems to conflict with a second stream of research, which argues that MCSs risk undermining the intrinsic motivation needed for effective performance in such settings. To solve this puzzle, we build on theories of perceived locus of causality and self-construal and develop an integrative model summarized in 15 propositions. To explicate our proposed solution and to show its robustness, we focus on the class of activities we call large-scale collaborative creativity (LSCC) – contexts where individuals face a dual challenge of demonstrating creativity and embracing the formal controls that coordinate their creative activities with others’. We argue that LSCC requires the simultaneous activation of intrinsic and identified forms of motivation, and simultaneously independent and interdependent self-construals. Against some scholarship that argues or assumes that such simultaneous combinations are infeasible, we argue that they can be fostered through appropriate attraction–selection–attrition policies and management control systems design. We also show how our propositions can enrich our understanding of motivation in other settings, where creativity and/or coordination demands are less pressing.

Combining Creativity and Control: Understanding Individual Motivation in Large-Scale Collaborative Creativity

Recent research has show that management control systems (MCS) can improve performance in contexts characterized by high levels of task uncertainty. This seems to conflict with a second stream of research, which argues that MCSs risk undermining the intrinsic motivation needed for effective performance in such settings. To solve this puzzle, we build on theories of perceived locus of causality and self-construal and develop an integrative model summarized in 15 propositions. To explicate our proposed solution and to show its robustness, we focus on the class of activities we call large-scale collaborative creativity (LSCC) — contexts where individuals face a dual challenge of demonstrating creativity and embracing the formal controls that coordinate their creative activities with others’. We argue that LSCC requires the simultaneous activation of intrinsic and identified forms of motivation, and simultaneously independent and interdependent self-construals. Against some scholarship that argues or assumes that such simultaneous combinations are infeasible, we argue that they can be fostered through appropriate attraction-selection-attrition policies and management control systems design. We also show how our propositions can enrich our understanding of motivation in other settings, where creativity and/or coordination demands are less pressing.

Recent Advances in the Development of Dual Topoisomerase I and II Inhibitors as Anticancer Drugs

DNA topoisomerases (topos) are essential enzymes that regulate the topological state of DNA during cellular processes such as replication, transcription, recombination, and chromatin remodeling. Topoisomerase I (Topo I) is a ubiquitous nuclear enzyme which catalyzes the relaxation of superhelical DNA generating a transient single strand nick in the duplex, through cycles of cleavage and religation. Topoisomerase II (Topo II) mediates the ATP-dependent induction of coordinated nicks in both strands of the DNA duplex, followed by crossing of another double strand DNA through the transiently broken duplex. Although the biological functions of Topoisomerases are important for ensuing genomic integrity, the ability to interfere with enzymes or generate enzyme-mediated damage is an effective strategy for cancer therapy and, in this connection, DNA topos (I and II) proved to be the excellent targets of clinically significant classes of anticancer drugs. Actually, specific Topo I and Topo II inhibitors reversibly trap the enzyme-DNA complexes, thus converting Topos into physiological poisons, able to produce permanent DNA damage, which triggers cell death. Given that both enzymes are good targets, it would be desirable to jointly inhibit them, but use-limiting toxicity of sequential or simultaneous combinations of topo I and II poisons include severe to life-threatening neutropenia and anemia. Furthermore, the emergence of resistance phenomena to topo I inhibitors is often accompanied by a concomitant rise in the level of topo II expression and viceversa, leading to the failure of clinical therapies. In this regard, a single compound able to inhibit both Topo I and II may present the advantage of improving antitopoisomerase activity, with reduced toxic side effects, with respect to the combination of two inhibitors. Due to the high interest in such compounds, this review represents an update of previous works dealing with the development of dual Topo I and II inhibitors as novel anti-cancer agents. The newly collected derivatives have been described focusing attention on their chemical structures and their biological profiles.

Schedule treatment design and quantitative in vitro evaluation of chemotherapeutic combinations for metastatic prostate cancer therapy

Preclinical evaluation is essential for a rational design of combination chemotherapy as some agents, with known mechanisms of action and non-overlapping toxicities may increase the therapeutic index of anticancer drugs, whose clinical success is hindered by side effects and drug resistance. The present study investigated new drug combinations with potential outcome for the treatment of metastatic prostate cancer. This final clinical stage exhibits predominantly hormone-refractory prostate cancer (HRPC) cells but also a minority of hormone responsive cells. Growth inhibition activity of simultaneous and sequential combinations was evaluated by resazurin assay. In vitro evaluation of synergism, additivity, or antagonism, against prostate cancer cell lines, was performed by the median effect analysis. The importance of dosage, exposure time, drug ratio, and type of treatment were investigated and compared. Most simultaneous combinations of two drugs with different mechanisms of action or of two topoisomerase II inhibitors resulted in mild antagonism of antiproliferative effects, particularly notorious at high cell death. Imatinib-mitoxantrone and ciprofloxacin-etoposide combinations were exceptions, as they yielded additivity and dose reduction index (DRI) values of 2.6 and 3.5-fold for mitoxantrone and etoposide, respectively. Sequential combinations (ciprofloxacin or imatinib pre-treatment) revealed additive growth inhibition effects, translated in much higher DRI values (from 7.0 to 15.3-fold). Moderate synergism was restricted to sequential ciprofloxacin combinations at high cell death. Ciprofloxacin and imatinib significantly improve growth inhibition activity of standard antineoplastic drugs in a schedule-dependent manner and, therefore, may have an important role as adjuvant therapeutic agents in a clinical setting.

Sign communication in Cri du chat syndrome

This paper presents findings from a study on the use of sign supported Norwegian (SSN) in two individuals with Cri du chat syndrome (CCS). The study gives a first account of some selected aspects of production and intelligibility of SSN in CCS. Possible deviance in manual parameters, in particular inter- and/or intra-subject variation in the use of handshape is investigated. Second, the question is addressed to what extent the isolated signs and isolated speech are intelligible and to what extent the combination of signs and speech in SSN contributes to a better intelligibility compared to each part in isolation. Results showed inter-subject variation, as well as individual consistency of deviancy in phonetic handshape parameters. Both participants were slightly more intelligible in their sign articulation when signs and speech production were analyzed separately. Importantly, intelligibility was greatly increased when signs and speech were combined. This emphasizes the importance of SSN for facilitating communication in children with CCS. Learning outcomes: The reader will be able to identify Signed Supported Communication as an artificial communication form, which can be used as an aid for language development in different groups of children, including children suffering from Cri du chat syndrome. The paper shows the reader to recognize that although children with Cri du chat do not produce words or signs accurately, their intelligibility can improve when they use simultaneous combinations of words and signs.

Drug resistance in leishmaniasis

The treatment options of leishmaniasis are limited and far from satisfactory. For more than 60 years, treatment of leishmaniasis has centered around pentavalent antimonials (Sbv). Widespread misuse has led to the emergence of Sbv resistance in the hyperendemic areas of North Bihar. Other antileishmanials could also face the same fate, especially in the anthroponotic cycle. The HIV/ visceral leishmaniasis (VL) coinfected patients are another potential source for the emergence of drug resistance. At present no molecular markers of resistance are available and the only reliable method for monitoring resistance of isolates is the technically demanding in vitro amastigote-macrophage model. As the armametrium of drugs for leishmaniasis is limited, it is important that effective monitoring of drug use and response should be done to prevent the spread of resistance. Regimens of simultaneous or sequential combinations should be seriously considered to limit the emergence of resistance.

6122 MicroRNA expression profile in stage II colorectal cancer

SN38 is the active metabolite of the anti-cancer agent irinotecan (CPT-11) and is a potent inhibitor of topoisomerase-I (topo-I), leading to DNA strand breaks and eventually cell death. The pyrimidine analog trifluorothymidine (TFT) is part of the anti-cancer drug formulation TAS-102, which was developed to enhance the bioavailability of TFT in vivo, and is currently being evaluated as an oral chemotherapeutic agent in phase I clinical studies. In this study, the combined cytotoxic effects of dual-targeted TFT with SN38 were investigated in a panel of human colon cancer cell lines (WiDr, H630, Colo320, SNU-C4, SW1116). We used different drug combination treatment schedules of SN38 with TFT, and possible synergism was evaluated using median drug effect analysis resulting in combination indexes (CI), in which CI < 0.9 indicates synergism, CI = 0.9–1.1 indicates additivity and CI > 1.1 indicates antagonism. Drug target analysis was performed to investigate the effect of TFT on SN38-induced DNA damage, cell cycle delay and apoptosis. Simultaneous exposure to SN38 in combination with TFT was not more than additive, whereas pre-incubation with TFT resulted in synergism with SN38 (CI = 0.3–0.6). Only for Colo320 synergism could be induced for both simultaneous and sequential drug combinations. SN38 and TFT induced most DNA damage in H630 and Colo320 cells, which was increased in combination. TFT pre-incubation further enhanced SN38-induced DNA strand breaks in H630 and Colo320 (>20%), which was most pronounced in H630 cells (p < 0.01). Exposure to SN38 alone induced a clear cell cycle G2M-phase arrest and pre-incubation with TFT enhanced this effect in WiDr and H630 (p < 0.05). Both drugs induced significant apoptosis; SN38-induced apoptosis increased significantly in the presence of TFT (p < 0.01), either when added simultaneously (about 3-fold) or at pre-incubation (about 2-fold). Topo-I protein levels varied among the cell lines and TFT hardly affected these. In conclusion, TFT pre-incubation can enhance SN38-induced cytotoxicity to colon cancer cells resulting in synergism between the drugs, thereby increasing DNA damage and apoptosis induction.

Association analysis of food allergens

Food allergy patients are known to present with allergic reactions to multiple allergens, but extrapolating these associations is difficult. Data mining, a procedure that analyzes characteristic combinations among large amounts of information, is often used to analyze and predict consumer purchasing behaviour. We applied this technique to the extrapolation of food allergen associations in allergy patients. We sent 1510 families our 'Questionnaire survey for the prevention of food allergies'. Responses noting 6549 allergens came from 878 families with 1383 patients, including 402 with anaphylaxis. Some results of the survey have already been published and here we presented the results of our association analysis of combinations of food allergens. Egg, milk, wheat, peanuts, and buckwheat are the most common food allergens. The most common simultaneous combinations of these allergens were 'egg-milk', 'egg-wheat', and 'milk-wheat'. The occurrence probability of a combination (i.e. one person suffering from a certain allergen also suffers from another) is called 'confidence'. Confidence was higher for 'chicken-egg', 'abalone-salmon eggs', and 'matsutake mushroom-milk'. As well, the combinations of 'crab-shrimp', 'squid-shrimp', and 'squid-crab' also indicated higher values in a statistical examination of the occurrence probabilities of these allergen combinations (Z-score). From the results of the association analysis, we speculated that some food allergens, such as abalone, orange, salmon, chicken, pork, matsutake mushroom, peach and apple did not independently induce food allergies. We also found that combinations, such as 'crab-shrimp', 'squid-shrimp', 'squid-crab', 'chicken-beef', and 'salmon-mackerel' had strong associations.

Anti proliferative activity of ELACYT™ (CP-4055) in combination with cloretazine (VNP40101M), idarubicin, gemcitabine, irinotecan and topotecan in human leukemia and lymphoma cells

This study evaluated combination drug partners for CP-4055, the C18:1Δ9,trans unsaturated fatty acid ester of cytarabine in HL-60 and U937 cells. Growth inhibition was assessed by ATP assay and drug interaction by the combination index and three dimensional methods. Synergy was observed in HL-60 cells for simultaneous combinations of CP-4055 with gemcitabine, irinotecan and topotecan, while combinations with cloretazine (VNP40101M) and idarubicin were additive. In U937 cells, synergy was observed with gemcitabine and additivity for the other drugs. In HL-60, the IC50 concentration of CP-4055 could be reduced 10-fold and that of gemcitabine 3-fold in combination versus the agents alone, an interaction that was independent of drug sequence, ratio and exposure time. In contrast, interactions of CP-4055 with the topoisomerase inhibitors became antagonistic when the drugs were administered 24 h prior to CP-4055 and at certain drug ratios, particularly in U937 cells. In summary, CP-4055 produced additive to synergistic anti proliferative activity when combined simultaneously with drugs from four mechanistic classes in cell culture models of human leukemia and lymphoma. The impact of drug sequence and ratio on the interactions argues for incorporation of these parameters into the design of combination chemotherapy regimens.

Natural organic matter (NOM) and pesticides removal using a combination of ion exchange resin and powdered activated carbon (PAC)

The combination of anion exchange resins (AERs) and powdered activated carbon (PAC) was studied to remove both natural organic matter (NOM) and pesticides. Experiments were conducted with high dissolved organic carbon (DOC) surface water (about 6.0 mg DOC/L) spiked with both atrazine and isoproturon. AERs, like MIEX ® and IRA938 ®, showed up to 75% removal of DOC after 30 min contact time. The addition of PAC after treatment with these AERs only slightly decreased the residual DOC from 1.4 to 1.2 mg/L. Experiments conducted with high (200 μg/L) and low (1 μg/L) initial pesticide concentrations showed that simultaneous and successive combinations of AER and PAC significantly improve the removal of both pesticides compared with PAC treatment on raw water. The improvement of short-term adsorption kinetics was explained by the adsorption of pesticides on AERs (about 5%) and the removal of high molecular weight (MW) NOM structures by AERs that reduce pore blockage phenomena. For 24 h contact time with PAC (adsorption isotherms), the benefit of AER treatment was lower, which indicates that the refractory DOC to AER treatment still competes through direct site competition mechanism. MIEX ® resin had a distinct behavior since the simultaneous treatment with PAC showed no benefit on pesticide adsorption. The presence of fine residues of MIEX ® was shown to interfere with PAC adsorption.

Antiproliferative effects of rapamycin as a single agent and in combination with carboplatin and paclitaxel in head and neck cancer cell lines

Recent data suggested that combining targeted therapies with chemotherapy may counteract drug resistance. Activation of the PI3K/AKT/mTOR pathway downstream to kinase receptors, such as EGFR, was found in 57-81% of head and neck squamous cell carcinoma (HNSCC), and was eventually associated with a loss of PTEN function. mTOR was shown to modulate cell proliferation, apoptosis, invasion, and angiogenesis. This study aimed to evaluate molecular and cellular effects of rapamycin in a panel of cell lines either as single agent or in combination with cytotoxics commonly used in HNSCC. Antiproliferative effects of rapamycin, carboplatin, and paclitaxel were evaluated in a panel of three HNSCC cell lines (SCC61, SQ20B and HEP2). Cells were exposed to rapamycin for 48 h, to carboplatin for 48 h, or to paclitaxel for 24 h. Antiproliferative effects of simultaneous and sequential rapamycin-based combinations were studied using MTT assay and median effect plot analysis. Cell cycle effects were analysed using flow cytometry. Rapamycin induced concentration dependent antiproliferative effects in HNSCC cell lines with IC(50) of 5 +/- 1, 12 +/- 2 and 20 +/- 2 microM in SCC61, SQ20B, and HEP2 cells, respectively. Higher antiproliferative effects were observed in SCC61 cells overexpressing NOXA and cyclin D1 than in HEP2 that overexpressed MDR1 and BCL2. In our panel, antiproliferative effects of rapamycin were associated with G0/G1 cell cycle accumulation and apoptosis induction, at concentrations ranging 3-30 microM. Combinations of rapamycin with paclitaxel and carboplatin displayed synergistic and additive effects. Synergistic effects were observed with paclitaxel in SQ20B and HEP2 cells and with carboplatin in SQ20B cells, when cells were exposed to cytotoxics prior to rapamycin. Our results show that rapamycin displays antiproliferative effects and induces apoptosis in HNSCC cell lines, cellular effects being more potent in cells that do not express BCL2 and MDR1. Additive and synergistic effects were observed when rapamycin was combined with carboplatin and paclitaxel.