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Several members of the kinesin family of microtubule motor proteins play essential roles in mitotic spindle function and are potential targets for the discovery of novel antimitotic cancer therapies. KSP, also known as HsEg5, is a kinesin that plays an essential role in formation of a bipolar mitotic spindle and is required for cell cycle progression through mitosis. We identified a potent inhibitor of KSP, CK0106023, which causes mitotic arrest and growth inhibition in several human tumor cell lines. Here we show that CK0106023 is an allosteric inhibitor of KSP motor domain ATPase with a Ki of 12 nm. Among five kinesins tested, CK0106023 was specific for KSP. In tumor-bearing mice, CK0106023 exhibited antitumor activity comparable to or exceeding that of paclitaxel and caused the formation of monopolar mitotic figures identical to those produced in cultured cells. KSP was most abundant in proliferating human tissues and was absent from cultured postmitotic neurons. These findings are the first to demonstrate the feasibility of targeting mitotic kinesins for the treatment of cancer.

Supplementary Fig. 1 from Antitumor Activity of a Kinesin Inhibitor

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Dataset for "Flora diversity survey and establishment of a plant DNA barcode database of Lomas ecosystems in Peru "

Dataset for "Flora diversity survey and plants DNA barcode database establishment in Lomas ecosystem, Peru"

HDAC6 is a cytoplasmic class IIB HDAC isoenzyme that is involved in the deacetylation of cytoplasmic proteins. HDAC6 also binds ubiquitinated proteins, facilitating the formation of the aggresome, to remove misfolded proteins. Previously, HDAC6-selective inhibitors were shown to decrease immunosuppression and enhance immune function of melanoma patient T-cells demonstrating an important role for HDAC6 inhibition for cancer immunotherapy. GB-1101 is a novel, orally bioavailable, nanomolar potent inhibitor of HDAC6. GB-1101 tested in vitro did not induce direct cytotoxicity to CD4+/CD8+ or NK cells at concentrations up to 300 nM. RNA-seq on GB-1101 exposed MHC-null human MSS colon cancer cell lines reveal potent induction of MHC Class I/II genes and expression numerous cancer neoantigens. To test the activity of GB-1101 in vivo, we established large (~450mm3) 4T1-luc syngeneic tumors and initiated treatment of GB-1101 given orally once daily alone and combined with anti-PD1, anti-CTLA4, and anti-PD1/anti-CTLA4 combination. The activity of anti-PD1 in this model was minimal (TGI: 3%); GB-1101 as a single agent showed more potent anti-tumor activity (TGI: 50%) compared to anti-PD1. We observed synergistic benefit when GB-1101 was combined with anti-PD1 (Combination TGI: 78%). GB-1101 showed comparable anti-tumor activity to single agent anti-CTLA4 (TGI: 43%) but revealed significant tumor regressions of large and well-established tumors when combined with anti-CTLA4 (Combination TGI: >100%). As a single agent, GB-1101 was superior to anti-PD1+anti-CTLA4 (TGI: 7%) and induced significant tumor regressions when combined with anti-PD1+anti-CTLA4 (Triple Combination TGI: >100%). In the TC-1, HPV-positive syngeneic model, GB-1101 reprogrammed the tumor immune microenvironment reducing the number of M-MDSC and TReg cells and increase the numbers of CD4+/CD8+ and NK cells. Taken together, these data support GB-1101 as an important new targeted epigenetic immunomodulator able to revoke immune privilege to enhance the clinical activity of immune checkpoint therapies. Citation Format: Kari Kotlarczyk, Mario Sepulveda, Tong Wang, Maggie Murray, Paul Gonzales, Stephen Thomas Gately. Selective HDAC6 inhibition by GB-1101 revokes tumor immune privilege and synergizes with immune checkpoint therapies to induce tumor regressions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1359.

HDAC3 is essential for transcriptional repression and is required for the activity of NCOR1 & SMRT co-repressors complexes. Inhibition of HDAC3 results in the suppression of genes responsible for DNA damage repair and maintenance of genomic stability. HDAC3/NCOR1 also play critical roles in tumor metabolism and immune cell biology. GB-3103 is a novel and potent inhibitor of HDAC3 with an IC50 of 0.56nM that was tested for activity against human neuroendocrine prostate (NEPC) and small cell lung cancers (SCLC). RNA-seq analysis of GB-3103 treated human tumor cells revealed induction of BRCAness, inhibition of genes from DNA repair pathways and inhibition of PI3K-AKT1, MYC and p53 signaling. GB-3103 showed potent in vitro anticancer activity against the human H660 NEPC line, with an IC50 of 28nM, and 21nM against the murine PNEC30 line and potent IC50 of 16nM against NCI-H209 human lung neuroendocrine cancer. Because of the potent induction of BRCAness we used zero interaction potency (ZIP) model to test the activity of the combination of GB-3103 with a PARP inhibitor against human H660 and murine PNEC30 cell lines. These experiments revealed synergy for the combination of PARPi with GB-3103 in NEPC. GB-3103 was subsequently tested alone and in combination with olaparib in a xenograft model of H660. GB3103 (TGI=3%) showed minimal activity at the selected dose against H660 compared to single agent olaparib (TGI=67%). However, when combined with olaparib, GB-3103 revealed potent synergy (TGI=96%, p100%, p Citation Format: Stephanie Nagl, Kendra Devore, Gregg Hirschfeld, Kari Kotlarczyk, Damaris Diaz, Tong Wang, Maggie Murray, Paul Gonzales, Stephen Thomas Gately. Inhibition of HDAC3 induces BRCAness and potent synergy with PARP inhibition in neuroendocrine prostate and small cell lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2607.

International audience

Hemophagocytic lymphohistiocytosis (HLH) is a rare, hyperinflammatory syndrome characterized by clinical signs and symptoms of extreme inflammation. In adults, HLH is typically a complication of infections, autoimmune diseases, and malignancies. While the disease is often fatal, classic management of HLH revolves around early diagnosis and initiation of protocolized therapy. We present a case of a previously healthy 56-year-old female who developed distributive shock requiring intubation, vasopressors, and continuous venovenous hemofiltration. In the setting of multiple infectious syndromes, severe cytopenias, and rising direct hyperbilirubinemia, her diagnosis of HLH was confirmed. Therapy was initiated with dexamethasone and two doses of reduced-intensity etoposide based on the patient’s clinical course. Over the next few weeks, she continued to improve on dexamethasone monotherapy and has maintained remission up to the present with complete resolution of her cytopenias and return of baseline renal function. Our case highlights the variability in the management of probable infection-associated HLH (IHLH) with a good patient outcome. We demonstrate the potential to treat IHLH with partial protocols and minimal chemotherapeutics.

Constitutive activation of Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most common oncogenic event in certain types of human cancer and is associated with poor patient survival. Small molecule signaling inhibitors have improved the clinical outcomes of patients with various cancer types but attempts to target KRAS have been unsuccessful. Plinabulin represents a novel class of agents that inhibit tubulin polymerization with a favorable safety profile in clinical trials. In the present study, the potency of plinabulin to inhibit tubulin polymerization and growth of KRAS-driven cancer cells was characterized. In vivo efficacy of plinabulin was tested in two different mouse models; one being the RCAS/t-va gene transfer system and the other being a xenograft model. In vitro cell culture tubulin polymerization assays were used to complement the mouse models. There was improved survival in a KRAS-driven mouse gene transfer glioma model, but lack of benefit in a similar model, without constitutively active KRAS, which supports the notion of a KRAS-specific effect. This survival benefit was mediated, at least in part, by the ability of plinabulin to inhibit tubulin polymerization and disrupt endosomal recycling. It was proposed a mechanism of compromised endosomal recycling of displaced KRAS through targeting microtubules that yields inhibition of protein kinase B, but not extracellular signal regulated kinase (ERK) signaling, therefore lending rationale to combination treatments of tubulin- and ERK-targeting agents in KRAS-driven cancer.

In his contribution, Philip Gonzales stages a dialogue between two seemingly antithetical thinkers, Desmond and Agamben. Gonzales argues that Desmond provides a reconstructed Christian metaphysics against the profaning thought of Agamben. Agamben is incapable of thinking the Sabbath or rest of God beyond the terms of retreat while metaxology provides the resources to think the Sabbath of God as part of the creatureliness of human beings.

Successful immunotherapy is dependent on the regulation of an immune response concomitant with modulation of the tumor microenvironment. To study this hypothesis, we utilized a replication-incompetent adenovirus engineered to conditionally express mouse IL-12 (Ad-RTS-mIL-12), via our RheoSwitch Therapeutic System® (RTS®) gene switch which is tightly controlled by the oral activator ligand veledimex (V) in combination with the chemotherapeutic CCNU (lomustine, alkylating nitrosourea) in a GL-261 orthotopic glioma mouse model. The effects of Ad-RTS-mIL-12+veledimex (Ad+V) alone Ad 5x109vp+V 3-30mg/m2QDx14po or concomitantly with CCNU 9-18mg/m2QDx5ip were studied. Mice without treatment succumb to disease progression by day 39 (median 22 days). Ad+V 3mg/m2 monotherapy prolonged median overall survival (mOS) to 37 days. Eighty days after immunotherapy (end of study), ~65% mice receiving Ad +V 10-30mg/m2/day survived. CCNU 9mg/m2 failed to improve mOS while 18mg/m2 increased mOS to 36 days. Ad+V 3mg/m2 combined with CCNU 9mg/m2 failed to improve mOS while Ad+V 3mg/m2+CCNU 18mg/m2 increased survival with 60% surviving at study end. Ad+V 10mg/m2+CCNU 9mg/m2 failed to increase mOS over monotherapy while Ad+V 10mg/m2+CCNU 18mg/m2 resulted in 100% survival at end of study. Ad+V 30mg/m2+CCNU (9-18mg/m2) did not further improve survival with increased clinical signs over monotherapy that recovered on discontinuance of dosing. Ad+V increased tumor IL-12 (80 pg/mg) which was ~15-times greater than that of plasma while CCNU alone or in combination with Ad+V did not affect tumor and serum cytokines. Within the tumor, Ad+V elicited a dose-related increase in cytotoxic T cells and macrophages and decrease in regulatory T cells consistent with immune-mediated anti-tumor effects. Ad+V+CCNU did not further alter the tumor immune profile over Ad+V monotherapy. In summary, the controlled local immunostimulation with IL-12 combined with CCNU, warrants further investigation in GBM.

Breast cancer remains the leading cause of cancer and the third leading cause of cancer related deaths among our population with an estimated number of 246,660 new cases and 40,450 deaths in 2016. With treatment advancements, including targeted agents such as Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, survivability and quality of life continue to improve. However, with the use of these agents come adverse effects, some of which are still being characterized. Our case demonstrates recurrent episodes of gastrointestinal bleeding in a 60-year-old woman being treated with Everolimus for progressive metastatic breast cancer. On endoscopy, bleeding was secondary to erosive gastritis. Previous case reports have described bleeding due to gastric antral vascular ectasia (GAVE), which was described in two prior reported cases. In our case, bleeding also occurred on a reduced dose of Everolimus compared to what is previously reported (5 mg versus 10 mg). As a result of her gastrointestinal bleeding, she required multiple endoscopic interventions including argon plasma coagulation and multipolar heater probe to achieve hemostasis. This is the first case reported of gastrointestinal bleeding not consistent with GAVE and occurring while being on a reduced dose of Everolimus. It is important to document our case so that the Gastroenterology and Hematology communities can be educated and made aware for their patient populations on Everolimus.

Dual loss of SMARCA4/SMARCA2 ATPases of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex has been reported in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) and other tumors. Loss of SMARCA4 is the result of inactivating mutations, and the loss of SMARCA2 results from the absence of mRNA expression. Restoration of either SMARCA4 or SMARCA2 can inhibit the growth of these cancers. We have evaluated the activity of a novel, structurally rigid, and potent, Class I/IIb HDAC inhibitor, GB-3103, against human SCCOHT and other cells lines deficient in SWI/SNF complex. GB-3103 shows potent anti-proliferative activities with low nM IC50 values against human SCCOHT lines BIN67 (51nM), COV434 (35nM) and SCCOHT-1 (293nM), and SWI/SNF-deficient rhabdoid and lung tumor lines A204 (95nM), A427 (174nM), G401 (138 nM), G402 (71nM), H522 (102nM). Treatment of human BIN67 SCCOHT cell line for 72h with GB-3103 revealed potent concentration- and time-dependent induction of SMARCA2 expression at both mRNA and protein levels. Treatment of mice bearing G401 human malignant rhabdoid tumor xenografts with GB-3103 at 5 mg/kg, QD resulted in 70% tumor growth inhibition (TGI) compared to vehicle control (P Citation Format: Tong Wang, Paul Gonzales, Kari Kotlarczyk, Myung-Ja Lee, Erin Bossert, Courtney Devore, Haiyong Han, Jessica Lang, William Hendricks, Jeffrey Trent, Stephen Gately. GB-3103, an epigenetic immunomodulator, shows potent antitumor activity against tumors harboring dual loss of SMARCA4/SMARCA2 ATPases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-058.

Background Adrenocortical carcinoma (ACC) is an aggressive cancer with a 5 year survival rate of 20–30 %. Various factors have been implicated in the pathogenesis of ACC including dysregulation of the G2/M transition and aberrant activity of p53 and MDM2. Polo-like kinase 1 (PLK-1) negatively modulates p53 functioning, promotes MDM2 activity through its phosphorylation, and is involved in the G2/M transition. Gene expression profiling of 44 ACC samples showed that increased expression of PLK-1 in 29 % of ACC. Consequently, we examined PLK-1’s role in the modulation of the p53 signaling pathway in adrenocortical cancer. Methods We used siRNA knock down PLK-1 and pharmacological inhibition of PLK-1 and MDM2 ACC cell lines SW-13 and H295R. We examined viability, protein expression, p53 transactivation, and induction of apoptosis. Results Knocking down expression of PLK-1 with siRNA or inhibition of PLK-1 by a small molecule inhibitor, BI-2536, resulted in a loss of viability of up to 70 % in the ACC cell lines H295R and SW-13. In xenograft models, BI-2536 demonstrated marked inhibition of growth of SW-13 with less inhibition of H295R. BI-2536 treatment resulted in a decrease in mutant p53 protein in SW-13 cells but had no effect on wild-type p53 protein levels in H295R cells. Additionally, inhibition of PLK-1 restored wild-type p53’s transactivation and apoptotic functions in H295R cells, while these functions of mutant p53 were restored only to a smaller extent. Furthermore, inhibition of MDM2 with nutlin-3 reduced the viability of both the ACC cells and also reactivated wild-type p53′s apoptotic function. Inhibition of PLK-1 sensitized the ACC cell lines to MDM2 inhibition and this dual inhibition resulted in an additive apoptotic response in H295R cells with wild-type p53. Conclusions These preclinical studies suggest that targeting p53 through PLK-1 is an attractive chemotherapy strategy warranting further investigation in adrenocortical cancer. Electronic supplementary material The online version of this article (doi:10.1186/s40169-015-0080-3) contains supplementary material, which is available to authorized users.

International audience; We present a new continuously-loaded high-pressure cell for neutron diffraction made from TiZr 'null-matrix' alloy that combines high mechanical resistance below 100 °C and negligible coherent neutron scattering. This cell operates at a maximum pressure of 700 MPa down to a temperature of 1.5 K. A sapphire optical window allows simultaneous illumination of the sample over the broad wavelength range ~0.4 to almost 5 μm. The pressure is applied with Fluorinert or helium gas to ensure the best possible hydrostatic conditions at cryogenic temperatures.

The design of new high pressure equipment for structural and dynamical studies on samples in solution is described. We present two sample cells for applying pressures up to 150 and 700 MPa (i.e. 1.5 and 7 kbar), respectively. These cells are mounted on special sticks and inserted into the calorimeter of a cryostat to regulate the temperature. Different parts of the equipment – the pressure controller, the sticks and the cells – are described. In addition, radiography tests which were performed with neutrons in situ at the Institut Laue Langevin to verify the tightness of the cells and the hydrostatic transmission of the pressure to the sample are presented. First results on model lipids are in agreement with former results by R. Winter et al. [Towards an understanding of the temperature/pressure configurational and free-energy landscape of biomolecules, J. Non-Equilib. Thermodyn. 32 (2007), pp. 41–97].

Moore's Law has created a popular perception of exponential progress in information technology. But is the progress of IT really exponential? In this paper we examine long time series of data documenting progress in information technology gathered by [1]. We analyze six different historical trends of progress for several technologies grouped into the following three functional tasks: information storage, information transportation (bandwidth), and information transformation (speed of computation). Five of the six datasets extend back to the nineteenth century. We perform statistical analyses and show that in all six cases one can reject the exponential hypothesis at statistically significant levels. In contrast, one cannot reject the hypothesis of superexponential growth with decreasing doubling times. This raises questions about whether past trends in the improvement of information technology are sustainable., Boeing Company, National Science Foundation (U.S.) Science of Science and Innovation Policy (NSF Award Number: 0738187)

Autologous CAR T therapeutics have recently been approved for use in B-cell malignancies. While responses have been impressive using CD19 directed CAR T cells there has been a lack of comparable success for CAR T cells directed at solid tumor antigens. In an effort to address the need for effective and durable off-the shelf therapies for both hematologic and solid tumors we have developed allogeneic CAR T cells targeting the CD70 antigen. CD70 is expressed in both hematologic malignancies as well as in solid cancers such as renal cell carcinoma (RCC), while its expression in normal tissues is restricted to a subset of lymphoid cell types. CAR-T cells expressing a CD70 targeting CAR were generated by CRISPR Cas9 genome editing. T cells from healthy donors were edited to express a CD70 CAR by knocking this construct into the concurrently knocked out TCR alpha constant region (TRAC). Loss of the TCR reduces the risk of graft versus host disease enabling an allogeneic therapeutic. CD70 CAR T cells displayed potent cell killing function in vitro against CD70 expressing lymphoid and renal cancer derived cell lines across a broad range of antigen expression levels. CD70 CAR T cells also secreted IFNg, released granzyme B and proliferated in a CD70 specific manner. Furthermore, the CD70 targeting CAR T cells were able to eliminate established ccRCC tumor xenografts in mice Citation Format: Zinkal Padalia, Ashley Porras, Mary Lee Dequeant, Jason Sagert, Thao Nguyen, Matthias John, Melanie Allen, Henia Dar, Daniel Henderson, Seshidar Police, Dakai Mu, Kelly Maeng, Elaine Huang, Sarah Spencer, Nickolaus Lorson, Paul Gonzales, Chelsea Holmquist, Gregg Hirschfeld, Jonathan A. Terrett, Demetrios Kalaitzidis. Allogeneic CRISPR engineered anti CD70 CAR T cells demonstrate potent preclinical activity against both solid and hematological cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2551.

Autophagy is a conserved cellular pathway used to recycle nutrients through lysosomal breakdown basally and under times of stress (e.g., nutrient deprivation, chemotherapeutic treatment). Oncogenes are known to induce autophagy, which may be exploited by cancers for cell survival. To identify autophagy inhibitors with potential therapeutic value for cancer, we screened a panel of antimalarial agents and found that quinacrine (QN) had 60-fold higher potency of autophagy inhibition than chloroquine (CQ), a well-known autophagy inhibitor that functions by disrupting lysosomal activity. Despite desirable autophagy inhibiting properties, QN showed considerable cytotoxicity. Therefore, we designed and synthesized a novel series of QN analogs and investigated their effects on autophagy inhibition and cell viability. Notably, we found two compounds (33 and 34), bearing a backbone of 1,2,3,4-tetrahydroacridine, had limited cytotoxicity yet strong autophagy inhibition properties. In conclusion, these improved lysomotropic autophagy inhibitors may have use as anticancer agents in combination with conventional therapies.

Within the framework of the Millennium Programme, we have started the design and building of novel equipment with the aim at facilitating and diversifying the experimental conditions on Institut Laue-Langevin (ILL) and ILL–CRG instruments. We anticipate new devices for applying external parameters (pressure, temperature, magnetic or electric fields, etc.), handling the neutron beam polarisation (RF wide-band flipper, TOF-Cryopad, etc.) or carrying multi-task experiments. The facilities already in operation are briefly reviewed: 3 K cryogen-free cryostat hosting the Paris–Edinburgh pressure cell, 3 K pulse-tube top-loading cryostat with 700 K high-temperature insert, 2 K Joule–Thomson cryogen-free cryostat for Eulerian cradles, 20 mK dilution fridge for the recently acquired 15 T cryomagnet and a low-temperature gas-injection sample stick for Orange cryostats.

A series of benzimidazole based HDAC inhibitors have been rationally designed, synthesized and screened. The SAR of this new chemotype is described. The lead compound, 11e, showed strong activity in several cellular assays and demonstrated in vivo efficacy in mouse xenograft pancreatic cancer models.

The utility of immunotherapy in the treatment of glioma may be improved through combination therapies that enhance cytotoxic immune-activation while concomitantly reducing immunosuppression. We provide data in mice to support evaluation of combining controlled local interleukin 12 (IL-12) administration and blockade of programmed cell death protein 1 (PD-1) in humans. To circumvent challenges surrounding the uncontrolled activation, we have implemented clinical trials using a replication-incompetent adenovirus engineered to conditionally express IL-12 (Ad-RTS-IL-12), via our RheoSwitch Therapeutic System® (RTS®) gene switch. When directly injected intra-tumorally in pre-clinical or clinical studies, IL-12 expression is “off” when devoid of the activator ligand (veledimex, V) and IL-12 production is turned “on” (in a dose-dependent manner) by oral administration of veledimex. PD-1 inhibitors using therapeutic monoclonal antibodies (mAbs) demonstrate an ability to reverse tumor immunosuppression and are effective in the treatment of some cancers. In the present pre-clinical study we assessed the effects of Ad-RTS-mIL-12+veledimex (Ad+V) alone, Ad 5×109 viral particles (vp) + V 10-30mg/m2/day for 14 days or in combination with the antiPD-1-specific mAb RMP1-14 (antiPD-1, 7.5 & 15.0 mg/m2 for 4/day for 5 days i.p.) in the orthotopic GL-261 mouse model. All mice without treatment succumb to disease progression by Day 35. Eighty days after immunotherapy, 70-80% receiving Ad +V monotherapy survived, 30-40% receiving antiPD-1 monotherapy survived and 100% receiving Ad +V 30 mg/m2 + antiPD-1 15.0 mg/m2 combination survived. There was an increase in tumor IL-12 (100 pg/mg) which was 15-times greater than that of plasma peak 5 days after Ad +V. Furthermore, the combination of Ad +V+antiPD-1 sustained peak IL-12 levels in tumor which was associated with a 100-150% increase of activated T cells in the spleen compared with the minimal changes observed with either immunotherapy alone. In addition, there was an additive reduction in regulatory T cells (FOXP3) compared with monotherapies. In summary we demonstrate that controlled local immunostimulation with IL-12 combined with inhibition of PD-1 is an attractive approach for the treatment of glioma. Since both Ad-RTS-IL-12 and mAb blocking PD-1 are clinically available, these data provide impetus for evaluating this combination immunotherapy in humans.

BACKGROUND Traditional drug discovery methods have a limited role in rare cancers. We hypothesized that molecular technology including gene expression profiling could expose novel targets for therapy in adrenocortical carcinoma (ACC), a rare and lethal cancer. SPARC (secreted protein acidic rich in cysteine) is an albumin-binding matrix-associated protein that is proposed to act as a mechanism for the increased efficacy of a nanoparticle albumin-bound preparation of the antimicrotubular drug Paclitaxel (nab-paclitaxel). METHODS The transcriptomes of 19 ACC tumors and 4 normal adrenal glands were profiled on Affymetrix U133 Plus2 expression microarrays to identify genes representing potential therapeutic targets. Immunohistochemical analysis for target proteins was performed on 10 ACC, 6 benign adenomas, and 1 normal adrenal gland. Agents known to inhibit selected targets were tested in comparison with mitotane in the 2 ACC cell lines (H295R and SW-13) in vitro and in mouse xenografts. RESULTS SPARC expression is increased in ACC samples by 1.56 ± 0.44 (μ ± SD) fold. Paclitaxel and nab-paclitaxel show in vitro inhibition of H295R and SW-13 cells at IC50 concentrations of 0.33 μM and 0.0078 μM for paclitaxel and 0.35 μM and 0.0087 μM for nab-paclitaxel compared with mitotane concentrations of 15.9 μM and 46.4 μM. In vivo nab-paclitaxel treatment shows a greater decrease in tumor weight in both xenograft models than mitotane. CONCLUSIONS Biological insights garnered through expression profiling of ACC tumors suggest further investigation into the use of nab-paclitaxel for the treatment of ACC.

Effectively operating artificial lift systems can be a very challenging endeavor when implementing tertiary recovery on a mature oil field. The desire to produce a maximum amount of oil must be balanced with the physical limitations of the artificial lift equipment. The traditional operating limitations of artificial lift equipment may be too liberal in a CO2 flood. Being too aggressive when attempting to reduce fluid levels can lead to excess failures and thus, reduced overall production and excessive costs. Attempting to determine the optimal artificial lift strategy in this environment can be a daunting task. Traditional models for determining operational policy may not capture all of the dynamics that affect the performance of the system. An empirical approach can be helpful in setting artificial lift guidelines. This paper discusses the results of an empirical analysis of an artificial lift system's performance in a mature CO2 flood vs. the performance in a mature water flood. For the analysis, data from two oil fields in southeastern Utah, the McElmo Creek Unit (mature CO2 flood) and the Ratherford Unit (mature water flood) was compared and contrasted. The data was analyzed using statistical modeling tools to determine the appropriate strategy for the system. The results from the review gave significant insights to the optimal strategy for operating the system and will be discussed.

Kras mutations, particularly at codons 12 and 13, are reported to occur in up to one-third of human cancer cells and are considered to be undruggable targets (Stoize et al, 2015). These mutations are especially prevalent in NSCLC and CRC. Plinabulin is a new chemical entity in Phase 3, with a multi-faceted mechanism of action, including anti-angiogenesis, inhibition of tubulin polymerization and activation of JNK, which is downstream of the Kras pathway. The combination of these vascular mechanisms together with activity downstream from Kras, suggests that plinabulin could express anti-tumor activity in the presence of Kras mutations. The present report summarizes the findings with plinabulin on tumors with Kras mutations (p.12V, p.12D, p.D153V, p.G12A, p.G12C, p.G12D, p.G12V or p.G13D) in vitro and in vivo. In vitro, plinabulin was very potent (IC50 7-33 nM) as a cytotoxic agent against CRC cell lines containing a Kras mutation at p.G13D (LoVo, HCT-15, HCT116) or a BRAF + P53 mutation (HT-29) and against multiple myeloma cell lines (Singh et al, Blood, 2010) with either Nras or p.G12A mutations (IC50 In vivo, plinabulin was tested as a single agent and in combination with SOC in the CRC Kras mutation murine models LoVo and HCT-15 and the P53/Braf mutant model HT-29, the NSCLC Kras mutation model A549, the multiple myeloma Kras mutation model MM.1S and the breast Kras mutation model MDA-MB-231. As a single agent plinabulin was at most moderately active in these models, with the greatest activity seen in the LoVo, HCT-15, and MDA-MB-231 models (TGI 21-43%); the exception was a marked single agent activity observed in the MM.1S model. However, in all cases plinabulin significantly increased the anti-tumor activity of the standard of care agents (TGI 59-84%, with several CRs and increased tolerability as compared to SOC alone). In summary, plinabulin exhibits a potent anti-tumor activity either in vitro, or in vivo as a single agent or in combination with SOC agents. This activity is observed across several tumor types and mutations, but the spectrum of activity does not extend across all tumor types (e.g. inactive in vivo in Kras mutations for pancreatic cancer or melanoma). These findings are encouraging in terms of clinical studies in Kras mutations in MM, NSCLC, CRC and breast cancers. Citation Format: George Kenneth Lloyd, Lihua Du, Gloria Lee, Jessica Dalsing-Hernandez, Kari Kotlarczyk, Paul Gonzales, Steffan Nawrocki, Jennifer Carew, Lan Huang. Activity of plinabulin in tumor models with Kras mutations. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A184.

e16556 Background: Anti-tumor activity has been predicted for glucocorticoid receptor antagonists (GRAs) for some solid organ malignanies. Org34517, the first selective GRA studied in humans, has s...

Depletion of the reservoirs in the San Juan Basin is causing production rates to drop below the minimum lift critical velocity (MCV) in a large number of wells.Traditional methods used to address this issue include plunger lift, pumping units, foam lift, and re-circulation for wells with a compressor and tubing.With declining reservoir pressures, both plunger lift and re-circulation become less effective and often times the expense of a pumping unit, both to purchase and operate, cannot be economically supported by the well.In some cases, injecting surfactant may offer the most cost effective method of removing fluids. To date, foam lift operations in the San Juan Basin have been accomplished by two methods.The most common method of applying surfactant to a well is dropping "soap sticks." This is very inexpensive but it demands a large amount of time from field personnel and can yield inconsistent production rates.The other common method of delivering surfactant to the well is through continuous injection of surfactant at the wellhead.The major problem with this method is that surfactant must drip down the annulus or tubing, which limits its effectiveness due to plating out on the wall surface. The problems described above are eliminated through the use of a Downhole Capillary Surfactant Injection System (DCSIS).The DCSIS delivers surfactant directly to the bottom of the well bore where it is needed to be effective.A capillary stainless steel tubing string is run in the well bore and is attached to a fluid pump and a chemical storage tank.The capillary string can be run inside the tubing, outside the tubing, or down the slim hole production casing.Once installed, a metered amount of surfactant is injected down hole to help unload the well. This paper discusses the results of a 10-well pilot of the DCSIS in the San Juan Basin.The pilot's objective was to determine the physical parameters necessary to estimate the MCV for foam flow and establish better criteria for selecting future installations.To accomplish these objectives, it was necessary to analyze the positive and negative responses to the installation of the DCSIS and determine the factors that led to each response.The data was then analyzed using statistical modeling tools to determine the most important factors affecting the response variable, percent increase in production (% uplift).This paper will discuss the results of a regression model that was built to determine the significance of several factors and to aid in the candidate selection process for future installations.Practical methods of determining the physical parameters necessary to generate foam flow will also be presented.

Several members of the kinesin family of microtubule motor proteins play essential roles in mitotic spindle function and are potential targets for the discovery of novel antimitotic cancer therapies. KSP, also known as HsEg5, is a kinesin that plays an essential role in formation of a bipolar mitotic spindle and is required for cell cycle progression through mitosis. We identified a potent inhibitor of KSP, CK0106023, which causes mitotic arrest and growth inhibition in several human tumor cell lines. Here we show that CK0106023 is an allosteric inhibitor of KSP motor domain ATPase with a Ki of 12 nm. Among five kinesins tested, CK0106023 was specific for KSP. In tumor-bearing mice, CK0106023 exhibited antitumor activity comparable to or exceeding that of paclitaxel and caused the formation of monopolar mitotic figures identical to those produced in cultured cells. KSP was most abundant in proliferating human tissues and was absent from cultured postmitotic neurons. These findings are the first to demonstrate the feasibility of targeting mitotic kinesins for the treatment of cancer.

The exploration of multi-dimensional phase diagrams is a topical subject. However, the simultaneous variation of several control parameters such as temperature, pressure and light irradiation requires a suitably optimized sample environment, particularly when the aim of the experiment is to obtain structural information. We report on a new such sample environment, developed in the context of neutron diffraction measurements, in which the sample can be submitted to pressures up to 7 kbar, temperatures down to 1.7 K and light irradiation in the 660 to 852nm wavelength range, simultaneously. The Ti-Zr alloy pressure cell combines a high mechanical resistance over a wide temperature range with an acceptable neutron background level. The pressure medium is helium gas, ensuring the best possible hydrostatic conditions over a very broad temperature range. The low-temperature environment is obtained from an ILL-type `orange cryostat'. After focusing into an optical fiber, laser light is transmitted to the sample through a sapphire optical window implemented in the pressure cell. The laser flux density at the sample position is of ~30mW/cm2. The geometry of the set-up is optimized to offer a wide optical access (+/- 500vertical, +/-1650horizontal), particularly well suited for Laue neutron diffraction techniques. First results obtained on the pressure-photo-induced spin crossover of a model coordination complex will be presented.

ODSH, a new chemical entity, is 2-0, 3-0 desulfated heparin, a desulfated heparin analog that has been shown to bind to the receptor for advanced glycation endproducts (RAGE). This interaction prevents RAGE from binding to a principal ligand, HMGB1, as well as to other ligands including S-100 calgranulin, which attenuates the activation of RAGE. RAGE activation is known to induce resistance to chemotherapy and promote pancreatic tumor cell survival. We have shown, in vivo, an increase in response with gemcitabine when combined with ODSH. ODSH was tested alone and in combination with standard of care agent, gemcitabine, against BxPC-3 human pancreatic tumor xenograft model. Single agent ODSH and gemcitabine treatment showed an 18.8% and 16.8% decrease in tumor weight, respectively. The combination regimen of ODSH and gemcitabine increased tumor growth inhibition to 37.9%. This decrease was statistically significant (P 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 3698. doi:1538-7445.AM2012-3698