Targeting Metabolism in Cancer Cells and the Tumour Microenvironment for Cancer Therapy.

Targeting altered tumour metabolism is an emerging therapeutic strategy for cancer treatment. The metabolic reprogramming that accompanies the development of malignancy creates targetable differences between cancer cells and normal cells, which may be exploited for therapy. There is also emerging evidence regarding the role of stromal components, creating an intricate metabolic network consisting of cancer cells, cancer-associated fibroblasts, endothelial cells, immune cells, and cancer stem cells. This metabolic rewiring and crosstalk with the tumour microenvironment play a key role in cell proliferation, metastasis, and the development of treatment resistance. In this review, we will discuss therapeutic opportunities, which arise from dysregulated metabolism and metabolic crosstalk, highlighting strategies that may aid in the precision targeting of altered tumour metabolism with a focus on combinatorial therapeutic strategies

TPL2 enforces RAS-induced inflammatory signaling and is activated by point mutations

NF-κB transcription factors, driven by the IRAK/IKK cascade, confer treatment resistance in pancreatic ductal adenocarcinoma (PDAC), a cancer characterized by near-universal KRAS mutation. Through reverse-phase protein array and RNA sequencing we discovered that IRAK4 also contributes substantially to MAPK activation in KRAS-mutant PDAC. IRAK4 ablation completely blocked RAS-induced transformation of human and murine cells. Mechanistically, expression of mutant KRAS stimulated an inflammatory, autocrine IL-1β signaling loop that activated IRAK4 and the MAPK pathway. Downstream of IRAK4, we uncovered TPL2 (also known as MAP3K8 or COT) as the essential kinase that propels both MAPK and NF-κB cascades. Inhibition of TPL2 blocked both MAPK and NF-κB signaling, and suppressed KRAS-mutant cell growth. To counter chemotherapy-induced genotoxic stress, PDAC cells upregulated TLR9, which activated prosurvival IRAK4/TPL2 signaling. Accordingly, a TPL2 inhibitor synergized with chemotherapy to curb PDAC growth in vivo. Finally, from TCGA we characterized 2 MAP3K8 point mutations that hyperactivate MAPK and NF-κB cascades by impeding TPL2 protein degradation. Cancer cell lines naturally harboring these MAP3K8 mutations are strikingly sensitive to TPL2 inhibition, underscoring the need to identify these potentially targetable mutations in patients. Overall, our study establishes TPL2 as a promising therapeutic target in RAS- and MAP3K8-mutant cancers and strongly prompts development of TPL2 inhibitors for preclinical and clinical studies

Bi-color atomic beam slower and magnetic field compensation for ultracold gases

Transversely loaded bidimensional-magneto-optical-traps (2D-MOT) have been recently developed as high flux sources for cold strontium atoms to realize a new generation of compact experimental setups. Here, we discuss on the implementation of a cross-polarized bi-color slower for a strontium atomic beam improving the 2D-MOT loading, and increasing the number of atoms in a final MOT by eleven times. Our slowing scheme addresses simultaneously two excited Zeeman substates of the 88Sr 1S0->1P1 transition at 461 nm. We also realized a 3-axis active feedback control of the magnetic field down to the microgauss regime. Such a compensation is performed thanks to a network of eight magnetic field probes arranged in a cuboid configuration around the atomic cold sample, and a pair of coils in Helmholtz configuration along each of three Cartesian directions. Our active feedback is capable of efficiently suppressing most of the magnetically-induced position fluctuations of the 689~nm intercombination-line MOT.Comment: 8 pages, 6 figure

Evaluation of Ertapenem use with Impact Assessment on Extended-Spectrum Beta-Lactamases (ESBL) Production and Gram-Negative resistance in Singapore General Hospital (SGH)

BACKGROUND: Ertapenem (preferred choice for ESBL-producing organisms) use exhibited an increasing trend from 2006 to 2008. As extensive use of ertapenem might induce the mutation of resistant bacteria strains to ertapenem, we aimed to assess the appropriateness and impact of ertapenem-use, on ESBL production, the trends of gram-negative bacterial resistance and on the utilization of other antibiotics in our institution. METHODS: Inpatients who received a dose of ertapenem during 1 January 2006 to 31 December 2008, were reviewed. Pertinent patient clinical data was extracted from the pharmacy databases and assessed for appropriateness based on dose and indication. Relevant data from Network for Antimicrobial Resistance Surveillance (Singapore) (NARSS) was extracted, to cross-correlate with ertapenem via time series to assess its impact on hospital epidemiology, trends of gram-negative resistance and consumption of other antibiotics from 2006 to mid-2010. RESULTS: 906 cases were reviewed. Ertapenem therapy was appropriate in 72.4% (93.7% success rate). CNS adverse events were noted in 3.2%. Readmission rate (30-day) due to re-infection (same pathogen) was 5.5%. Fifty cases had cultures growing Pseudomonas aeruginosa within 30 days of ertapenem initiation, with 25 cases growing carbapenem-resistant Pseudomonas aeruginosa. Ertapenem use increased from 0.45 DDD/100 patient days in 2006 to 1.2 DDD/100 patient days in mid-2010. Overall, the increasing trend of ertapenem consumption correlated with 1) increasing incidence-densities of ciprofloxacin-resistant/cephalosporin-resistant E. coli at zero time lag; 2) increasing incidence-densities of ertapenem-resistant Escherichia. coli and Klebsiella spp. at zero time lag; 3) increasing incidence-density of carbapenem-resistant Pseudomonas aeruginosa, at zero time lag. Increasing ertapenem consumption was significantly correlated with decreasing consumption of cefepime (R(2) = 0.37344) 3 months later. It was significantly correlated with a decrease in imipenem consumption (R(2) = 0.31081), with no time lag but was correlated with subsequent increasing consumption of meropenem (R(2) = 0.4092) 6 months later. CONCLUSION: Ertapenem use was appropriate. Increasing Ertapenem consumption did not result in a decreasing trend of ESBL producing enterobacteriaceae and could result in the selection for multi-drug resistant bacteria

Decline in Clostridium difficile-associated disease rates in Singapore public hospitals, 2006 to 2008

<p>Abstract</p> <p>Background</p> <p><it>Clostridium difficile </it>is the major cause of pseudomembranous colitis associated with antibiotic use, and the spread of the hypervirulent epidemic ribotype 027/NAP-1 strain across hospitals worldwide has re-focused attention on this nosocomial pathogen. The overall incidence and trend of <it>C. difficile</it>-associated disease (CDAD) in Singapore is unknown, and a surveillance program to determine these via formal laboratory-based reporting was established.</p> <p>Findings</p> <p>Laboratory and pharmacy data were collated from one tertiary and two secondary hospitals on a quarterly basis between 2006 and 2008. All hospitals tested for <it>C. difficile </it>using Immunocard Toxins A&B (Meridian Bioscience Inc., Cincinnati, OH) during this period. Duplicate positive <it>C. difficile </it>results within a 14-day period were removed. The CDAD results were compared with trends in hospital-based prescription of major classes of antibiotics.</p> <p>Overall CDAD incidence-density decreased from 5.16 (95%CI: 4.73 - 5.62) cases per 10,000 inpatient-days in 2006 to 2.99 (95%CI: 2.67 to 3.33) cases per 10,000 inpatient-days in 2008 (<it>p </it>< 0.001), while overall rates for <it>C. difficile </it>testing increased significantly (<it>p </it>< 0.001) within the same period. These trends were mirrored at the individual hospital level. Evaluation of antibiotic prescription data at all hospitals showed increasing use of carbapenems and fluoroquinolones, while cephalosporin and clindamycin prescription remained stable.</p> <p>Conclusions</p> <p>Our results demonstrate a real decline of CDAD rates in three large local hospitals. The cause is unclear and is not associated with improved infection control measures or reduction in antibiotic prescription. Lack of <it>C. difficile </it>stool cultures as part of routine testing precluded determination of the decline of a major clone as a potential explanation. For more accurate epidemiological trending of CDAD and early detection of epidemic clones, data collection will have to be expanded and resources set in place for reference laboratory culture and typing.</p

GEOS S2S Version 3: The New NASA/GMAO High Resolution Seasonal Prediction System

The NASA/Goddard Global Modeling and Assimilation Office (GMAO) released Version 2 of the Subseasonal to Seasonal (GEOS-S2S) forecast system in the fall of 2017, and it has been producing near-real time subseasonal to seasonal forecasts and a weakly coupled atmosphere-ocean data assimilation record since then. A new version of the coupled modeling and analysis system (Version 3) was released by the GMAO at the end of 2019. The new version runs at higher oceanic resolution than the previous (approximately 1/2 degree for the atmosphere, 1/4 degree for the ocean), and includes interactive earth system model components not typically present in seasonal prediction systems (two moment cloud microphysics for aerosol indirect effect and an interactive aerosol model). The weakly coupled atmosphere-ocean data assimilation system now includes assimilation of sea surface salinity, that has been shown to result in improved ocean mixed layer simulation and ENSO prediction skill

In-Vitro Activity of Polymyxin B, Rifampicin, Tigecycline Alone and in Combination against Carbapenem-Resistant Acinetobacter baumannii in Singapore

OBJECTIVE: Carbapenem-resistant Acinetobacter baumannii (CR-AB) is an emerging cause of nosocomial infections worldwide. Combination therapy may be the only viable option until new antibiotics become available. The objective of this study is to identify potential antimicrobial combinations against CR-AB isolated from our local hospitals. METHODS: AB isolates from all public hospitals in Singapore were systematically collected between 2006 and 2007. MICs were determined according to CLSI guidelines. All CR-AB isolates were genotyped using a PCR-based method. Clonal relationship was elucidated. Time-kill studies (TKS) were conducted with polymyxin B, rifampicin and tigecycline alone and in combination using clinically relevant (achievable) unbound concentrations. RESULTS: 31 CR AB isolates were identified. They are multidrug-resistant, but are susceptible to polymyxin B. From clonal typing, 8 clonal groups were identified and 11 isolates exhibited clonal diversity. In single TKS, polymyxin B, rifampicin and tigecycline alone did not exhibit bactericidal activity at 24 hours. In combination TKS, polymyxin plus rifampicin, polymyxin B plus tigecycline and tigecycline plus rifampicin exhibited bactericidal killing in 13/31, 9/31 and 7/31 isolates respectively at 24 hours. Within a clonal group, there may be no consensus with the types of antibiotics combinations that could still kill effectively. CONCLUSION: Monotherapy with polymyxin B may not be adequate against polymyxin B susceptible AB isolates. These findings demonstrate that in-vitro synergy of antibiotic combinations in CR AB may be strain dependant. It may guide us in choosing a pre-emptive therapy for CR AB infections and warrants further investigations

Combined KRAS-MAPK pathway inhibitors and HER2-directed drug conjugate is efficacious in pancreatic cancer

Targeting the mitogen-activated protein kinase (MAPK) cascade in pancreatic ductal adenocarcinoma (PDAC) remains clinically unsuccessful. We aim to develop a MAPK inhibitor-based therapeutic combination with strong preclinical efficacy. Utilizing a reverse-phase protein array, we observe rapid phospho-activation of human epidermal growth factor receptor 2 (HER2) in PDAC cells upon pharmacological MAPK inhibition. Mechanistically, MAPK inhibitors lead to swift proteasomal degradation of dual-specificity phosphatase 6 (DUSP6). The carboxy terminus of HER2, containing a TEY motif also present in extracellular signal-regulated kinase 1/2 (ERK1/2), facilitates binding with DUSP6, enhancing its phosphatase activity to dephosphorylate HER2. In the presence of MAPK inhibitors, DUSP6 dissociates from the protective effect of the RING E3 ligase tripartite motif containing 21, resulting in its degradation. In PDAC patient-derived xenograft (PDX) models, combining ERK and HER inhibitors slows tumour growth and requires cytotoxic chemotherapy to achieve tumour regression. Alternatively, MAPK inhibitors with trastuzumab deruxtecan, an anti-HER2 antibody conjugated with cytotoxic chemotherapy, lead to sustained tumour regression in most tested PDXs without causing noticeable toxicity. Additionally, KRAS inhibitors also activate HER2, supporting testing the combination of KRAS inhibitors and trastuzumab deruxtecan in PDAC. This study identifies a rational and promising therapeutic combination for clinical testing in PDAC patients

An Introduction to the NASA GMAO Coupled Atmosphere-Ocean System - GEOS-S2S Version 3

Recently NASA's Global Modeling and Assimilation Office (GMAO) has developed a new Subseasonal to Seasonal Prediction system Version 3 (GEOS-S2S-3). This upgrade replaces the GEOS-S2S-2 which is NASA's current contribution to the North American Multi-Model Experiment seasonal prediction project (Kirtman et al., 2014). The main improvements for our S2S-3 system include 1) a higher resolution MOM5 (Griffies et al., 2005) ocean model (now 0.25o x 0.25o x 50 layers), 2) an improved atmospheric/ocean interface layer (Akella and Suarez, 2018), and 3) assimilation of a long-track satellite salinity into the ocean model (Hackert et al, 2019). Atmospheric forcing is provided by the NASA MERRA-2 reanalysis (Gelaro et al., 2017). Initialization for the ocean relies on the GMAO ocean reanalysis system which assimilates all available in situ temperature and salinity, satellite sea surface salinity, and sea level using the Local Ensemble Transform Kalman Filter (LETKF) implementation of (Penny et al., 2013) on a 5 day assimilation cycle with 20 fixed ensemble members.In this presentation, we will authenticate our new S2S-3 ocean reanalysis using standard GODAE validation metrics. For example, we will compare gridded fields of mean and standard deviation of the ocean reanalysis versus observed fields. We will show correlation/RMS of model versus observations and temperature and salinity mean profiles for the various basins and latitude bands. Basin-scale volume transports, such as the Atlantic Meridional Overturning Circulation and the Indonesian Throughflow will be validated. Equatorial ocean waves will be compared by decomposing sea level into Kelvin and Rossby components. For each of these metrics, we plan to validate the results and then compare our new S2S-3 against the current production version, S2S-2. Finally, we will compare 9-month seasonal forecasts initialized from these two systems for the tropical Pacific NINO3.4 region over the period 1981-present