Growth Rebound Research Articles

World Economic Prospects Monthly

Overview: Downturn to spur monetary policy loosening ▀ We now expect global GDP growth to dip slightly below 2016's post‐crisis low of 2.6% in 2019. Moreover, despite a swathe of insurance policy loosening, we do not see a rebound in GDP growth in 2020 and have revised down our forecast from 2.7% to 2.5%. This is in contrast to the previous downturn when growth rebounded sharply in 2017. ▀ Timely global activity indicators have remained soft and while they do not point to a sharp loss of momentum in the shorter term, neither do they suggest that the economic situation is likely to get better imminently. Nonetheless, there are two key reasons why we have become more pessimistic about growth prospects next year. ▀ First, we have added further US‐China tariffs to our baseline forecast, which, despite likely more aggressive policy action by the Fed and China, is set to lower GDP growth in both economies next year, with inevitable spill‐overs to the rest of the world. ▀ Second, the ongoing uncertainty surrounding US‐China relations, coupled with growing recession fears in response to the inversion of the US yield curve, is prompting the manufacturing‐focused weakness to spread. Consumers are generally still in good health, but declining business confidence has triggered weaker hiring intentions which may weaken consumer spending growth further ahead. ▀ Our baseline assumes that insurance policy loosening prevents consumer panic and a deep economic slowdown from here. But the reduced effectiveness of monetary policy in the current environment and the small likelihood of a definitive and imminent end to US‐China tensions imply that a notable growth pick‐up, as seen in 2017, is unlikely. ▀ While our baseline assumes no end to the global expansion, we would warn against complacency over the risk of recession. For monetary policy loosening to place a floor under global growth, it will need to be augmented by more accommodative fiscal policy and perhaps a bit of luck in the form of no further major negative shocks.

Oilfield Flares Provide a Glaring Reminder of the Drive To Produce More Oil

Natural gas flared in just two major US shale plays exceeded the amount of gas consumed last year in Colombia and Israel. The prolific waste from the Permian and the Bakken (Figs. 1 and 2) is a side effect of rising oil production in plays where gas growth is so strong pipeline construction cannot keep up. Flaring is a glaring reminder of the realities of the never-ending rush to drill that is driving down the cost of oil and gas around the globe. These oil-producing wells also produce more gas than processing plants and pipelines can move to market. Pipelines and refineries have recognized that ultralight oil in the Permian is fundamentally different from West Texas Intermediate (WTI), with a make-up that puts it somewhere between oil and gas•liquids. As those wells age, oil production falls as the output shifts to gas. And the cost of sustaining production for the vast majority of producers has consistently exceeded the cash generated by these wells (Fig.• 3). The gap between capital expenditures and revenues was “a staggering $4.7•billion” during the first quarter of 2019, according to a study by Alisa Lukash, a senior analyst on Rystad Energy’s North American shale team, who described it as a “tremendous overspend.” Both the US Energy Information Administration (EIA) and Rystad have raised outlooks that already predicted strong US oil growth. Flaring growth and overspending have accompanied a rebound in growth in the Permian and Bakken, which are the flaring leaders by far in the US. More than half of the total comes from the Permian, which has surpassed the Bakken by more than tripling the volume of gas burned per day since early 2017. The severity of the problem, though, is more acute in the Bakken. While Rystad said about 5% of the Permian gas is flared, in the Bakken, 19% of the gas is flared, according to the oil and gas division of the North Dakota Industrial Commission. The Permian produces far more gas but has the advantage of being close to growing markets for it—chemical plants, export pipelines to Mexico, and natural gas liquefaction facilities—while North Dakota is a distant option for Midwestern markets well supplied by other plays. Limited pipeline capacity means those shippers without contracts ensuring they can move their gas are paid little or less than nothing—prices at Waha gas hub in west Texas repeatedly sank into negative territory over the winter, and pipeline shortages will linger until a big new pipeline goes into service. Oil pipeline construction also has lagged supply growth in the Bakken. Trains and trucks can ship oil, but that is a costly option. North Dakota oil regulators reported that Bakken prices hovered around $50/bbl early this year when the benchmark US oil grade was about $10/bbl higher.

Pulsatile MEK inhibition improves anti-tumor immunity and T cell function in Kras mutant lung cancer

Abstract KRAS is one of the most commonly identified driver oncogene in non-small cell lung cancer (NSCLC) and is commonly associated with disease refractory to current available modalities of treatment. Targeted therapy to inhibit MEK has shown promising tumor growth control in preclinical models, but is followed by quick rebound of tumor growth. Recently, immune checkpoint blockade has shown clinical activity by dis-inhibiting T cells that are suppressed in the tumor microenvironment. We sought to identify the most effective therapy for the treatment of KRAS mutant NSCLC patients by targeting cancer cells and activating infiltrating immune cells concurrently. We focused on studying the impact of pulsatile MEK inhibition on the immune microenvironment. We found that pulsatile MEK inhibition maintained T cell activation better than continuous treatment ex vivo and in vivo. Treatment with two different MEK inhibitors (selumetinib and trametinib) each resulted in higher CTLA-4 and PD-1 expression in tumor-infiltrating T cells using pulsatile treatment, compared to continuous treatment in Kras mutant lung cancer mice. In addition, the pulsatile schedule showed a superior anti-tumor effect and delayed drug resistance compared to the continuous schedule. Further, combination of pulsatile MEK inhibitor treatment and CTLA-4 blockade resulted in the longest survival of Kras tumor-bearing mice. Similar experiments in immune deficient mice confirmed that this prolonged survival is conferred by adaptive immunity. Our findings set the foundation for a combinatorial therapeutic strategy using pulsatile targeted therapy together with immunotherapy in patients to optimally enhance tumor apoptosis and promote immune response simultaneously.

Abstract A125: Pulsatile MEK inhibition improves antitumor immunity and T-cell function in Kras mutant lung cancer

Abstract KRAS is one of the most commonly identified driver oncogene in non-small cell lung cancer (NSCLC) and is commonly associated to NSCLC that is refractory to current available modalities of treatment. Targeted therapy to inhibit MEK has shown promising tumor growth control, but is followed by quick rebound of tumor growth. Recently, cancer immunotherapy has shown great promise by activating T-cells that are suppressed in the tumor microenvironment, especially through targeting co-inhibitory molecules and their counterparts. We sought to identify the most effective therapy for the treatment of KRAS mutant NSCLC patients by targeting cancer cells and activating immune infiltrates at the same time, by studying the impact of MEK inhibition on the immune microenvironment. We utilized Kras mutant lung cancer cell lines and Kras mutant transgenic lung cancer animals. We found that pulsatile treatment of MEK inhibitors activates T-cells and releases their proliferation suppression ex vivo and in vivo. Both selumetinib and trametinib showed highly increased CTLA-4 expression and mild increase of PD-1 in T-cells in pulsatile treatment, compared to continuous treatment in vivo. In addition, the pulsatile schedule alone showed superior antitumor effect and delayed drug resistance, in contrast with continuous dosing schedule. Based on the above observations, we combined pulsatile MEK inhibitor treatment and anti-CTLA-4 and found that it showed most prolonged survival of Kras tumor-bearing mice. All together, our findings will set the foundation for a combinatorial therapeutic strategy using pulsatile targeted therapy together with immunotherapy in patients, to optimally enhance tumor apoptosis and promote long-term immune response simultaneously. Citation Format: Hyejin Choi, Jiehui Deng, Shuai Li, Tarik Silk, Elliott J. Brea, Jonathan Boiarsky, Esra A. Akbay, Paul D. Smith, Taha D. Merghoub, Kwok-Kin Wong, Jedd D. Wolchok. Pulsatile MEK inhibition improves antitumor immunity and T-cell function in Kras mutant lung cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A125.

A new approach for assessing the macroeconomic growth energy rebound effect

Our paper presents a new approach to estimating the macroeconomic growth energy rebound effect. Utilizing data envelopment analysis, our suggested methodology, unlike the standard macroeconomic growth rebound effect estimation, considers other factors of production. Through an output-oriented data envelopment analysis, optimal economic growth is derived considering all factors of production. The difference between the optimal economic growth and actual economic growth represents information on energy overspending. This overspent energy directly equates to the macroeconomic growth energy rebound effect. For the empirical case study, time-series data of economic growth and factors of production, demonstrated by energy supply, capital stocks, and labor force, are collected for the period of 1971 to 2012 in Korea. While the energy rebound effect results using the standard approach to estimating macroeconomic growth energy rebound effect are in the vicinity of 100%, our empirical results show that there is a 1% rebound effect in most of the years. Our method is plausible since our results show that the energy rebound effect is high when the economy is in recession or energy prices are shocked. That is, energy, one of the factors of production, is wasted from an economic viewpoint, which is consistent with the definition of energy rebound effect.

Survival Prolongation Index as a Novel Metric to Assess Anti-Tumor Activity in Xenograft Models.

A single efficacy metric quantifying anti-tumor activity in xenograft models is useful in evaluating different tumors' drug sensitivity and dose-response of an anti-tumor agent. Commonly used metrics include the ratio of tumor volume in treated vs. control mice (T/C), tumor growth inhibition (TGI), ratio of area under the curve (AUC), and growth rate inhibition (GRI). However, these metrics have some limitations. In particular, for biologics with long half-lives, tumor volume (TV) of treated xenografts displays a delay in volume reduction (and in some cases, complete regression) followed by a growth rebound. These observed data cannot be described by exponential functions, which is the underlying assumption of TGI and GRI, and the fit depends on how long the tumor volumes are monitored. On the other hand, T/C and TGI only utilizes information from one chosen time point. Here, we propose a new metric called Survival Prolongation Index (SPI), calculated as the time for drug-treated TV to reach a certain size (e.g., 600mm3) divided by the time for control TV to reach 600mm3 and therefore not dependent on the chosen final time point tf. Simulations were conducted under different scenarios (i.e., exponential vs. saturable growth, linear vs. nonlinear kill function). For all cases, SPI is the most linear and growth-rate independent metric. Subsequently, a literature analysis was conducted using 11 drugs to evaluate the correlation between pre-clinically obtained SPI and clinical overall response. This retrospective analysis of approved drugs suggests that a predicted SPI of 2 is necessary for clinical response.

World Economic Prospects Monthly

Overview: Equity falls unlikely to worsen slowdown ▀ The equity market sell‐off in October may have soured the general mood but we do not think this is the start of a wider market decline and expect the impact on the global economy to be small. We still see world GDP growth slowing from 3.1% this year to 2.8% in 2019 and 2.7% in 2020, the same as last month. ▀ Our estimate of global GDP in Q3 indicates that quarterly growth eased from 0.9% in Q2 to 0.7% in Q3 ‐ the weakest result since Q3 2016. Although we see a rebound in eurozone GDP growth in Q4 after a disappointing Q3, this may be offset by a further loss of momentum in the US. Overall, another quarter of steady but unspectacular global growth appears likely in Q4, a view that is supported by the surveys. ▀ Looking to 2019, the key issue will be the speed at which global growth is likely to slow. The recent equity market sell‐off highlights the risk that financial markets could be the trigger for a further downward leg for global growth. We remain sanguine on the risks of a surge in inflation and the need for aggressive policy action. Partly due to this, we do not see the recent financial market moves as the start of a more substantial correction. Nor do we expect October developments to have a sustained impact on the global economy via confidence or wealth effects. ▀ We believe that growth in the advanced economies will not slow too sharply. With oil prices expected to remain broadly stable, overall inflation should ease in 2019 and the resilience of the labour market is positive for household incomes. With fiscal policy supportive, we still forecast US growth of 2.5% in 2019, down from an expected 2.9% this year, while the eurozone is seen slowing to 1.7% from 2% this year. ▀ We remain cautious about Emerging Markets (EMs). Recent large financial market moves along with tighter policy, receding liquidity and slowing global trade are an unhelpful backdrop. While some slowing is unlikely to be avoided, solid fundamentals should mean that a major slowdown or financial crisis can be avoided.

Efficacy, safety and recurrence of new progestins and selective progesterone receptor modulator for the treatment of endometriosis: a comparison study in mice

BackgroundCurrent medical treatments for endometriosis are very limited. Progestin and selective progesterone receptor modulators (SPRM) are developed but their efficacy, safety, mechanism and recurrence in endometriosis are not fully studied.MethodsIn order to compare therapeutic, side effects and therapeutic actions of Esmya, Duphaston and Dienogest in endometriosis. Experimental endometriosis was induced by either intraperitoneal or subcutaneous mouse endometrium transplantation. Lesion size, weight and histology at the end of intervention were compared. Expression of related markers in the endometriotic lesions were examined. Body, uterus and ovary weights, endometrial glands and thickness (ETI), and follicle count were measured. For recurrent study, lesion growth before and after intervention was monitored.ResultsAfter Esmya, Duphaston, Dienogest treatment, lesion size and weight were significantly decreased. Proliferation Pcna expression was significantly decreased in all groups, but proliferation cells were significantly decreased only in Duphaston group. Apoptosis Mapk1 expression and TUNEL-positive cells were significantly increased in Duphaston group. Adhesion Mmp2 and Itgavβ3 expression were significantly increased in Esmya group. Plau, Hif1α and Vegfa expression, peritoneal fluid PGE2 levels, and ERα and ERβ expression were not affected; while PR expression was significantly lower in all groups. Endometrial gland count in uterus was significantly increased in Dienogest group, ETI was significantly decreased in Duphaston group, and AFC were significantly increased in Esmya group. Upon treatment cessation, lesion growth rebound quickly in Dienogest and Duphaston groups, but slowly in Esmya group.ConclusionEsmya, Duphaston and Dienogest are effective anti-endometriosis drugs targeting proliferation, apoptosis and adhesion. Esmya, Duphaston and Dienogest are all well tolerable, although endometrial glandular hyperplasia was found in Dienogest, endometrial atrophy in Duphaston, follicle accumulation in Esmya.

Impact of the Global Financial Crisis on the Business Cycle in the Visegrad Group

Objective: The aim of the research was to analyse morphological changes in the Visegrad Group business cycles before and after the global financial crisis of 2007/2008, and to provide comparison of their overall economic performance in terms of the real GDP growth, unemployment rate changes and price stability. Research Design & Methods: Visegrad Group’s business cycles were determined by employing Hodrick and Prescott filter to extract cyclical fluctuations, while Bry and Boschan algorithm was applied to identify the turning points of the cycles. Morphological features of business cycles were examined. The analysis was supplemented by examining unemployment rate and price stability. Findings: The financial crisis resulted in the drop of the GDP growth and a periodical increase in unemployment. Nevertheless, in the 20 analysed years the unemployment rate tends to attain lower values, while prices become more stable. The last two economic cycles resulted in post-crisis rebound of the GDP growth. At the same time, the performance of the countries (except for outperforming Poland) becomes more and more correlated. Implications & Recommendations: The Visegrad Group was affected by the crisis and it is plausible that any future disturbances in the world economy might affect it again. Further research aiming at deeper understanding of how a particular country was affected could help mitigate a negative impact of future crises. Contribution & Value Added: The article helps to understand how the crisis affected the V4 economies in terms of the real GDP growth, unemployment rate and price stability. It indicates how the economic aggregates behaved before and after the crash.

The macroeconomic rebound effect in China

The rebound effect measures the fraction of an energy efficiency improvement that is offset by increased energy consumption. A rebound effect can arise at both the microeconomic level and the macroeconomic level. The macroeconomic rebound effect measures the effect of an increase in energy efficiency on overall energy demand after markets adjust and re-equilibrate. At the macroeconomic level, energy efficiency gains can increase energy consumption through two channels: the macroeconomic price effect and the macroeconomic growth effect. In this paper, we econometrically estimate the macroeconomic energy rebound effect in China. Our results show that there is a statistically significant macroeconomic price rebound effect for China, for each province, and for the short run, intermediate run, and the long run. We also find some evidence of a macroeconomic growth rebound in the short run and the intermediate run for some years either nation-wide or for some provinces in China; moreover, for some years and some provinces, we cannot reject backfire. The rebound effect is an important phenomenon that the government of China should not neglect when making energy policy, as it affects how improvements in energy efficiency translate into changes in energy consumption.

Iraq

This 2017 Article IV Consultation highlights a double shock facing Iraq as a result of the conflict with the Islamic State and the plunge in oil prices. In 2016, real GDP increased by 11 percent owing to a 25 percent increase in oil production, which was little affected by the conflict with the Islamic State. Falling oil prices have driven the decline in Iraq’s international reserves from $54 billion at the end of 2015 to $45 billion at the end of 2016. Medium-term growth prospects are positive. Growth will be driven by the projected moderate increase in oil production and the rebound in non-oil growth supported by the expected improvement in security and implementation of structural reform.

United States

Economic OutlookVolume 41, Issue 3 p. 32-33 Article United States First published: 10 August 2017 https://doi.org/10.1111/1468-0319.12293Citations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract Real GDP growth slowed to an annualised rate of 1.4% in Q1 2017 from 2.1% in Q4 2016. Growth in Q1 was constrained by weak consumer spending and inventories, while residential and business investment rose strongly. But, we believe this lull will be short-lived and forecast a rebound in GDP growth to around 3.0% in Q2. The factors that constrained consumer spending, including higher inflation, unusually warm weather and slower tax refunds, were not repeated in Q2. Citing Literature Volume41, Issue3July 2017Pages 32-33 RelatedInformation

Islamic Republic of Iran: 2016 Article IV Consultation-Press Release; Staff Report; and Statement by the Executive Director for the Islamic Republic of Iran

This 2016 Article IV Consultation highlights a rebound in economic growth in the Islamic Republic of Iran over the course of 2016–17 based on higher oil production. Real GDP grew 7.4 percent in the first half of 2016–17, rebounding from the 2015–16 recession. However, growth in the non-oil sector averaged 0.9 percent, despite having picked up in the second quarter, reflecting continued difficulties in access to financing and domestic financial sector and structural weaknesses. Growth is projected to stabilize at 4.5 percent over the medium term as the recovery broadens. The current account is forecast to remain in surplus as higher exports offset the pickup in imports related to investment.

Guinea

This paper discusses Guinea’s Eighth and Final Review Under the Extended Credit Facility (ECF) Arrangement and Financing Assurances Review, and Request for Extension of the Current Arrangement. Guinea’s medium-term economic prospects are good. Growth is projected to average 5 percent during 2017–20, on the back of higher investments in the mining sector, increases in food production, and better electricity services. The recovery in the agricultural sector will allow the growth rebound to be shared by larger segments of the population, but the sector remains vulnerable to weather-related supply shocks. The IMF staff supports the completion of the eighth review under the ECF arrangement and financing assurances review.

Metronomic cyclophosphamide activation of anti-tumor immunity: tumor model, mouse host, and drug schedule dependence of gene responses and their upstream regulators.

BackgroundCyclophosphamide (CPA) can activate immunogenic tumor cell death, which induces immune-based tumor ablation and long-term anti-tumor immunity in a syngeneic C57BL/6 (B6) mouse GL261 glioma model when CPA is given on a 6-day repeating metronomic schedule (CPA/6d). In contrast, we find that two other syngeneic B6 mouse tumors, LLC lung carcinoma and B16F10 melanoma, do not exhibit these drug-induced immune responses despite their intrinsic sensitivity to CPA cytotoxicity.MethodsTo elucidate underlying mechanisms, we investigated gene expression and molecular pathway changes associated with the disparate immune responsiveness of these tumors to CPA/6d treatment.ResultsGlobal transcriptome analysis indicated substantial elevation of basal GL261 immune infiltration and strong CPA/6d activation of GL261 immune stimulatory pathways and their upstream regulators, but without preferential depletion of negative immune regulators compared to LLC and B16F10 tumors. In LLC tumors, where CPA/6d treatment is shown to be anti-angiogenic, CPA/6d suppressed VEGFA target genes and down regulated cell adhesion and leukocyte transendothelial migration genes. In GL261 tumors implanted in adaptive immune-deficient scid mice, where CPA/6d-induced GL261 regression is incomplete and late tumor growth rebound can occur, T cell receptor signaling and certain cytokine-cytokine receptor responses seen in B6 mice were deficient. Extending the CPA treatment interval from 6 to 9 days (CPA/9d) − which results in a strong but transient natural killer cell response followed by early tumor growth rebound − induced fewer cytokines and increased expression of drug metabolism genes.ConclusionsThese findings elucidate molecular response pathways activated by intermittent metronomic CPA treatment and identify deficiencies that characterize immune-unresponsive tumor models and drug schedules.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2597-2) contains supplementary material, which is available to authorized users.

Abstract 5048: Platelet FAK is a critical regulator of tumor growth after withdrawal of anti-angiogenic therapy

Abstract Objective: In most clinical trials, anti-angiogenic therapies have offered only modest improvements in progression-free survival without impacting overall survival. Following cessation of anti-angiogenic therapy, concerns have been raised about a possible rebound in tumor growth, but the underlying mechanisms are poorly understood. Therefore, in this study we aimed at comparing tumor growth and the effects on tumor microenvironment after therapy withdrawal compared to continuous treatment with anti-angiogenic agents. Methods: Mice were intraperitoneally injected with human or mouse ovarian cancer cells and were treated with the anti-angiogenic drugs pazopanib, bevacizumab or B20 for either a short-term with subsequent withdrawal or continuous therapy until necropsy. Immunohistochemical staining was used to evaluate platelet infiltration into the tumor microenvironment, tumor angiogenesis and vascular leakage. To assess the significance of focal adhesion kinase (FAK) in the process of platelet infiltration and tumor rebound after withdrawal of therapy, we either used the FAK inhibitor GSK2256098 or a mouse model with platelet-specific FAK deletion. Results: Cessation of therapy with pazopanib, bevacizumab and the cross-human and murine anti-VEGF antibody B20 was associated with up to 4-fold increased tumor growth in mouse models of ovarian cancer when compared to continuous treatment. Tumor outgrowth was associated with significant tumor hypoxia, increased tumor angiogenesis and vascular leakage. More importantly, we found 380% increased hypoxia-induced ADP production and 3-fold increased platelet infiltration into tumors where anti-angiogenic therapy was withdrawn. Lowering platelet levels significantly inhibited tumor rebound after withdrawal of anti-angiogenic therapy. Interestingly, FAK in platelets regulated their migration into tumor microenvironment and FAK knock-out specifically in platelets completely prevented the rebound tumor growth. Additionally, combined therapy with the FAK inhibitor GSK2256098 and the anti-angiogenic agents pazopanib and bevacizumab led to up to 5-fold reduced orthotopic tumors and likewise inhibited negative effects of withdrawal of anti-angiogenic therapy. Conclusions: Collectively, our results characterize a previously unknown role for platelets in the tumor microenvironment and provide a potential therapeutic benefit for FAK inhibitors in preventing rebound in tumor growth following discontinuation of anti-angiogenic agents. Additionally, dual targeting of FAK and VEGF could have important therapeutic implications for ovarian cancer management. Citation Format: Monika Haemmerle, Justin Bottsford-Miller, Sunila Pradeep, Morgan L. Taylor, Hyun-Jin Choi, Rebecca L. Stone, Min Soon Cho, Alpa M. Nick, Gabriel Lopez-Berestein, Vahid Afshar-Khargan, Anil K. Sood. Platelet FAK is a critical regulator of tumor growth after withdrawal of anti-angiogenic therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5048.

Abstract 2731: Impact of hypomethylating agents on hTERT expression and synergistic effect in combination with imetelstat, a telomerase inhibitor, in AML cell lines

Abstract The catalytic subunit of human telomerase (hTERT) is highly expressed in acute myeloid leukemia (AML). Transcriptional factors and epigenetic modifications regulate this expression. Studies suggest hypermethylation promotes hTERT overexpression. Imetelstat is a competitive telomerase inhibitor. Decitabine (DAC) and azacitidine (AZA) are DNA methyltransferase inhibitors (DNMTIs) used in the treatment of AML. Combining imetelstat and DNMTI may be an improved treatment option for AML. We investigated effects of DAC and AZA on hTERT expression and cell viability in AML cell lines OCI-AML3 and OCI-AML5, and evaluated growth inhibition when combined with imetelstat. OCI-AML3 had higher baseline expression of hTERT compared with OCI-AML5. Dose-dependent downregulation of hTERT expression was observed with DAC and AZA treatments. OCI-AML5 was more sensitive to DAC (1 μM, 46% viability) than OCI-AML3 (1 μM, 95% viability) whereas sensitivity to AZA was similar in both cell lines (1 μM, 29% vs 33% viability). After removal of the drugs, growth inhibition was not sustained and cell proliferation rebounded. Single-agent imetelstat reduced both hTERT expression and telomerase activity but resulted in only limited growth inhibition in these cell lines. It was hypothesized that combining DNMTI with imetelstat may exert more potent growth inhibition. To test this, both cell lines were treated with DAC or AZA for 72 hours followed by different concentrations of imetelstat for 2 to 4 weeks. Dose-dependent synergistic activity was demonstrated for DAC followed by imetelstat: OCI-AML3 cell viability changed from 95% with DAC to 61% and 10% after 2 and 4 weeks of imetelstat, respectively; OCI-AML5 cell viability changed from 46% with DAC to 6% and 1% after 2 and 4 weeks of imetelstat, respectively. In contrast, no enhanced activity was observed in either cell line with AZA followed by imetelstat, but imetelstat was able to slow the growth rebound after AZA removal. Additional studies are ongoing to further understand the mechanism of action of this drug combination in AML and to evaluate different combination sequences of DNMTI with imetelstat for optimal anticancer activity. In summary, DAC and AZA reduced hTERT expression and differentially inhibited cell viability in AML cell lines. Although at the same concentration AZA was more active than DAC in OCI-AML3 and OCI-AML5 lines, the sustainability of growth inhibition after washout differed. Growth rebounded after removal of AZA or DAC treatment. Dose-dependent synergistic activity demonstrated by DAC followed by imetelstat was not seen with AZA followed by imetelstat. Distinctly different mechanisms of action of DAC and AZA may underlie their differential activity when combined with imetelstat, warranting further investigation. Citation Format: Joshua Rusbuldt, Jacqueline Bussolari, Aleksandra Rizo, Fei Huang. Impact of hypomethylating agents on hTERT expression and synergistic effect in combination with imetelstat, a telomerase inhibitor, in AML cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2731.

Cyclical Misconceptions Driving Policy Mistakes: Keys to the Productivity Puzzle

The authors see little reason for a rebound in productivity growth, which has downshifted in part due to policies rooted in overly optimistic assumptions about trend growth, and mistaken notions about business cycle dynamics. If they are right, slow trend growth will prevail for the foreseeable future.

Mechanism-based modeling of the clinical effects of bevacizumab and everolimus on vestibular schwannomas of patients with neurofibromatosis type 2.

To describe the natural growth of vestibular schwannoma in patients with neurofibromatosis type 2 and to predict tumor volume evolution in patients treated with bevacizumab and everolimus. Clinical data, including longitudinal tumor volumes in patients treated by bevacizumab (n=13), everolimus (n=7) or both (n=2), were analyzed by means of mathematical modeling techniques. Together with clinical data, data from the literature were also integrated to account for drugs mechanisms of action. We developed a model of vestibular schwannoma growth that takes into account the effect of vascular endothelial growth factors and mammalian target of rapamycin complex 1 on tumor growth. Behaviors, such as tumor growth rebound following everolimus treatment stops, was correctly described with the model. Preliminary results indicate that the model can be used to predict, based on early tumor volume dynamic, tumor response to variation in treatment dose and regimen. The developed model successfully describes tumor volume growth before and during bevacizumab and/or everolimus treatment. It might constitute a rational tool to predict patients' response to these drugs, thus potentially improving management of this disease.

Assessing relationships between red spruce radial growth and pollution critical load exceedance values

Acidic sulfur (S) and nitrogen (N) deposition depletes cations such as calcium (Ca) from forest soils and has been linked to increases in foliar winter injury that led to the decline of red spruce (Picea rubens Sarg.) in the northeastern United States. We used results from a 30m resolution steady-state S and N critical load exceedance model for New England to better understand the spatial connections between Ca depletion and red spruce productivity. Atmospheric deposition and other inputs were estimated for a 5-year period (1984–1988) in order to smooth year-to-year variations in climate and patterns of atmospheric transport. Deposition levels prior to the reductions that followed the 1990 Amendments to the Clean Air Act were used because tree health and productivity declines were expected to be most responsive to high acid loading. We examined how radial growth (basal area increment) of 441 dominant and co-dominant red spruce trees from 37 sites across Vermont and New Hampshire was related to modeled estimates of S and N critical load exceedance. We assessed growth using statistical models with exceedance as a source of variation, but which also included “year” and “elevation class” (to help account for climatic variability) and interactions among factors. As expected, yearly climate-related sources of variation accounted for most of the differences in growth. However, exceedance was significantly and negatively associated with mean growth for the study period (1951–2010) overall, and particularly for the 1980s and 2000s – periods of numerous and/or severe foliar winter injury events. Because high winter injury reflects the convergence of predisposing (cation depletion) and inciting (weather) factors, exceedance alone appears insufficient to define associated patterns of growth reduction. Significant interactions indicated that exceedance had little influence on growth at low elevations (where intrinsic conditions for growth were generally good) or high elevations (where growth was uniformly poor), whereas exceedance was significantly associated with reduced growth at mid elevations over long periods of time. Exceedance was also linked to reduced growth rebounds following a region-wide foliar winter injury event in 2003. Overall, our analyses suggest that modeled S and N critical load exceedance can help account for red spruce growth and rebound from injury in the field. Interestingly, recent growth for red spruce is above average for the 20th to 21st century dendrochronological record – indicating that the factors shaping growth may be changing. The influence of reduced pollution inputs on this recent growth surge is under investigation.