854 research outputs found
Abstract 5103: The dark cancer kinome - untapped opportunities for the development of novel drugs
No full textAbstract Kinases are firmly established drug targets in cancer. There are currently 44 FDA approved kinase drug and hundreds of compounds are in clinical development. However, less than 10% of the Kinome is currently targeted and a large proportion is considered understudied by the NIH Illuminating the Druggable Genome Program (https://druggablegenome.net/). No small molecule inhibitors are known for these “dark” proteins, yet many may be opportune novel cancer targets.We developed a computational pipeline to identify and prioritize understudied kinases as cancer drug targets. We analyzed the complete set of tumors in The Cancer Genome Atlas (TCGA). For 33 different cancers we performed differential expression analysis and identified 39 dark kinases that exhibit significant upregulation in at least four types. Using co-expression analysis we built functional networks prioritizing drug targets. To identify small molecules that reverse their expression levels, we leveraged transcriptional response signatures obtained from dozens of human cancer cell lines exposed to tens of thousands of small molecules from the Library of Integrated Network-based Cellular Signatures (LINCS). To identify small molecules that directly bind to and inhibit dark kinases, we have have combined an advanced AI (artificial intelligence) model trained on activity data from across the Kinome with structure-based simulations.Using the computational pipeline, we identified the dark Ca2+/Calmodulin dependent kinase PNCK as the most differentially overexpressed kinase in kidney cancer patients. Our analyses have demonstrated statistically significant correlation between PNCK mRNA levels and various clinical and pathological outcomes, including histologic grade, clinical staging and overall survival. We have confirmed high levels of PNCK expression in 5 renal cell carcinoma cell lines (Caki-1, ACHN, 786-O, A704 and A498). Knockdown and overexpression studies have suggested PNCK and the CaMK pathway may contribute to cellular proliferation and cell cycle progression. We have applied our AI-based screening pipeline to a library of >20 million commercially available compounds and confirmed three PNCK inhibiting chemotypes. In summary, using a novel computational pipeline, we have identified and experimentally validated PNCK as a prospective novel drug target in an understudied pathway that is highly upregulated in kidney cancer. We identified first in class small molecules that target this previously dark kinase as prospective starting points for optimization into a clinical candidate. Citation Format: Derek J. Essegian, Rimpi Khurana, Vasileios Stathias, Valery Chavez, Jaime R. Merchan, Stephan Schürer. The dark cancer kinome - untapped opportunities for the development of novel drugs [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 5103
Organisational risks matter and should be discussed during consent: survey of 980 neurosurgery patients from the UK
No full textIntroduction
During consent, surgeons discuss surgical and anaesthetic risks with patients. We investigated whether patients also wish to be informed about hospital organisational risks.
Methods
We used a cross-sectional survey. A questionnaire with three real-life scenarios of hospital organisational problems likely to increase the risk of surgery was given to 1,003 patients in neurosurgical departments of three United Kingdom (UK) teaching hospitals. The scenarios were: (1) computer failure in the operating room; (2) lack of surgical equipment; and (3) bed shortage or lack of operating capacity causing postponement of surgery. We quantified how strongly participants wish to be informed about organisational risks, whether this information alters a patient’s decision to have surgery, and the desire of patients to discuss these risks further.
Results
In total, 980 of 1,003 (97.7%) questionnaires were returned and 84.3%–88.5% of patients wished to be informed about hospital organisational risks – more women than men (odds ratio [OR] 1.6–1.8, p < 0.05). Knowledge of the hospital organisational risks would influence 69.2%–70.4% of participants’ decisions to have surgery; 74.9%–78.3% of participants wished to discuss the organisational risks with surgeons and 50.0%–60.8% with hospital managers before surgery. Some 69.4% of patients were concerned about organisational risks vs 77.1% who were concerned about surgical risks.
Conclusions
Most neurosurgery patients consider hospital organisational risks to be material. To comply with the Montgomery ruling in UK medicolegal case law, neurosurgeons and hospital managers should discuss with patients the organisational risks in addition to the surgical and anaesthetic risks during consent
Trading arrangements and industrial development
No full textHow do different trading arrangements influence the industrialization process of developing countries? Can preferential trading arrangements (PTAs) be superior to multilateral liberalization, or at least an alternative when multilateral liberalization proceeds slowly? If so, what form should the PTAs take? Are developing countries better advised to seek PTAs with industrial countries or among themselves? Traditional analysis of these issues has been based on the idea of trade creation and trade diversion. The problem with this analysis is that it starts from assuming a pattern of comparative advantage of newly industrialized countries. The experience of these countries suggests the need for an analysis in which the pattern of comparative advantage is not set in stone but is potentially flexible, and in which less developed countries can develop and converge in both income and economic structure to industrial economies. The authors outline an alternative approach for analyzing the role of trade in promoting industrial development. There are few fundamental differences between countries that generate immutable patterns of comparative advantage. Instead the pattern of trade and development in the world economy is determined mainly by history. Cumulative causation has created concentrations of industrial activity in particular locations (industrial countries) and left other areas more dependent on primary activities. Economic development can be thought of as the spread of these concentrations from country to country. Different trading arrangements may have a major impact on this development process. By changing the attractiveness of countries as a base for manufacturing production they can potentially trigger or postpone industrial development. This approach explains why firms are reluctant to move to economies that have lower wages and labor costs, and shows how trade liberalization can change the incentives to become established in developing countries. It provides a mechanism through which import liberalization can have a powerful effect in promoting industrialization. And it suggests that import liberalization may create or amplify differences between liberalizing countries with the possible political tensions this may create. While these features are consistent with the world economy, they fall short of providing convincing empirical support for the approach. Using the approach, the authors derive number of conclusions about the effects of trade liberalization. First, that unilaterally liberalizing imports of manufactures can promote development of the local manufacturing industry. The mechanism is forward linkages from imported intermediates, but this may be interpreted as part of a wider package of linkages coming from these imports. Second, the gains from liberalization through PTA membership are likely to exceed those obtained from unilateral action. South-South PTAs will be sensitive to the market size of member states, and North-South PTAs seem to offer better prospects for participating Southern economies, if not for North and excluded countries. Third, the effects of particular schemes (such as the division of benefits between Southern economies) will depend on the characteristics of the countries and cross-country differences in these characteristics.Economic Theory&Research,Environmental Economics&Policies,Water and Industry,Labor Policies,Banks&Banking Reform,Economic Theory&Research,Environmental Economics&Policies,TF054105-DONOR FUNDED OPERATION ADMINISTRATION FEE INCOME AND EXPENSE ACCOUNT,Trade and Regional Integration,Water and Industry
The discovery of SycO reveals a new function for type three secretion effector chaperones
No full textThe Type Three Secretion (T3S) system is a device used by many Gram-negative pathogens that allows bacteria to deliver effector proteins straight into the eukaryotic cell cytosol. These effectors interfere with various signaling pathways to subvert the host cell functions. The secretion machinery of the T3S system consist of a basal body spanning the bacterial inner and outer membrane followed by a stiff hollow needle outside the bacterium. The fully assembled secretion apparatus constitute a continuous hollow conduit that connects the bacteria to the eukaryotic target cell. After cell contact, virulence proteins -called effectors- are injected directly into the cytosol of the host cell via the T3S apparatus. Several effectors of the T3S system require the assistance of specific cytosolic chaperones to be efficiently exported. There are three classes of T3S chaperones. Effector proteins are assisted by Class I chaperones. Although Class I chaperones are well characterized, their main function is still a matter of controversy. In this thesis, we demonstrate that orf155 encodes a specific chaperone for the effector YopO that we called SycO. We showed that SycO enhances YopO secretion in vitro and is required for translocation of YopO into infected cells. By pulldown assay we demonstrated that residues 20 to 77 of YopO are required and sufficient for SycO binding. Using crosslinking experiments and size exclusion chromatography analysis, we determined the stoichiometry of purified SycO and YopO-SycO complexes. SycO alone forms dimers in solution and the YopO-SycO complex has a 1:2 stoichiometry. These results suggested that SycO is a typical chaperone of the Class I. YopO is a serine/theronine kinase that interacts with Rho and Rac and disrupts the cytoskeleton of the target cells. YopO has been shown to localize at the cell plasma-membrane. By transfection of YopO-EGFP hybrid proteins into HEK293T cells, we demonstrated that the chaperone-binding domain (CBD) coincides with the membrane localization domain of YopO. Nevertheless, the CBD was not needed for the kinase activity of YopO. By ultracentrifugation, we also showed that the CBD causes YopO aggregation in the bacteria, when SycO does not cover it. Further, we show that the CBD of YopE and YopT also caused aggregation in the bacteria in the absence of SycE and SycT respectively. YopE, YopT and T3S effectors in other systems also act at the membrane of the eukaryotic host cell. We propose a new hypothesis concerning the role of T3S chaperones. The sub-cellular localization domain of effectors is aggregation-prone and creates the need for a chaperone inside bacteria. We propose that masking such aggregation-prone localization domains may be a general function for type III effector chaperones
Immunotherapy in Renal Cell Carcinoma
No full textRenal cell carcinoma (RCC) is a chemotherapy-resistant disease, and current molecularly targeted therapies offer limited clinical benefit but no cures. The observation that RCC is immunogenic led to immune-based strategies for the treatment of this disease. Immunotherapy with high-dose IL-2 can induce long-term, complete responses in a small percentage of patients. IFN has been used as an immune intervention as well but with much less success than IL-2. Currently IFN is used only in combination with the anti-VEGF monoclonal antibody bevacizumab. Further investigation of novel immune interventions in RCC is ongoing with promising results. Dendritic cell vaccines have been tested in single-arm clinical trials suggesting improved survival when added to standard anti-angiogenic therapy. Monoclonal antibodies against PD-1 and PD-L1, novel immune targets, have shown promising response in phase I trials. Peptide vaccines have shown efficacy in phase II trials as well. Phase III trials to test these immune interventions are currently ongoing and have the potential to bring new, effective treatment options for patients with advanced RCC
Lessons of trade liberalization in Latin America for economies in transition
No full textAfter four decades as prime examples of inward-looking trade policies and import-substituting industrialization, several Latin American countries undertook comprehensive trade liberalization and macroeconomic adjustment in the 1980s. The authors contend that the experiences in those countries are relevant for the economies in Eastern Europe and the former Soviet Union in transition from socialism to market economies. In all of these Latin American countries, the move toward an outward orientation occurred: when the economy was facing a large negative external shock because of falling terms of trade and rising debt payments; after several decades of protectionism; and under severe macroeconomic imbalances. The authors study the reform package of trade liberalization, stabilization, and supporting policies in Argentina, Bolivia, Chile, Mexico, and Uruguay. They conclude that for the economies in transition: Rationalizing the foreign trade regime is crucial for the success of stabilization measures. Rapid, far-reaching reform is possible in sectors that were subject to prolonged periods of heavy protection. Sustained growth requires a comprehensive reform package, with supporting policies for labor, capital, and domestic product markets. Liberalization of the financial sector requires investigating the links between commercial banks and private sector firms. If trade liberalization is to succeed in the long run, it is important to study the evolution of the real exchange rate and measures to stabilize it. In the final section of the paper, the authors study the recent impetus toward trade liberalization through regional arrangements in Latin America. The issue is relevant to countries in Eastern Europe and the former Soviet Union because they belonged to the CMEA, a regional trading arrangement, and because such arrangements are evolving anew among countries in the former Soviet Union.Economic Theory&Research,Environmental Economics&Policies,Economic Stabilization,TF054105-DONOR FUNDED OPERATION ADMINISTRATION FEE INCOME AND EXPENSE ACCOUNT,Macroeconomic Management
Export quota allocations, export earnings and market diversifications
No full textNon-tariff barriers (NTBs) present a growing threat to a liberal world-trading system and slow the reallocation of production of mature industries from developed to developing countries. Among NTBs, voluntary export restraints (VERs) are proliferating and constitute a major element of the"new protectionism". It has been repeatedly observed that export markets which are not currently part of the VER agreement often follow suit and enter into a VER agreement. Exporting countries may then wish to prepare themselves for this eventuality by actively promoting export diversification towards non-restricted countries as a precautionary measure against future restrictions. Section II of this paper briefly describes how export diversification is typically achieved. In Section III, a simple model is set up that analyzes the implications of the two tier quota allocation rule. Section IV briefly examines alternative instruments and motivations for achieving export diversification. Implications are also drawn for policy actions by nonrestricted countries and the suggestion made that the recent increase in anti-dumping cases may be linked to this two-tier quota allocation practice.Economic Theory&Research,Markets and Market Access,Access to Markets,Environmental Economics&Policies,TF054105-DONOR FUNDED OPERATION ADMINISTRATION FEE INCOME AND EXPENSE ACCOUNT
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Abstract B040: Understanding disparities in clinical trial enrollment: A study of screen failures to phase I clinical trials in a minority-serving institution in the post-COVID period
No full textAbstract Background: Phase 1 clinical trials offer a novel therapeutic option to individuals who have progressed past standard of care treatment and valuable data oncological field advancement. Previous research has shown that a significant proportion of patients referred for clinical trials do not meet eligibility criteria and are considered screen failure (SF) after consenting and even more patients referred are pre-screen failure before consenting (PSF). In addition, historically, the rate of clinical trial enrollment has been low in underrepresented minorities. These SF rates and disparities could have further increased due to COVID challenges. In this study, we aim to define the most common reasons for SF and study disparities in trial enrollment demographics in the post-COVID period. Methods: A cross-sectional sample of patients referred to the Sylvester Comprehensive Cancer Center Phase I Clinic during the pre-COVID period (11/2018-12/2019) and post-COVID period (11/2021-12/2022) was analyzed. Patients’ demographics, malignancies and SF patterns were analyzed. Reasons for SF were categorized as: cancer progression, clinical trial ineligibility, lack of applicable trial, system delays due to staffing, patient hesitancy/refusal or loss to follow-up. Chi square tests were then used to analyze the SF rate based on patient demographics. Results: During the pre-COVID period, 98 patients consented and 75 enrolled with a screen failure of 21.4%, compared to the post-COVID period when 101 patients consented and 74 enrolled with a screen failure of 27.7%. During the post-COVID period, 69 patients were PSFs, and 4 patients waitlisted and never consented. Of the PSF (n=69), 37 (55%) were female, 27 (40%) were Hispanic, 10 (15%) were Black, and 1 (1%) was Asian. The majority of PSFs were patients with thoracic cancer (45.5%), followed by GI (19%) and GYN malignancies (16.1%). The main reasons endorsed for PSFs were patients refusal/loss to follow up (35%), not consented due to system delays (20.5%), cancer progression (20.5%), trial ineligibility (17%), and lack of applicable trial (7%). When using chi square tests to analyze the prescreen failure vs. enrollment rate based on patient demographics, there was no statistically significant difference between race (p=0.19), ethnicity (p=0.45), or gender (p=0.22). Conclusion: Though the number of patients enrolled in the pre- and post-COVID period was similar, the rate of screen and prescreen failures differed. Trial design ineligibility, patient hesitancy/loss to follow up, and systemic challenges due to staff shortages contributed to SFs in the post COVID period. Staff shortages after the COVID-19 pandemic affected Phase 1 trial enrollment but was not the predominant SF reason. Studies to address clinical trial complexity and issues of patient hesitancy and withdrawal from clinical trial process are needed. The lack of demographic disparities in enrollment and SFs suggest that these system issues did not disproportionately affect any demographic group in this diverse cohort. Citation Format: Sapna A. Kedia, Rakhi Modak, Nora A. El-Abbar, Jaime R. Merchan, Estelamari Rodriguez. Understanding disparities in clinical trial enrollment: A study of screen failures to phase I clinical trials in a minority-serving institution in the post-COVID period [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B040
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