Clinical trials in pregnancy and the “shadows of thalidomide”: Revisiting the legacy of Frances Kelsey

Despite great need for improved understanding of the use of drugs and biological products in pregnancy, clinical trials in pregnancy are rare, therapeutics in pregnancy are woefully understudied, and pregnant individuals are routinely excluded as trial participants. Recently, however, the U.S. Food and Drug Administration (FDA) has signaled strong support for advancing scientific research with pregnant populations, marking a significant shift from the past. Over the last sixty years, precaution and fear have largely characterized clinical research in pregnancy, deriving in large part from a protectionist ethic that materialized after the thalidomide drug disaster. FDA reviewer Frances Kelsey courageously prevented thalidomide from being marketed in the United States, and her work guided and solidified the FDA's image as protector of the general population from unsafe and ineffective drugs. Yet, when it comes to protection, pregnant persons have been left behind, and experts refer to the "shadows of thalidomide" that hamper clinical trials in pregnancy. Drawing on analysis of Frances Kelsey's archived papers in addition to focused media coverage of Kelsey and thalidomide, we discuss the durable cultural narrative surrounding Kelsey's important work. We argue that revisiting Kelsey's legacy with attention to themes that have characterized her achievement-staying vigilant, prioritizing safety, and mitigating pharmaceutical-based harm-in fact facilitates progress toward the ethical obligation to protect pregnant people through research, toward the generation of pregnancy-specific data for evidence-based care, and toward realizing Kelsey's legacy of safeguarding pregnant people and their offspring from the harms of untested drugs

Targeting NaPi2b in ovarian cancer.

Novel biomarkers are needed to direct new treatments for ovarian cancer, a disease for which the standard of care remains heavily focused on platinum-based chemotherapy. Despite the success of PARP inhibitors, treatment options are limited, particularly in the platinum-resistant setting. NaPi2b is a cell surface sodium-dependent phosphate transporter that regulates phosphate homeostasis under normal physiological conditions and is a lineage marker that is expressed in select cancers, including ovarian, lung, thyroid, and breast cancers, with limited expression in normal tissues. Based on its increased expression in ovarian tumors, NaPi2b is a promising candidate to be studied as a biomarker for treatment and patient selection in ovarian cancer. In preclinical studies, the use of antibodies against NaPi2b showed that this protein can be exploited for tumor mapping and therapeutic targeting. Emerging data from phase 1 and 2 clinical trials in ovarian cancer have suggested that NaPi2b can be successfully detected in patient biopsy samples using immunohistochemistry, and the NaPi2b-targeting antibody-drug conjugate under evaluation appeared to elicit therapeutic responses. The aim of this review is to examine literature supporting NaPi2b as a novel biomarker for potential treatment and patient selection in ovarian cancer and to discuss the critical next steps and future analyses necessary to drive the study of this biomarker and therapeutic targeting forward

Tumor-Targeted Synergistic Blockade of MAPK and PI3K from a Layer-by-Layer Nanoparticle

Purpose: Cross-talk and feedback between the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR cell signaling pathways is critical for tumor initiation, maintenance, and adaptive resistance to targeted therapy in a variety of solid tumors. Combined blockade of these pathways—horizontal blockade—is a promising therapeutic strategy; however, compounded dose-limiting toxicity of free small molecule inhibitor combinations is a significant barrier to its clinical application. Experimental Design: AZD6244 (selumetinib), an allosteric inhibitor of Mek1/2, and PX-866, a covalent inhibitor of PI3K, were co-encapsulated in a tumor-targeting nanoscale drug formulation—layer-by-layer (LbL) nanoparticles. Structure, size, and surface charge of the nanoscale formulations were characterized, in addition to in vitro cell entry, synergistic cell killing, and combined signal blockade. In vivo tumor targeting and therapy was investigated in breast tumor xenograft-bearing NCR nude mice by live animal fluorescence/bioluminescence imaging, Western blotting, serum cytokine analysis, and immunohistochemistry. Results: Combined MAPK and PI3K axis blockade from the nanoscale formulations (160 ± 20 nm, −40 ± 1 mV) was synergistically toxic toward triple-negative breast (MDA-MB-231) and RAS-mutant lung tumor cells (KP7B) in vitro, effects that were further enhanced upon encapsulation. In vivo, systemically administered LbL nanoparticles preferentially targeted subcutaneous MDA-MB-231 tumor xenografts, simultaneously blocked tumor-specific phosphorylation of the terminal kinases Erk and Akt, and elicited significant disease stabilization in the absence of dose-limiting hepatotoxic effects observed from the free drug combination. Mice receiving untargeted, but dual drug-loaded nanoparticles exhibited progressive disease. Conclusions: Tumor-targeting nanoscale drug formulations could provide a more safe and effective means to synergistically block MAPK and PI3K in the clinic.United States. Department of Defense (OCRP Teal Innovator Award)National Institutes of Health (U.S.) (Grant NIBIB 1F32EB017614-02)Misrock FoundationNational Science Foundation (U.S.)Swiss National Science FoundationDavid H. Koch Institute for Integrative Cancer Research at MIT (Support Grant P30-CA14051)National Cancer Institute (U.S.)National Science Foundation (U.S.) (Massachusetts Institute of Technology. Materials Research Science and Engineering Center. Shared Experimental Facilities Grant DMR-0819762)Breast Cancer Alliance (Exceptional Project Grant

Grain and phase stress criteria for behaviour and cleavage in duplex and bainitic steels

Stress analyses by X-ray diffraction are performed on a cast duplex (32% ferrite) stainless steel elbow and a bainitic (95% ferrite) pressure vessel steel. During an in situ tensile test, micrographic observations are made (visible glides and microcracks) and related to the stress state determined in the individual ferritic grains (aged duplex) and the ferritic phase (bainite loaded at low temperatures). Several material parameters have been identified at different scales, as for example, the critical resolved shear stress of 245 MPa for the aged ferritic grain (duplex) or 275 MPa for bainite (–60 ◦C), a crystallographic cleavage propagation criterion of 465 MPa (stress normal to {100} planes), and a fracture stress of approximately 700 MPa in the ferritic phase. Even though the two steels are different in many respects, the macroscopic fracture strains and stresses are well predicted by the polycrystalline model developed for bainite, whatever the temperatures tested (considering 7% of the grains reaching the local criterion)

Inhibition of the Integrin/FAK Signaling Axis and c-Myc Synergistically Disrupts Ovarian Cancer Malignancy

Integrins, a family of heterodimeric receptors for extracellular matrix, are promising therapeutic targets for ovarian cancer, particularly high-grade serous-type (HGSOC), as they drive tumor cell attachment, migration, proliferation and survival by activating focal adhesion kinase (FAK)-dependent signaling. Owing to the potential off-target effects of FAK inhibitors, disruption of the integrin signaling axis remains to be a challenge. Here, we tackled this barrier by screening for inhibitors being functionally cooperative with small-molecule VS-6063, a phase II FAK inhibitor. From this screening, JQ1, a potent inhibitor of Myc oncogenic network, emerged as the most robust collaborator. Treatment with a combination of VS-6063 and JQ1 synergistically caused an arrest of tumor cells at the G2/M phase and a decrease in the XIAP-linked cell survival. Our subsequent mechanistic analyses indicate that this functional cooperation was strongly associated with the concomitant disruption of activation or expression of FAK and c-Myc as well as their downstream signaling through the PI3K/Akt pathway. In line with these observations, we detected a strong co-amplification or upregulation at genomic or protein level for FAK and c-Myc in a large portion of primary tumors in the TCGA or a local HGSOC patient cohort. Taken together, our results suggest that the integrin–FAK signaling axis and c-Myc synergistically drive cell proliferation, survival and oncogenic potential in HGSOC. As such, our study provides key genetic, functional and signaling bases for the small-molecule-based co-targeting of these two distinct oncogenic drivers as a new line of targeted therapy against human ovarian cancer

Foreign Direct Investment and International Trade: Empirical Analysis of Mutual Influence

Foreign direct investment and international movement of commodities are interrelated in the world economy. At the same time, the nature of this relationship and the causality issues are ambiguous and need to be studied from both theoretical and empirical sides. The aim of this paper is to estimate empirically the mutual influence of foreign direct investment and international trade in the modern economy. The econometric model is based on the gravity approach, the estimation is made using the Poisson pseudo maximum likelihood method on the data for 67 host and 109 home FDI countries for the period of 2001-2016. The hypotheses on the positive mutual influence of foreign direct investment and international trade are tested. A positive and significant influence of export and import flows on inward foreign direct investment is observed. The largest impact of export and import on foreign direct investment is observed when a two-year lag is considered. We could not reveal a significant influence of foreign direct investment on export and import flows either within one year, or for the lagged FDI values. The authors argue that pro-trade government policy, aimed at the integration of the country into global value chains is an important factor stimulating the inflow of foreign direct investment to the country. From the practical point of view, understanding the causal linkages between export, import and foreign direct investment helps state authorities better forecast the direct and indirect effects of various trade policy incentives.В открытой экономике потоки прямых иностранных инвестиций тесно связаны с потоками экспорта и импорта товаров. В то же время характер данной связи, а также вопросы причинности не являются однозначными и представляют собой предмет для рассмотрения многих теоретических работ и эмпирических исследований. Целью данной работы является изучение взаимного влияния прямых иностранных инвестиций и международной торговли в современной мировой экономике. Используемый инструментарий – эмпирическая оценка базы данных с использованием регрессионно-корреляционного анализа. Эконометрическая модель основывается на гравитационном подходе, оценивание осуществляется методом псевдомаксимального правдоподобия Пуассона на базе данных по 67 импортерам и 109 экспортерам прямых иностранных инвестиций за период 2001–2016 гг. В работе проверяются гипотезы о взаимном положительном влиянии потоков прямых иностранных инвестиций и потоков международной торговли. Авторами обнаружено статистически значимое положительное влияние потоков экспорта и импорта на приток прямых иностранных инвестиций в страну. Наиболее сильное положительное влияние импорта и экспорта на приток прямых иностранных инвестиций в страну наблюдается с двухлетним временным лагом. Статистически значимого влияния прямых иностранных инвестиций на потоки экспорта и импорта не выявлено ни для наблюдений внутри одного года, ни для лагированных значений прямых иностранных инвестиций. Авторами делается вывод, что проторговая внешняя политика, направленная на интеграцию страны в систему мирохозяйственных связей, является существенным фактором, стимулирующим приток прямых иностранных инвестиций в страну. С практической точки зрения понимание причинно-следственных связей между экспортом, импортом и прямыми иностранными инвестициями в открытой экономике позволяет профильным органам государственной власти точнее прогнозировать прямые и косвенные эффекты от различных мер государственной внешнеторговой политики.В открытой экономике потоки прямых иностранных инвестиций тесно связаны с потоками экспорта и импорта товаров. В то же время характер данной связи, а также вопросы причинности не являются однозначными и представляют собой предмет для рассмотрения многих теоретических работ и эмпирических исследований. Целью данной работы является изучение взаимного влияния прямых иностранных инвестиций и международной торговли в современной мировой экономике. Используемый инструментарий – эмпирическая оценка базы данных с использованием регрессионно-корреляционного анализа. Эконометрическая модель основывается на гравитационном подходе, оценивание осуществляется методом псевдомаксимального правдоподобия Пуассона на базе данных по 67 импортерам и 109 экспортерам прямых иностранных инвестиций за период 2001–2016 гг. В работе проверяются гипотезы о взаимном положительном влиянии потоков прямых иностранных инвестиций и потоков международной торговли. Авторами обнаружено статистически значимое положительное влияние потоков экспорта и импорта на приток прямых иностранных инвестиций в страну. Наиболее сильное положительное влияние импорта и экспорта на приток прямых иностранных инвестиций в страну наблюдается с двухлетним временным лагом. Статистически значимого влияния прямых иностранных инвестиций на потоки экспорта и импорта не выявлено ни для наблюдений внутри одного года, ни для лагированных значений прямых иностранных инвестиций. Авторами делается вывод, что проторговая внешняя политика, направленная на интеграцию страны в систему мирохозяйственных связей, является существенным фактором, стимулирующим приток прямых иностранных инвестиций в страну. С практической точки зрения понимание причинно-следственных связей между экспортом, импортом и прямыми иностранными инвестициями в открытой экономике позволяет профильным органам государственной власти точнее прогнозировать прямые и косвенные эффекты от различных мер государственной внешнеторговой политики.This article has been prepared with the support of the grant No. MD-6402.2018.6 of the President of the Russian Federation on state support of young scientists «Institutional determinants of foreign direct investment inflows: country and region level analysis».Исследование выполнено при поддержке гранта Президента РФ для государственной поддержки молодых докторов наук «Институциональные факторы привлечения прямых зарубежных инвестиций: страновой и региональный анализ» (проект № МД-6402.2018.6)