bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A34: Cancer prevention in practice at FDA
Authors: Elespuru Rosalie K. 
Published: June 2022

Abstract
Most major categories of products reviewed at the U.S. Food and Drug Administration (FDA) undergo assessment for cancer hazard, which generally is accomplished by using qualitative findings from genotoxicity tests. In some instances, two-year rodent bioassays are used for quantitative risk assessment. In the attempt to minimize the use of animals, more recently alternative approaches have included the assessment of data from chemical characterizations, QSAR, and toxicology risk assessments. Although the focus is primarily on hazard identification, or classification of agents as genotoxic or nongenotoxic, the scope of consideration is broader, including identification of potential nongenotoxic carcinogens and consideration of negative factors for carcinogenesis, such as the absence of hormonal action, rodent neoplasia, and certain histopathologic risk factors. For many (but not all) product categories, review generally includes a risk/benefit assessment. A diversity of laws, regulations, standards, and products affects the approach to cancer risk assessment in different FDA centers. Other than tobacco, little is known about the actual human risk of many products or combinations of foods, drugs, medical devices, and other exposures, over days, years, or a lifetime, relative to cancer risk. Thus, it is difficult to find yardsticks against which to consider new products. In thinking about risks to human health and the potential for tumor development, it is useful to consider the factors generally understood to be important from animal and human studies in carcinogenesis, especially from human experience with tobacco: dose, frequency, and duration of exposure; multiple exposures to agents acting via different mechanisms; inflammatory or proliferative responses; susceptible systems (based on genetics, age, or development); and time available for tumor development. High-dose single-agent testing in animals has been validly criticized as a poor model for human cancer risk, particularly given the expense, time, and large numbers of animals required. Replacement models suitable for FDA premarket product safety review are needed, particularly representing the real world of multiple exposures and individual human susceptibilities.
Citation Format: Rosalie K. Elespuru. Cancer prevention in practice at FDA [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A34.
Abstract A40: Induction of oxidative/nitrosative stress, proinflammatory cytokines and dysregulation of Wnt/beta-catenin signaling by benzo(a)pyrene in colons of BALB/c mice
Authors: Farombi Ebenezer O. , Ajayi Babajide O. , Adedara Isaac A. , Owumi Solomon E. 
Published: June 2022

Abstract
Epidemiologic surveys and experimental data have revealed that environmental and dietary factors contribute to the etiology of colon cancer, which ranks third in cancer-related mortalities in the United States and fourth worldwide. In particular, human diet containing environmental carcinogens such as benzo(a)pyrene (B(a)P), a polycyclic aromatic hydrocarbon, has been the focus of investigators recently in relation to generated interest in looking at how it exerts its colorectal cancer. The present study investigated the effects of B(a)P on biomarkers of oxidative stress, inflammation and Wnt-signaling in colon of BALB/c mice following exposure to varying doses of 62.5, 125, and 250 mg/kg B(a)P for 7 days by oral gavage. Exposure to B(a)P induced marked oxidative stress accompanied by decrease in the colonic antioxidant enzyme activities and glutathione level with concomitant increase in myeloperoxidase activity, nitric oxide, and lipid peroxidation levels. Colon histopathology results showed B(a)P-related lesions characterized by atrophy, mucosal ulceration, and gland erosion in the mice. Immunohistochemistry analysis showed that B(a)P treatment increased the protein expression of nuclear factor kappa B, proinflammatory cytokines, namely tumor necrosis factor alpha and interleukin-1 β, as well as cyclooxygenase-2 and inducible nitric oxide synthase in the mice colon. Altered canonical Wnt signaling was confirmed by strong diaminobenzidine staining for p38 mitogen-activated protein kinase, b-catenin expression, and absence of adenomatous polyposis coli following B(a)P administration. Overall, our results show that exposure of mice to B(a)P induces colonic toxicity by mechanism involving oxidative and nitrosative stress, inflammation, and dsyregulation of Wnt/b-catenin signaling, and emphasizes the role of environmental polycyclic aromatic hydrocarbons like B(a)P in the pathology of colonic toxicity and tumorigenesis.
Citation Format: Ebenezer O. Farombi, Babajide O. Ajayi, Isaac A. Adedara, Solomon E. Owumi. Induction of oxidative/nitrosative stress, proinflammatory cytokines and dysregulation of Wnt/beta-catenin signaling by benzo(a)pyrene in colons of BALB/c mice [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A40.
Abstract IA25: A brief orientation to implementation science at the National Cancer Institute
Authors: Neta Gila 
Published: June 2022

Abstract
Implementation science seeks to bridge the gap between research and practice by building a knowledge base about how health information and evidence-based interventions, tools, programs, and policies are disseminated and implemented. It is focused on understanding and accelerating the adoption and integration of evidence and evidence-based interventions into practice settings to improve health. Participants will learn what the field of implementation science is (and is not), the key components to design and conduct an implementation study, and how the field is relevant to cancer control research.
Citation Format: Gila Neta. A brief orientation to implementation science at the National Cancer Institute [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr IA25.
Stress Granules Determine the Development of Obesity-Associated Pancreatic Cancer
Authors: Fonteneau Guillaume , Redding Alexandra , Hoag-Lee Hannah , Sim Edward S. , Heinrich Stefan , Gaida Matthias M. , Grabocka Elda 
Published: June 2022

AbstractObesity is a global epidemic and a major predisposing factor for cancer. Increasing evidence shows that obesity-associated stress is a key driver of cancer risk and progression. Previous work has identified the phase-separation organelles,﻿ stress granules (SG), as mutant KRAS–dependent mediators of stress adaptation. However, the dependence of tumorigenesis on these organelles is unknown. Here, we establish a causal link between SGs and pancreatic ductal adenocarcinoma (PDAC). Importantly, we uncover that dependence on SGs is drastically heightened in obesity-associated PDAC. Furthermore, we identify a previously unknown regulator and component of SGs, namely, the serine/arginine protein kinase 2 (SRPK2), as a specific determinant of SG formation in obesity-associated PDAC. We show that SRPK2-mediated SG formation in obesity-associated PDAC is driven by hyperactivation of the IGF1/PI3K/mTOR/S6K1 pathway and that S6K1 inhibition selectively attenuates SGs and impairs obesity-associated PDAC development.Significance:We show that stress adaptation via the phase-separation organelles SGs mediates PDAC development. Moreover, preexisting stress conditions such as obesity are a driving force behind tumor SG dependence, and enhanced SG levels are key determinants and a chemopreventive target for obesity-associated PDAC.This article is highlighted in the In This Issue feature, p. 1825
Abnormal Cyclic Nucleotide Signaling at the Outer Mitochondrial Membrane In Sympathetic Neurons During the Early Stages of Hypertension
Authors: Li Dan , Liu Kun , Davis Harvey , Robertson Calum , Neely Oliver C. , Tarafdar Adib , Li Ni , Lefkimmiatis Konstantinos , Zaccolo Manuela , Paterson David J. 
Published: June 2022

Background:

Disruption of cyclic nucleotide signaling in sympathetic postganglionic neurons contributes to impaired intracellular calcium handling (Ca
2+
) and the development of dysautonomia during the early stages of hypertension, although how this occurs is poorly understood. Emerging evidence supports the uncoupling of signalosomes in distinct cellular compartments involving cyclic nucleotide–sensitive PDEs (phosphodiesterases), which may underpin the autonomic phenotype in stellate neurons.

Methods:
Using a combination of single-cell RNA sequencing together with Forster resonance energy transfer–based sensors to monitor cyclic adenosine 3’,5’-monophosphate, PKA (protein kinase A)-dependent phosphorylation and cGMP (cyclic guanosine 3’,5’-monophosphate), we tested the hypothesis that dysregulation occurs in a sub-family of PDEs in the cytosol and outer mitochondrial membrane of neurons from the stellate ganglion.

Results:
PDE2A, 6D, 7A, 9A genes were highly expressed in young Wistar neurons and also conserved in neurons from spontaneously hypertensive rats (SHRs). In stellate neurons from prehypertensive SHRs, we found the levels of cyclic adenosine 3’,5’-monophosphate and cGMP at the outer mitochondrial membrane were decreased compared with normal neurons. The reduced cyclic adenosine 3’,5’-monophosphate response was due to the hydrolytic activity of overexpressed PDE2A2 located at the mitochondria. Normal cyclic adenosine 3’,5’-monophosphate levels were re-established by inhibition of PDE2A. There was also a greater PKA-dependent phosphorylation in the cytosol and at the outer mitochondrial membrane in spontaneously hypertensive rat neurons, where this response was regulated by protein phosphatases. The cGMP response was only restored by inhibition of PDE6.

Conclusions:
When taken together, these results suggest that site-specific inhibition of PDE2A and PDE6D at the outer mitochondrial membrane may provide a therapeutic target to ameliorate cardiac sympathetic impairment during the onset of hypertension.
Role of Antihypertensive Treatment and Blood Pressure Control in the Occurrence of Adverse Pregnancy Outcomes: a Population-Based Study of Linked Electronic Health Records
Authors: Al Khalaf Sukainah , Khashan Ali S. , Chappell Lucy C. , O’Reilly Éilis J. , McCarthy Fergus P. 
Published: June 2022

Background:
Chronic hypertension (CH) adversely impacts pregnancy. It remains unclear whether antihypertensive treatment alters these risks. We examined the role of antihypertensive treatment in the association between CH and adverse pregnancy outcomes.

Methods:
Electronic health records from the UK Caliber and Clinical Practice Research Datalink were used to define a cohort of women delivering between 1997 and 2016. Primary outcomes were preeclampsia, preterm birth (PTB), and fetal growth restriction (FGR). We used multivariable logistic regression to compare outcomes in women with CH to women without CH and propensity score matching to compare antihypertensive agents.

Results:
The study cohort consisted of 1 304 679 women and 1 894 184 births. 14 595 (0.77%) had CH, and 6786 (0.36%) were prescribed antihypertensive medications in pregnancy. Overall, women with CH (versus no CH), had higher odds of preeclampsia (adjusted odds ratio [aOR], 5.74 [95% CI, 5.44–6.07]); PTB (aOR, 2.53 [2.39–2.67]); and FGR (aOR, 2.51 [2.31–2.72]). Women with CH prescribed treatment (versus untreated women) had higher odds of preeclampsia (aOR, 1.17 [1.05–1.30]), PTB (1.25 [1.12–1.39]), and FGR (1.80 [1.51–2.14]). Women prescribed methyldopa (versus β-blockers) had higher odds of preeclampsia (aOR, 1.43 [1.19–1.73]); PTB (1.59 [1.30–1.93]), but lower odds of FGR (aOR, 0.66 [0.48–0.90]). Odds of adverse outcomes were similar in relation to calcium channel blockers (versus β-blockers) except for PTB (aOR, 1.94 [1.15–3.27]). Among women prescribed treatment, lower average blood pressure (<135/85 mm Hg) was associated with better pregnancy outcomes.

Conclusions:
Treatment with antihypertensive agents and control of hypertension ameliorates some effects but higher risks of adverse outcomes persist. β-Blockers versus methyldopa may be associated with better pregnancy outcomes except for FGR. Powered trials are needed to inform optimal treatment of CH during pregnancy.
Performance of a Multianalyte ‘Rule-Out’ Assay in Pregnant Individuals With Suspected Preeclampsia
Authors: Costantine Maged M. , Sibai Baha , Bombard Allan T. , Sarno Mark , West Holly , Haas David M. , Tita Alan T. , Paidas Michael J. , Clark Erin A.S. , Boggess Kim , Grotegut Chad , Grobman William , Su Emily J , Burd Irina , Saade George , Chavez Martin R. , Paglia Michael J. , Merriam Audrey , Torres Carlos , Habli Mounira , Macones Georges , Wen Tony , Bofill James , Palatnik Anna , Edwards Rodney K. , Haeri Sina , Oberoi Pankaj , Mazloom Amin , Cooper Matthew , Lockton Steven , Hankins Gary D. 
Published: June 2022

Background:
The ability to diagnose preeclampsia clinically is suboptimal. Our objective was to validate a novel multianalyte assay and characterize its performance, when intended for use as an aid to rule-out preeclampsia.

Methods:

Prospective, multicenter cohort study of pregnant individuals presenting between 28
0/7
and 36
6/7
weeks’ with preeclampsia-associated signs and symptoms. Individuals not diagnosed with preeclampsia after baseline evaluation were enrolled in the study cohort, with those who later developed preeclampsia, classified as cases and compared with a negative control group who did not develop preeclampsia. Individuals with assay values at time of enrollment ≥0.0325, determined using a previously developed algorithm, considered at risk. The primary analysis was the time to develop preeclampsia assessed using a multivariate Cox regression model.

Results:

One thousand thirty-six pregnant individuals were enrolled in the study cohort with an incidence of preeclampsia of 30.3% (27.6%–33.2%). The time to develop preeclampsia was shorter for those with an at-risk compared with negative assay result (log-rank
P
<0.0001; adjusted hazard ratio of 4.81 [3.69–6.27,
P
<0.0001]). The performance metrics for the assay to rule-out preeclampsia within 7 days of enrollment showed a sensitivity 76.4% (67.5%–83.5%), negative predictive value 95.0% (92.8%–96.6%), and negative likelihood ratio 0.46 (0.32–0.65). Assay performance improved if delivery occurred <37 weeks and for individuals enrolled between 28 and 35 weeks.

Conclusions:
We confirmed that a novel multianalyte assay was associated with the time to develop preeclampsia and has a moderate sensitivity and negative likelihood ratio but high negative predictive value when assessed as an aid to rule out preeclampsia within 7 days of enrollment.

Registration:

The study was registered on
Clinicaltrials.gov
(Identifier NCT02780414).
Transfer of two Arabidella and two Cuphonotus species to the genus Lemphoria (Brassicaceae) and a description of the new species L. queenslandica
Authors: LYSAK MARTIN A. , EDGINTON MARK , ZUO SHENG , GUO XINYI , MANDÁKOVÁ TEREZIE , AL-SHEHBAZ IHSAN A. 
Published: June 2022

The taxonomic limits of Arabidella, Cuphonotus, and Lemphoria (Brassicaceae, Microlepidieae) are revised based on a critical evaluation of morphology in light of recent cytogenomic and molecular phylogenetic findings. As a result, Lemphoria is re-established to include two species previously placed in Cuphonotus and two in Arabidella. Lemphoria queenslandica is described as a new species, and the new combinations L. andraeana, L. eremigena, L. humistrata, and L. procumbens are proposed. Keys to distinguish Arabidella and Lemphoria species and an expanded generic description of Lemphoria are provided.
Shear Turbulence in the High-Wind Southern Ocean Using Direct Measurements
Authors: Ferris Laur , Gong Donglai , Clayson Carol Anne , Merrifield Sophia , Shroyer Emily L. , Smith Madison , Laurent Louis St. 
Published: June 2022

Abstract
The ocean surface boundary layer is a gateway of energy transfer into the ocean. Wind-driven shear and meteorologically forced convection inject turbulent kinetic energy into the surface boundary layer, mixing the upper ocean and transforming its density structure. In the absence of direct observations or the capability to resolve subgrid-scale 3D turbulence in operational ocean models, the oceanography community relies on surface boundary layer similarity scalings (BLS) of shear and convective turbulence to represent this mixing. Despite their importance, near-surface mixing processes (and ubiquitous BLS representations of these processes) have been undersampled in high-energy forcing regimes such as the Southern Ocean. With the maturing of autonomous sampling platforms, there is now an opportunity to collect high-resolution spatial and temporal measurements in the full range of forcing conditions. Here, we characterize near-surface turbulence under strong wind forcing using the first long-duration glider microstructure survey of the Southern Ocean. We leverage these data to show that the measured turbulence is significantly higher than standard shear-convective BLS in the shallower parts of the surface boundary layer and lower than standard shear-convective BLS in the deeper parts of the surface boundary layer; the latter of which is not easily explained by present wave-effect literature. Consistent with the CBLAST (Coupled Boundary Layers and Air Sea Transfer) low winds experiment, this bias has the largest magnitude and spread in the shallowest 10% of the actively mixing layer under low-wind and breaking wave conditions, when relatively low levels of turbulent kinetic energy (TKE) in surface regime are easily biased by wave events.

Significance Statement
Wind blows across the ocean, turbulently mixing the water close to the surface and altering its properties. Without the ability to measure turbulence in remote locations, oceanographers use approximations called boundary layer scalings (BLS) to estimate the amount of turbulence caused by the wind. We compared turbulence measured by an underwater robot to turbulence estimated from wind speed to determine how well BLS performs in stormy places. We found that in both calm and stormy conditions, estimates are 10 times too small closest to the surface and 10 times too large deeper within the turbulently mixed surface ocean.
Of Stag Hunts and secret societies: Cooperation, male coalitions and the origins of multiplicity
Authors: Lees Nicholas 
Published: June 2022

In many circumstances where multiple, autonomous actors exist, cooperation is only a viable strategy if other actors also pursue a strategy of cooperation. Such situations can be characterised in terms of the Stag Hunt, based on a parable told by Rousseau. Although traditionally interpreted as a device for understanding how mutually beneficial cooperation can emerge, Harrison Wagner points out that would-be exploiters must overcome similar problems to succeed at subjugating others. Successful cooperation may have the ironic consequence of enabling deeper conflict within and between a multiplicity of societies. Despite its canonical status, the importance of the Stag Hunt for understanding the interaction between multiple societies may have been underestimated. Nonetheless, rational choice theory alone cannot explain how cooperation-for-predation became established, while historical sociology’s conventional ‘materialist metanarrative’ of the origin of war and the state may have unduly neglected the role of gender relations. The phenomenon of men’s secret societies, found in many stateless societies, indicates that fraternal solidarity within coalitions of men competing to control women’s labour and bodies may provide a path to the nucleation of warlike states. If this is correct, it becomes clear that in many societies, men and women experience multiplicity in qualitatively different ways.
Public Finance Management in India in the Time of COVID-19 Pandemic
Authors: Mukherjee Sacchidananda , Badola Shivani 
Published: June 2022

Due to the COVID-19 pandemic, public finance management (PFM) in the FY 2020–2021 and 2021–2022 have become extremely challenging. The economic contraction has created pressures on PFM in India in terms of lower revenue mobilisation and higher expenditure needs. Both the union and state governments are facing dual problem of arresting economic contraction and managing public finance with limited resources. The present article analyses public finance management of the union as well as 16 major Indian states during the time of COVID-19 pandemic. For comparison, we have also analysed pre-COVID public finance monthly data of state governments. The shock to PFM came from both the revenue as well as expenditure side. Apart from aggregate analysis of state finances of 16 major states, we present state-wise analysis to highlight measures adopted by states to deal with the unprecedented fiscal crisis. JEL Codes: H20, H61, H62, H63
Non-domination and constituent power: Socialist republicanism versus radical democracy
Authors: Popp-Madsen Benjamin Ask 
Published: June 2022

Two of the dominant frameworks for criticizing capitalism and liberal democracy in contemporary political theory is Socialist republicanism, on the one hand, and radical democracy, on other hand. Whereas radical democratic thinkers have for decades criticized liberal democracy for being elitist, hierarchical and outright anti-popular, socialist republicans have for the last 10 years developed critiques of capitalism centred on the neo-republican idea of freedom as non-domination and proposed various arguments for workplace democracy and cooperative forms of ownership. Despite the common ambition of uncovering hierarchical relations of economic, political and social power, and creating new egalitarian and participatory modes of political organization, no systematic comparison of socialist republicanism and radical democracy exists. This paper fills this gap by comparing the different understandings of (a) institutions and (b) political action and (c) their diverging historical and political relations to socialism.