bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA006: Somatic mutation in normal tissues
Authors: Martincorena Iñigo 
Published: May 2022

Abstract
Somatic mutations underpin cancer development and have been speculated to contribute to ageing and a range of diseases. Over the past decade, the ability to sequence cancer genomes has transformed our understanding of the genetics and evolution of a wide range of cancers. However, owing to technical limitations, much less is known about the earliest steps of cancer and how cells in our tissues accumulate mutations during normal ageing. In this talk, I will summarize our recent work to unravel the extent of somatic mutation and clonal selection in normal tissues. I will also discuss how recent technological developments are opening new frontiers in this nascent field.
Citation Format: Iñigo Martincorena. Somatic mutation in normal tissues [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA006.
Abstract IA007: Outcompeting cancer in the intestine
Authors: Vermeulen Louis 
Published: May 2022

Abstract
Cancers develop in a stepwise fashion as mutations in oncogenes and tumor suppressor genes accumulate. The mutations provide the cells in which they occur typically an advantage over the surrounding wild type neighbors, resulting in clonal expansion. Understanding the nature of the competitive benefit of oncogenic cells might result in the identification of targets for prevention of cancer. In particular in individuals affected by hereditary cancer syndromes, in which the initiating mutations are well-described, this is a promising strategy. I will discuss our work on intestinal carcinogenesis and the impact on stem cell properties of mutations associated with familial cancer syndromes affecting the gut. In particular I will discuss how inactivation of the tumor suppressor gene APC, which is affected in individuals suffering from Familial Adenomatous Polyposis (FAP), generates supercompetitor cells that actively suppress their neighbors. As we will see, the uncovered mechanism directly suggests a potent chemopreventive strategy that is currently being tested in a proof-of-concept clinical trial in FAP individuals.
Citation Format: Louis Vermeulen. Outcompeting cancer in the intestine [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA007.
Abstract IA023: Selection for a glycolytic phenotype
Authors: Damaghi Mehdi 
Published: May 2022

Abstract
In early breast carcinogenesis, neoplastic cells grow in multiple layers towards the lumens of ducts, which subjects the periluminal cells to harsh conditions of low oxygen, low pH, and nutrient deprivation. Adaptation to these harsh conditions is a pre-requisite for survival of incipient tumor cells and also responsible for selecting cells with a more aggressive phenotype. Based on the first principle of Darwinian evolution, common phenotypes of cancer cells must have conferred a selective advantage at some point during their evolutionary trajectory. Adaptations are initially acute and reversible, but eventually Darwinian selection results in cells with hardwired phenotypes. A prominent example of this is aerobic glycolysis, or the Warburg Effect (WE), wherein cells are hard-wired to ferment glucose, even in the presence of oxygen. WE provides and evolutionary advantage which leads to higher fitness of the cancer cells, who have acquired mechanisms of adaptation, such as autophagy and lysosome redistribution. Notably, a WE is highly correlated with a cancer’s metastatic potential and poor outcome. Hence, a major question in carcinogenesis is: “What are the mechanisms by which a harsh microenvironment eventually selects for hard-wired (heritable) phenotypes, such as a WE?”. Rather than simply selection of pre-existing phenotypes, we contend that the microenvironment actively induces phenotypic diversity through a systematic set of epigenetic and genetic alterations.
Citation Format: Mehdi Damaghi. Selection for a glycolytic phenotype [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA023.
Abstract IA024: The role of the epigenome and phenotypic plasticity in colorectal cancer evolution
Authors: Graham Trevor A. 
Published: May 2022

Abstract
The evolutionary dynamics of colorectal metastasis and the role of the epigenome in disease progression remain to be fully determined. We have used multi-region, multi-omic profiling (DNA, RNA and chromatin), together with computational modelling, of a prospectively collected cohort of primary CRCs (pCRCs) and DNA and RNA analysis of a retrospective series of metastatic CRCs (mCRCs) to define pCRC biology and track clonal evolution from primary tumour to metastasis. Computational analysis of multi-region sequencing data provided a sensitive test confirming subclonal selection is rare in pCRCs. We detected substantial epigenetic rewiring at the outset of pCRC formation, implicating changes in chromatin accessibility in the initial genesis of CRCs. Using DNA to trace clonal ancestry and overlaying RNA to measure gene expression phenotypes, we observe widespread gene expression changes without underlying clonal selection, indicative that pCRC cells are phenotypically plastic. In mCRCs, we observe that the karyotype of the primary tumour is often not substantially modified in metastasis, across multiple organs, through treatment and over substantial periods of time. This is suggestive that stabilising selection, acting on copy number alterations, constrains karyotype evolution. Paired analysis of DNA and RNA in metastasis indicate that the phenotypic plasticity persists during metastatic spread. Epigenetic rewiring and phenotypic plasticity play potentially causative roles in the genesis and progression of colorectal cancer.
Citation Format: Trevor A. Graham. The role of the epigenome and phenotypic plasticity in colorectal cancer evolution [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA024.
Abstract PR008: Immunosuppressive niche engineering at the onset of human colorectal cancer
Authors: Gatenbee Chandler D. , Baker Ann-Marie , Schenck Ryan O. , Strobl Maximilian , West Jeffrey , Robertson-Tessi Mark , Graham Trevor A. , Anderson Alexander R.A. 
Published: May 2022

Abstract
The evolutionary dynamics of tumor initiation remain undetermined, and the interplay between neoplastic cells and the immune system is hypothesized to be critical in transformation. Colorectal cancer (CRC) presents a unique opportunity to study the transition to malignancy as pre-cancers (adenomas) and early-stage cancers are frequently detected and surgically removed. Here, we demonstrate a key role for the immune response in tumor initiation by studying tumor-immune eco-evolutionary dynamics from pre-cancer to carcinoma using a computational model, ecological analysis of digital pathology data, and multi-region exome sequencing and neoantigen prediction in a total of 62 patient samples. Modelling indicates there are several potential routes to malignancy, each of which uniquely sculpts tumor ecology and intra-tumor antigenic heterogeneity (aITH). In patient samples, the immune microenvironment was characterized using the spatial distribution of 17 markers across registered whole-slide images, as well as patterns of intra-lesion aITH measured using multi-region exome sequencing and neoantigen prediction. The patient data were best described by a model where adenomas that become immunogenic early on do not progress to CRC because they are under immune control; progression therefore proceeds in adenomas with low immunogenicity. In these tumors, immune suppression is initially low, but gradually an immunosuppressive niche that is depleted in CD8+ cytotoxic T cells expands. There was little evidence for immune blockade (PD-L1 expression) in tumor initiation or progression. These results suggest that re-engineering the immunosuppressive niche may prove to be an effective immunotherapy in CRC.
Citation Format: Chandler D. Gatenbee, Ann-Marie Baker, Ryan O. Schenck, Maximilian Strobl, Jeffrey West, Mark Robertson-Tessi, Trevor A. Graham, Alexander R.A. Anderson. Immunosuppressive niche engineering at the onset of human colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr PR008.
Ultrashort Door‐to‐Needle Time for Intravenous Thrombolysis Is Safer and Improves Outcome in the Czech Republic: Nationwide Study 2004 to 2019
Authors: Mikulík Robert , Bar Michal , Bělašková Silvie , Černík David , Fiksa Jan , Herzig Roman , Jura René , Jurák Lubomír , Klečka Lukáš , Neumann Jiří , Ostrý Svatopluk , Šaňák Daniel , Ševčík Petr , Škoda Ondřej , Šrámek Martin , Tomek Aleš , Václavík Daniel ,   the Czech Stroke Unit Network
Published: May 2022

Background
The benefit of intravenous thrombolysis is time dependent. It remains unclear, however, whether dramatic shortening of door‐to‐needle time (DNT) among different types of hospitals nationwide does not compromise safety and still improves outcome.

Methods and Results
Multifaceted intervention to shorten DNT was introduced at a national level, and prospectively collected data from a registry between 2004 and 2019 were analyzed. Generalized estimating equation was used to identify the association between DNT and outcomes independently from prespecified baseline variables. The primary outcome was modified Rankin score 0 to 1 at 3 months, and secondary outcomes were parenchymal hemorrhage/intracerebral hemorrhage (ICH), any ICH, and death. Of 31 316 patients treated with intravenous thrombolysis alone, 18 861 (60%) had available data: age 70±13 years, National Institutes of Health Stroke Scale at baseline (median, 8; interquartile range, 5–14), and 45% men. DNT groups 0 to 20 minutes, 21 to 40 minutes, 41 to 60 minutes, and >60 minutes had 3536 (19%), 5333 (28%), 4856 (26%), and 5136 (27%) patients. National median DNT dropped from 74 minutes in 2004 to 22 minutes in 2019. Shorter DNT had proportional benefit: it increased the odds of achieving modified Rankin score 0 to 1 and decreased the odds of parenchymal hemorrhage/ICH, any ICH, and mortality. Patients with DNT ≤20 minutes, 21 to 40 minutes, and 41 to 60 minutes as compared with DNT >60 minutes had adjusted odds ratios for modified Rankin score 0 to 1 of the following: 1.30 (95% CI, 1.12–1.51), 1.33 (95% CI, 1.15–1.54), and 1.15 (95% CI, 1.02–1.29), and for parenchymal hemorrhage/ICH: 0.57 (95% CI, 0.45–0.71), 0.76 (95% CI, 0.61–0.94), 0.83 (95% CI, 0.70–0.99), respectively.

Conclusions
Ultrashort initiation of thrombolysis is feasible, improves outcome, and makes treatments safer because of fewer intracerebral hemorrhages. Stroke management should be optimized to initiate thrombolysis as soon as possible optimally within 20 minutes from arrival to a hospital.
New Evidence on Welfare’s Disincentive for the Youth Using Administrative Panel Data
Authors: Bargain Olivier B. , Jonassen Anders B. 
Published: May 2022

Abstract
We estimate the impact of social assistance on youth employment in Denmark, 2000 to 2006. For childless unmarried individuals, maximum welfare payments increased by 55% at age 25. Using administrative panel data, we find a significant disincentive effect among the low-skilled only, for whom employment fell by 2% to 3% and benefit take-up increased by 10% to 14%. Two-thirds of the effect is attributable to transitions from work to welfare and one-third to reduced labor market entry. Heterogeneous estimates along the earnings distribution show that employment responses are concentrated at very low earnings. We find no evidence of an age discontinuity in criminal activities.
Subjective Job Insecurity and the Rise of the Precariat: Evidence from the United Kingdom, Germany, and the United States
Authors: Manning Alan , Mazeine Graham 
Published: May 2022

Abstract
There is a widespread belief that work is less secure than in the past, that an increasing share of workers are part of the “precariat.” It is hard to find much evidence for this in objective measures of job security, but perhaps subjective measures show different trends. This paper shows that in the United States, the United Kingdom, and Germany, workers feel as secure as they ever have in the past 30 years. This is partly because job insecurity is very cyclical and (pre-COVID) unemployment rates very low, but there is also no clear underlying trend towards increased subjective measures of job insecurity. This conclusion seems robust to controlling for the changing mix of the labor force, and it is true for specific subsets of workers.
Fireside Chats: Communication and Consumers’ Expectations in the Great Depression
Authors: Pedemonte Mathieu 
Published: May 2022

Abstract
This paper shows how policy announcements can be used to manage expectations. Using regional variation in radio exposure, I evaluate the impact of FDR’s 1935 Fireside Chat, in which he showcased the introduction of important social policies, establishing a new expansionary cycle of the New Deal. I document that cities with higher exposure to the announcement exhibited a significant increase in spending on durable goods. The estimated effect is consistent with changes in expectations in line with the policies announced. This paper shows the power of communication as a policy tool.
A Structural Investigation of Quantitative Easing
Authors: Boehl Gregor , Goy Gavin , Strobel Felix 
Published: May 2022

Abstract
Using nonlinear Bayesian methods that fully account for the binding zero lower bound (ZLB), we estimate a large-scale macrofinance DSGE model on U.S. data. Counterfactual analysis suggests that by easing financing conditions, quantitative easing facilitated a net increase in aggregate investment. The resulting expansion of firms’ production capacities lowered their marginal costs. These disinflationary supply side effects dominated over the inflationary effects induced by the stimulus to aggregate demand. At the ZLB, the concomitant rise in real interest rates, in turn, induced a net fall in aggregate consumption.
Mechanisms of Valley Precipitation Enhancement over Da-Tun Mountain
Authors: Yu Cheng-Ku , Liu Wei-Fan , Cheng Lin-Wen , Lin Chuan-Yao 
Published: May 2022

Abstract
This study explores the mechanisms responsible for valley precipitation enhancement over Da-Tun Mountain under the prevailing northeasterly monsoonal flow. Da-Tun Mountain, located adjacent to the northern coast of Taiwan, is a small-scale (15 km), concave-like terrain feature with two ridge arms and a funnel-shaped valley. A typical valley precipitation enhancement event that occurred on 13 December 2018 was chosen for detailed analyses. Upstream conditions were characterized by the absence of convective available potential energy with a large-Froude-number (>1) flow regime. Observational and modeling results indicate a consistent, important signature of flow splitting due to partial blocking as the low-level northeasterly flow encountered the ridge arms. Fine-scale structures of airflow and precipitation evident from the simulations further reveal that the deflected flows over the two ridge arms interacted with each other to produce lateral convergence and enhanced precipitation inside the valley. The smaller-scale splitting flows tended to occur over the ridge arms as upstream moist Froude number decreased from relatively higher (5–11) to lower (3–5) values due to the temporal change in moist static stability. Quantitative diagnoses of vertical velocities performed over the region of primary precipitation support that upward motions associated with lateral convergence greatly overwhelmed the upslope-forced lifting over the valley region during the valley precipitation enhancement periods. However, vertical motions over the ridge arms with steeper slopes were dominantly contributed by the upslope forcing, but their intensities were also modulated by the flow-splitting-induced divergence.

Significance Statement
Many mountain ranges around the world exhibit a concave-like terrain feature with various spatial scales and orientations. Orographic modulations of rainfall by concave mountains are of great importance to local weather, as torrential rainfall has been frequently reported over these ridges in different geographical locations. This study aims to advance our knowledge of precipitation mechanisms over Da-Tun Mountain, a small-scale concave topography located in northern Taiwan. Observational and modeling analyses reveal evidence of splitting flows over different ridge arms of this mountain barrier. These smaller-scale splitting flows and their interactions play important roles in modulating the intensity of upslope-forced lifting and contributing to valley precipitation enhancement. These identified processes are anticipated to be commonly active over highly three-dimensional, concave-like topography.
Which features of ambulatory healthcare are preferred by people aged 80 and over? Findings from a systematic review of qualitative studies and appraisal of confidence using GRADE-CERQual
Authors: Herrler Angélique , Kukla Helena , Vennedey Vera , Stock Stephanie 
Published: May 2022

Abstract
Background
Despite healthcare providers’ goal of patient-centeredness, current models for the ambulatory (i.e., outpatient) care of older people have not as yet systematically incorporated their views. Moreover, there is no systematic overview of the preferable features of ambulatory care from the perspective of people aged 80 and over. Therefore, the aim of this study was to summarize their specific wishes and preferences regarding ambulatory care from qualitative studies.

Methods
The study was based on qualitative studies identified in a prior systematic review. Firstly, the findings of the qualitative studies were meta-summarized, following Sandelowski and Barroso. Secondly, a list of preferred features of care from the perspective of older people was derived from the included studies’ findings through inductive coding. Thirdly, the review findings were appraised using the GRADE-CERQual tool to determine the level of confidence in the qualitative evidence. The appraisal comprised four domains: methodological limitations, coherence, data adequacy, and data relevance. Two reviewers independently evaluated every review finding in each domain. The final appraisals were discussed and ultimately summarized for the respective review finding (high, moderate, low, or very low confidence).

Results
The 22 qualitative studies included in the systematic review were mainly conducted in Northern and Western Europe (n = 15). In total, the studies comprised a sample of 330 participants (n = 5 to n = 42) with a mean or median age of 80 and over. From the studies’ findings, 23 preferred features of ambulatory care were identified. Eight features concerned care relationships (e.g., “Older people wish to receive personal attention”), and 15 features concerned healthcare structures (e.g., “Older want more time for their care”). The findings emphasized that older people wish to build strong relationships with their care providers. The majority of the review findings reached a moderate or high confidence appraisal.

Conclusions
While the listed features of healthcare structures are common elements of care models for older people (e.g., Geriatric Care Model), aspects of care relationships are somewhat underrepresented or are not addressed explicitly at all. Future research should further explore the identified preferred features and their impact on patient and care outcomes.
Low awareness of oral and injectable PrEP among high-risk adolescent girls and young women in Kampala, Uganda
Authors: Lunkuse Jane Frances , Kamacooko Onesmus , Muturi-Kioi Vincent , Chinyenze Kundai , Kuteesa Monica O. , Price Matt A. , Mayanja Yunia 
Published: May 2022

Abstract
Background
Adolescent girls and young women (AGYW) account for a disproportionate number of new HIV infections worldwide. HIV prevalence among young sex workers in Uganda is 22.5%. Although pre-exposure prophylaxis (PrEP) is a highly effective biomedical HIV prevention method, awareness of PrEP among AGYW in Uganda has not been studied systematically. We aimed to assess awareness of PrEP and factors associated with awareness of PrEP among AGYW who frequently reported paid sex.

Methods
We conducted a cross-sectional study among 14–24-year old AGYW at high risk of HIV infection in Kampala, Uganda from January to October 2019. Participants were screened for PrEP eligibility using a national screening tool of whom 82.3% were eligible. Data on socio-demographics, behavioral and sexual risks were collected by interview. Awareness of oral or injectable PrEP, the latter of which is currently in late-stage trials, was defined as whether an individual had heard about PrEP as an HIV prevention method. Multivariable robust poisson regression model was used to assess factors associated with oral PrEP awareness.

Results
We enrolled 285 participants of whom 39.3% were under 20 years old, 54.7% had completed secondary education, 68.8% had multiple sex partners in the past 3 months, 8.8% were screened as high risk drinkers’/ alcohol dependent (AUDIT tool) and 21.0% reported sex work as main occupation. Only 23.2% were aware of oral PrEP and 3.9% had heard about injectable PrEP. The prevalence of oral PrEP awareness was significantly higher among volunteers screened as alcohol dependents (aPR 1.89, 95% CI 1.08–3.29) and those with multiple sexual partners (aPR 1.84, 95% CI 1.01–3.35), but was lower among those who reported consistent condom use with recent sexual partners (aPR 0.58, 95% CI 0.37–0.91).

Conclusions
Majority of AGYW were not aware of any kind of PrEP. Those with higher risk behavior, i.e. alcohol dependents or multiple sexual partners, were more aware of oral PrEP. Interventions to increase awareness among female youth are needed. Improving PrEP awareness is critical to increasing PrEP uptake among high-risk AGYW in Uganda.
Bromisoval-induced bromism with status epilepticus mimicking Wernicke’s encephalopathy: report of two cases
Authors: Biyajima Masahiro , Satoh Shunichi , Morikawa Takahiro , Morita Yuki , Watanabe Rie , Matsui Daisuke , Konno Masataka , Morimoto Nobutoshi , Yatsu Yuichi , Hirasaki Akihito , Yahikozawa Hiroyuki 
Published: May 2022

Abstract
Background
Bromine compounds are used in several drugs, including over-the-counter drugs. They sometimes cause intoxication known as bromism. Although the acute neurological symptoms and sequelae of bromism vary, few reports have mentioned acute encephalopathy.

Case presentation
We report two cases of bromisoval-induced bromism with status epilepticus. Presence of pseudohyperchloremia and history of over-the-counter medication use guided the diagnosis. In the acute phase, our patients showed bilateral medial thalamic lesions on magnetic resonance imaging. The imaging findings were similar to those of Wernicke’s encephalopathy. Although these findings improved in the chronic phase, neuropsychiatric sequelae, such as confabulation and amnesia, occurred.

Conclusion
Bromism can cause acute encephalopathy, and it is important to differentiate it from Wernicke–Korsakoff syndrome.