bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract IA012: Aging, tissue ecology, and the evolution of cancer within us
Authors: DeGregori James , Pham-Danis Catherine , Rozhok Andrii I , Evans Edward J. , Marongiu Fabio , Scarborough Hannah , Henry Curtis J.
Published: May 2022

Why do we get cancer? Why is cancer highly associated with old age? Of course, aging is associated with the accumulation of more mutations, and some of these mutations can contribute to cancer phenotypes. But we now understand that carcinogenesis is much more complex than originally appreciated. In particular, there are tissue environmental forces that both impede and promote cancer evolution. Just as organismal evolution is known to be driven by environmental changes, cellular (somatic) evolution in our bodies is similarly driven by changes in tissue environments, whether caused by the normal process of aging, by lifestyle choices or by extrinsic exposures. Environmental change promotes selection for new phenotypes that are adaptive to the new context. In our tissues, aging or insult-driven alterations in tissues drives selection for adaptive mutations, and some of these mutations can confer malignant phenotypes. We have been using mouse models of cancer initiation, mathematical models of cellular evolution, and analyses of human tissue samples to better understand the evolutionary forces that control somatic cell evolution and thus cancer risk. We have shown that aging and inflammation dependent changes in tissue environments dramatically dictate whether cancer-causing mutations are advantageous to stem cells in our tissues, starting the cells down the path to cancer. Our studies have focused on cancer initiation within the hematopoietic system and the lung. These studies have also uncovered molecular explanations for mutation-driven adaptation to aged and inflammatory tissue environments. In all, these studies indicate that strategies to prevent or treat cancers will need to incorporate interventions that alter tissue microenvironments.

Citation Format: James DeGregori, Catherine Pham-Danis, Andrii I Rozhok, Edward J. Evans, Fabio Marongiu, Hannah Scarborough, Curtis J. Henry. Aging, tissue ecology, and the evolution of cancer within us [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 IA012.
Abstract IA013: Genetic heterogeneity and tumor microenvironment in glioblastoma
Authors: Walentynowicz Kacper A. , Engelhardt Dalit , Yadav Shreya , Onubogu Ugoma , Salatino Roberto , Vincentelli Cristina , McDonald Thomas O. , Michor Franziska , Janiszewska Michalina
Published: May 2022

Glioblastoma (GBM), the most aggressive brain tumor, remains an unmet medical need. Despite aggressive chemotherapy, radiation and surgery, only 5.6% of patients survive beyond 5 years post-diagnosis. Targeted approaches have not been successful in this tumor type due to the extreme heterogeneity of GBM. Mosaic amplification of oncogenes suggests that multiple genetically distinct clones are present in each tumor. However, little is known about how different subpopulations of GBM cells interact with each other or with the surrounding tumor microenvironment (TME). To address this, we employed spatial protein profiling coupled with single-cell spatial maps of fluorescence in situ hybridization (FISH) for key oncogenes frequently amplified in GBM. Our analysis spanned 3-4 areas from 17 formalin-fixed paraffin-embedded (FFPE) GBM cases, 96 sub-regions of interest and total of 35,843 single nuclei. Digital spatial profiling for 79 protein markers associated with GBM biology, TME and neurobiology revealed high intra-tumor variability of vasculature, between distinct regions of the same tumor biopsy. The single-cell FISH signal quantification allowed us to classify tumors based on the relative frequency of cells harboring co-occurring of EGFR and CDK4 amplifications. Tumors with low odds ratio for EGFR and CDK4 co-amplification in a cell had a significantly higher EGFR copy number in cells harboring this amplification. Cell-to-cell variation in EGFR copy number was also much higher in these tumors, suggesting a possibility for extrachromosomal origin of this amplification. Interestingly, the tumors with high frequency of cells harboring co-amplification of EGFR and CDK4 exhibit higher infiltration by CD163+ immunosuppressive macrophages. Our results suggest that high throughput assessment of genomic alterations at the single cell level could provide a measure for predicting the immune state of GBM.

Citation Format: Kacper A. Walentynowicz, Dalit Engelhardt, Shreya Yadav, Ugoma Onubogu, Roberto Salatino, Cristina Vincentelli, Thomas O. McDonald, Franziska Michor, Michalina Janiszewska. Genetic heterogeneity and tumor microenvironment in glioblastoma [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 IA013.
Abstract IA014: Insights from comparative oncology
Authors: Maley Carlo
Published: May 2022

Comparative biology facilitates the exploration of the major factors that determine cancer susceptibility and resistance. We are only at the beginning of exploring the solutions that nature has found to the problem of preventing cancer, and the weaknesses that have evolved, leaving some animals exceptionally vulnerable to particular types of cancers. Some cancer defenses appear to be cell-intrinsic, such as the propensity of elephant cells to apoptose when they suffer DNA damage. Other defenses appear to depend on the environment, such as the invasion suppressive effects of fibroblasts of some species discovered by Wagner and his colleagues. I will review our early data on patterns of cancer prevalence across species and our initial results supporting Peto’s paradox but showing that contrary to our predictions, life history factors do not seem to explain patterns of cancer prevalence across species.

Citation Format: Carlo Maley. Insights from comparative oncology [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 IA014.
Abstract IA026: Charting genotype to phenotype maps of tumorigenesis
Authors: Curtis Christina
Published: May 2022

Cancers often arise from a mutated cell that undergoes premalignant clonal expansion, all the while accruing additional mutations. These somatic mutations accumulate and spread in phenotypically normal tissues prior to apparent morphological changes, with aneuploidy and driver gene mutations often preceding cancer diagnosis by years. Identifying the causes of malignant transformation requires characterization of abnormal molecular phenotypes that precede this event in a tissue-specific manner. However, repeated sampling of healthy tissue or pre-neoplasia is not practical. Critically, neither the order of somatic alterations nor the clonal dynamics that precede malignant transformation can be reliably inferred from genomic sequencing of established tumors. New approaches are therefore needed to characterize pre-neoplastic clonal evolution. Here we model this occult process via CRISPR/dCas9 engineering of human epithelial organoids, followed by multi-year experimental evolution. Through longitudinal genome sequencing, transcriptional profiling and lineage tracing, we define causal relationships between common initiating genetic lesions and resulting phenotypes. The resultant data illuminate evolutionary constraints and barriers to malignant transformation with implications for early detection and risk stratification.

Citation Format: Christina Curtis. Charting genotype to phenotype maps of tumorigenesis [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 IA026.
Critical Analysis of the Applicability of Small Bowel Capsule Endoscopy Performance Measures among 2 Portuguese Centers with Different Capsule Endoscopy Platforms
Authors: Gomes Catarina , O’Neill Catarina , Pinho Rolando , Barosa Rita , Ponte Ana , Magalhães-Costa Pedro , Rodrigues Adélia , Chagas Cristina , Carvalho João
Published: May 2022

Introduction: The European Society of Gastrointestinal Endoscopy (ESGE) identified the need to benchmark the quality of small bowel capsule endoscopy (SBCE) and produced a set of performance measures (PM). The aim of this study is to critically evaluate the accordance of the PM for SBCE in two Portuguese centers with different SBCE platforms. Methods: The authors conducted a cross-sectional analysis of consecutive SBCE performed in an 18-month period in 2 Portuguese centers that used two different SBCE platforms Mirocam® (IntroMedic, Seoul, South Korea) and PillCam® (Medtronic, Yokneam, Israel). A total of 10 PM (6 key, 4 minor) were evaluated and compared between the 2 centers. Results: A total of 493 SBCE were included. The minimum standard established by ESGE was reached in 3/6 key PM (complete visualization, lesion detection rate, and capsule retention rate), and none of the 4 minor PM. PM compliance significantly differed between the 2 centers: complete small bowel visualization 95.9 and 90% (p = 0.01), diagnostic yield 50.6 and 63% (p = 0.005), adequate small bowel cleansing level according to Brotz scale 69.54 and 84.6% (p ≤ 0.001), patients with high risk of capsule retention offered a patency capsule 4.2 and 73% (p ≤ 0.001), respectively. Conclusion: This study highlights and critically discusses technical and organizational issues that should be considered in defining more realistic PM thresholds, aiming to improve SBCE quality.
Advanced Therapy Medicinal Products and the Changing Role of Academia
Authors: Priesner Christoph , Hildebrandt Martin
Published: May 2022

Academic institutions coin the ATMP landscape but do not possess an industry-like capacity to vigorously pursue the full developmental pathway to marketing authorization. At the same time, industry has fostered clinical trials with ATMPs, brought the first products to marketing authorization, and defined novel modes of interaction with academia. A regulatory niche for local manufacturing of ATMPs within an academic institution had been foreseen in Regulation (EU) 1394/2007 under the term “Hospital Exemption” but remained ill-defined. Manufacture in close proximity to the patient is difficult to accomplish, as “point of care” systems for the manufacture of ATMPs have encountered regulatory challenges hovering between process and product. The efforts and costs for the development of ATMPs continue to be dramatically underestimated, and few academic centers were persistent enough to invest in the GMP infrastructure needed and to recruit personnel trained in ATMP development. As a consequence, the contribution by hospitals to ATMP development has shifted from the finished ATMP toward the procurement of starting materials, selected manufacturing steps, storage of the product, clinical application, and participation in clinical trials. As the development and use of cell-based therapies and ATMPs continue to attract and challenge clinicians and scientists, this review aims to discuss logistical, financial, and regulatory issues that might contribute to the changing role of Academia in ATMP development, with an outlook into possible developments in the future and proposals for ways to reshape the academic environment under the auspices of what might truly have been meant by the hospital exemption clause.
Cross-Sectional Analysis of US Health Insurance Payer Policies for Humanitarian Device Exemption Indications for Deep Brain Stimulation
Authors: Kusyk Dorian M. , Costa Gabriel , Schirmer Clemens M. , Whiting Alexander C. , Rosenow Joshua M.
Published: May 2022

Background: The US Food and Drug Administration (FDA) has granted deep brain stimulation (DBS) approval under the humanitarian device exemption (HDE) pathway for both dystonia and obsessive-compulsive disorder (OCD). However, recent reports from the community of functional neurosurgeons suggest that insurance authorization remains a disproportionate barrier to OCD DBS implantation despite both conditions having similar support from the FDA. This cross-sectional study of health insurance policies quantifies the current payer landscape for these two interventions. Objectives: The aim of this study was to quantify the current payer policy coverage of DBS under HDE status for OCD as compared to DBS for dystonia for eligible patients in the US insurance market. Methods: A commercial health insurance policy database was queried for documentation on DBS for dystonia and OCD. Results were individually analyzed for payer policy coverage statements on DBS for either dystonia or OCD and categorized as unique or nonunique policies. Unique policy positions were then coded for the geographic region, whether coverage was offered, and guidelines cited as evidence and justification. Results: From the 80 policies in the database, there were 34 unique policies addressing DBS for either dystonia or OCD representing coverage of all 50 states. Of the 34 unique policies, 3 (9%) covered DBS for OCD, while 32 (94%) covered dystonia. Only 2 policies covered neither intervention. Conclusions: In spite of similar levels of support from the FDA, DBS for OCD has less support from insurance companies on a national level. This study begins to quantify the disparity noted by functional neurosurgeons in recent literature.
Increased Concentrations of Circulating Interleukins following Non-Invasive Vagus Nerve Stimulation: Results from a Randomized, Sham-Controlled, Crossover Study in Healthy Subjects
Authors: Veiz Elisabeth , Kieslich Susann-Kristin , Czesnik Dirk , Herrmann-Lingen Christoph , Meyer Thomas , Staab Julia
Published: May 2022

Objective: The vagus nerve constitutes the main component of the parasympathetic nervous system and plays an important role in the regulation of neuro-immune responses. Invasive stimulation of the vagus nerve produces anti-inflammatory effects; however, data on humoral immune responses of transcutaneous vagus nerve stimulation (tVNS) are rare. Therefore, the present study investigated changes in serum cytokine concentrations of interleukin-1β (IL-1β), IL-6, IL-8, and tumor necrosis factor α (TNFα) following a short-term, non-invasive stimulation of the vagus nerve. Methods: Whole blood samples were collected before and after a short-lived application of active tVNS at the inner tragus as well as sham stimulation of the earlobe. Cytokine serum concentrations were determined in two healthy cohorts of younger (n = 20) and older participants (n = 19). Differences between active and sham conditions were analyzed using linear mixed models and post hoc F tests after applying Yeo-Johnson power transformations. This trial was part of a larger study registered on ClinicalTrials.gov (NCT05007743). Results: In the young cohort, IL-6 and IL-1β concentrations were significantly increased after active stimulation, whereas they were slightly decreased after sham stimulation (IL-6: p = 0.012; IL-1β: p = 0.012). Likewise, in the older cohort, IL-1β and IL-8 concentrations were significantly elevated after active stimulation and reduced after sham application (IL-8: p = 0.007; IL-1β: p = 0.001). In contrast, circulating TNFα concentrations did not change significantly in either group. Conclusion: Our results show that active tVNS led to an immediate increase in the serum concentrations of certain pro-inflammatory cytokines such as IL-1β, IL-6, and/or IL-8 in two independent cohorts of healthy study participants.
Fulminant Idiopathic Intracranial Hypertension in Pregnancy
Authors: Tyndel Felix , Steriade Claude , Gallo Antonio , Wennberg Richard , Radovanovic Ivan
Published: May 2022

Fulminant IIH in pregnancy requires multidisciplinary collaboration and immediate CSF diversion.
Nitrite Generating and Depleting Capacity of the Oral Microbiome and Cardiometabolic Risk: Results from ORIGINS
Authors: Goh Charlene E. , Bohn Bruno , Marotz Clarisse , Molinsky Rebecca , Roy Sumith , Paster Bruce J. , Chen Ching‐Yuan , Rosenbaum Michael , Yuzefpolskaya Melana , Colombo Paolo C. , Desvarieux Moïse , Papapanou Panos N. , Jacobs David R. , Knight Rob , Demmer Ryan T.
Published: May 2022

Background

The enterosalivary nitrate–nitrite–nitric oxide (NO
3
–NO
2
–NO) pathway generates NO following oral microbiota‐mediated production of salivary nitrite, potentially linking the oral microbiota to reduced cardiometabolic risk. Nitrite depletion by oral bacteria may also be important for determining the net nitrite available systemically. We examine if higher abundance of oral microbial genes favoring increased oral nitrite generation and decreased nitrite depletion is associated with a better cardiometabolic profile cross‐sectionally.

Methods and Results

This study includes 764 adults (mean [SD] age 32 [9] years, 71% women) enrolled in ORIGINS (Oral Infections, Glucose Intolerance, and Insulin Resistance Study). Microbial DNA from subgingival dental plaques underwent 16S rRNA gene sequencing; PICRUSt2 was used to estimate functional gene profiles. To represent the different components and pathways of nitrogen metabolism in bacteria, predicted gene abundances were operationalized to create summary scores by (1) bacterial nitrogen metabolic pathway or (2) biochemical product (NO
2
, NO, or ammonia [NH
3
]) formed by the action of the bacterial reductases encoded. Finally, nitrite generation‐to‐depletion ratios of gene abundances were created from the above summary scores. A composite cardiometabolic
Z
score was created from cardiometabolic risk variables, with higher scores associated with worse cardiometabolic health. We performed multivariable linear regression analysis with cardiometabolic
Z
score as the outcome and the gene abundance summary scores and ratios as predictor variables, adjusting for sex, age, race, and ethnicity in the simple adjusted model. A 1 SD higher NO versus NH
3
summary ratio was inversely associated with a −0.10 (false discovery rate
q
=0.003) lower composite cardiometabolic
Z
score in simple adjusted models. Higher NH
3
summary score (suggestive of nitrite depletion) was associated with higher cardiometabolic risk, with a 0.06 (false discovery rate
q
=0.04) higher composite cardiometabolic
Z
score.

Conclusions

Increased net capacity for nitrite generation versus depletion by oral bacteria, assessed through a metagenome estimation approach, is associated with lower levels of cardiometabolic risk.
Invasive Hemodynamic Predictors of Survival in Patients With Mitral Stenosis Secondary to Mitral Annular Calcification
Authors: El Sabbagh Abdallah , Nishimura Rick A. , Eleid Mackram F. , Pislaru Sorin V. , Pellikka Patricia A. , Rihal Charanjit S. , Guerrero Mayra , Hodge David O. , Miranda William R.
Published: May 2022

Background

The aim of this study was to establish prognostic hemodynamic parameters in patients with mitral stenosis secondary to mitral annular calcification.

Methods and Results

A retrospective cohort of 105 patients undergoing transseptal catheterization for hemodynamic evaluation of mitral annular calcification–related mitral stenosis between 2004 and 2020 was studied. Mitral valve gradient (MVG) and mitral valve area (MVA; calculated by the Gorlin formula) were measured using direct left atrial and left ventricular pressures. The median age of the patients was 70.3 years (58.4–76.7 years), and 53.3% were women. The median MVA was 1.7 cm
2
(1.3–2.3 cm
2
) and MVG was 7.3 mm Hg (5.3–10.3 mm Hg); left ventricular end‐diastolic pressure was 17.6±28.3 mm Hg. During a median of 2.1 years (0.7–4.5 years), there were 63 deaths; 1‐ and 5‐year survival were 76% and 40%, respectively. There was no association between left ventricular end‐diastolic pressure and survival. After adjusting for age and comorbidities, both MVA (hazard ratio [HR], 0.50 per cm
2
; 95% CI, 0.34–0.73) and MVG (HR, 1.1 per mm Hg; 95% CI, 1.05–1.20) were independent predictors of death. Atrial fibrillation was also independently associated with mortality. When added to a combined model, MVA remained associated with death (HR, 0.51 per cm
2
; 95% CI, 0.33–0.79) while MVG was not.

Conclusions

In patients with mitral annular calcification–related mitral stenosis, survival was poor. MVA and MVG were independently associated with death, but MVA was a better predictor of outcomes.
Stroke Risk Stratification in Patients With Postoperative Atrial Fibrillation After Coronary Artery Bypass Grafting
Authors: Taha Amar , Nielsen Susanne J. , Franzén Stefan , Rezk Mary , Ahlsson Anders , Friberg Leif , Björck Staffan , Jeppsson Anders , Bergfeldt Lennart
Published: May 2022

Background

The CHA
2
DS
2
‐VASc (congestive heart failure, hypertension, age ≥75 years, diabetes, previous stroke or TIA [transient ischemic attack], vascular disease, age 65 to 74 years, sex category female; 2 indicates 2 points, otherwise 1 point) scoring system is recommended to guide decisions on oral anticoagulation therapy for stroke prevention in patients with nonsurgery atrial fibrillation. A score ≥1 in men and ≥2 in women, corresponding to an annual stroke risk exceeding 1%, warrants long‐term oral anticoagulation provided the bleeding risk is acceptable. However, in patients with new‐onset postoperative atrial fibrillation, the optimal risk stratification method is unknown. The aim of this study was therefore to evaluate the CHA
2
DS
2
‐VASc scoring system for estimating the 1‐year ischemic stroke risk in patients with new‐onset postoperative atrial fibrillation after coronary artery bypass grafting.

Methods and Results

All patients with new‐onset postoperative atrial fibrillation and without oral anticoagulation after first‐time isolated coronary artery bypass grafting performed in Sweden during 2007 to 2017 were eligible for this registry‐based observational cohort study. The 1‐year ischemic stroke rate at each step of the CHA
2
DS
2
‐VASc score was estimated using a Kaplan‐Meier estimator. Of the 6368 patients included (mean age, 69.9 years; 81% men), >97% were treated with antiplatelet drugs. There were 147 ischemic strokes during the first year of follow‐up. The ischemic stroke rate at 1 year was 0.3%, 0.7%, and 1.5% in patients with CHA
2
DS
2
‐VASc scores of 1, 2, and 3, respectively, and ≥2.3% in patients with a score ≥4. A sensitivity analysis, with the inclusion of patients on anticoagulants, was performed and supported the primary results.

Conclusions

Patients with new‐onset atrial fibrillation after coronary artery bypass grafting and a CHA
2
DS
2
‐VASc score <3 have such a low 1‐year risk for ischemic stroke that oral anticoagulation therapy should probably be avoided.
Feasibility, Safety, and Short‐Term Outcomes of Transcatheter Patent Ductus Arteriosus Closure in Premature Infants on High‐Frequency Jet Ventilation
Authors: Shibbani Kamel , Mohammad Nijres Bassel , McLennan Daniel , Bischoff Adrianne Rahde , Giesinger Regan , McNamara Patrick J. , Klein Jonathan , Windsor Jimmy , Aldoss Osamah
Published: May 2022

Background

Prolonged exposure to a hemodynamically significant patent ductus arteriosus (PDA) is associated with major morbidity, particularly in infants born at <27 weeks’ gestation. High‐frequency jet ventilation (HFJV) is a standard of care at our center. There are no data about transcatheter PDA closure while on HFJV. The aim of this study was to assess the feasibility, safety, and outcomes of HFJV during transcatheter PDA closure.

Methods and Results

This is a retrospective cohort study of premature infants undergoing transcatheter device closure on HFJV. The primary outcome was successful device placement. Secondary outcomes included procedure time, fluoroscopy time and dose, time off unit, device complications, need for escalation in respiratory support, and 7‐day survival. Subgroup comparative evaluation of patients managed with HFJV versus a small cohort of patients managed with conventional mechanical ventilation was performed. Thirty‐eight patients were included in the study. Median age and median weight at PDA device closure for the HFJV cohort were 32 days (interquartile range, 25.25–42.0 days) and 1115 g (interquartile range, 885–1310 g), respectively. There was successful device placement in 100% of patients. There were no device complications noted. The time off unit and the procedure time were not significantly different between the HFJV group and the conventional ventilation group. Infants managed by HFJV had shorter median fluoroscopy times (4.5 versus 6.1 minutes;
P
<0.05) and no increased risk of adverse respiratory outcomes.

Conclusions

Transcatheter PDA closure in premature infants on HFJV is a safe and effective approach that does not compromise device placement success rate and does not lead to secondary complications.
The Effects of Transit Systems on International Trade
Authors: Carballo Jerónimo , Graziano Alejandro G. , Schaur Georg , Volpe Martincus Christian
Published: May 2022

In this paper, we estimate the trade effects of a transit system upgrading that streamlines border processing in developing countries. Our empirical approach combines transaction-level export data from El Salvador with unique data that distinguishes export flows that were processed on the transit system. Our results indicate that the new transit system lowered regulatory border costs and raised exports. At the low end, our back-of-the-envelope estimate of the return to investment is US$ 3-to-1. This evidence informs a policy covered by the 2013 WTO Agreement of Trade Facilitation.
Testing the Presence of Implicit Hiring Quotas with Application to German Universities
Authors: Janys Lena
Published: May 2022

Women are underrepresented in academia in general and economics in particular. I introduce a test to detect an underresearched form of hiring bias: implicit quotas. I derive a test under the null hypothesis of gender-blind hiring that requires no additional information about individual hires and can be used to analyze hiring bias in a variety of other hiring settings. I derive its asymptotic distribution and propose a parametric bootstrap procedure that resamples from the exact distribution. I analyze the distribution of female professors at German universities and find an implicit quota of one or two women on the department level.
Random Assignment with Nonrandom Peers: A Structural Approach to Counterfactual Treatment Assessment
Authors: Griffith Alan
Published: May 2022

Efforts to leverage peer effects by changing assignment have often fallen short due to endogenous peer choice. To address this, I build a two-part model: agents form networks via continuous linking decisions; conditional on realized networks, outcomes are determined. I provide results on identification of both parts of the model. Using data from a randomized study in India, I estimate the model, assess its performance in out-of-sample prediction, and simulate outcomes under preferential assignment rules. This paper contributes new methodology for identifying effects of alternative assignments in the presence of network endogeneity, as well as identification of network formation models.
Congressional Elections and Union Officer Prosecutions
Authors: Downey Mitch
Published: May 2022

Politicizing the investigation of politically active groups is harmful for both the justice system and democratic accountability. I test whether members of the U.S. Congress affect the investigation and prosecution of politically active labor unions. Union officers are 1.5 percentage points more likely to be prosecuted when their supported candidate barely loses instead of barely wins (compared to the 3% base rate). Anecdotal evidence and a novel decomposition suggest a role for both union-supported winners protecting allies and union-opposed winners pushing for aggressive prosecution of their opponents. I show that prosecutions undermine unions' strength, and I calculate implications for the incumbency advantage.
The Targeting and Impact of Partisan Gerrymandering: Evidence from a Legislative Discontinuity
Authors: Jeong Dahyeon , Shenoy Ajay
Published: May 2022

A party’s influence over redistricting increases discontinuously when its seat share in the state legislature exceeds 50%. We apply bunching tests to show that, in the election before redistricting, parties systematically win narrow majorities in legislatures of states where they have lost recent U.S. House races. This trend of losses is reversed after redistricting despite no change in overall House vote shares in states near the cutoff. The pre-to-post-redistricting change in regression discontinuity estimates implies that the party that controls redistricting engineers an 11 percentage point increase in its probability of winning a House race.
A preliminary list of the Pyraloid moths (Lepidoptera: Pyraloidea) of Kyrgyzstan
Authors: SINEV SERGEY YU. , KORB STANISLAV K.
Published: May 2022

A preliminary list of the pyraloid moths of Kyrgyzstan is provided. In total, 264 species are mentioned for this country, among them 117 listed by literature data and 146 species recorded in current paper for the first time. Another 97 species are known from the neighboring territories and most probably are also present in Kyrgyzstan.
A new species of the shortnose batfish genus Halicmetus from Madagascar (Family Ogcocephalidae)
Authors: HO HSUAN-CHING
Published: May 2022

A new species of the batfish genus Halicmetus is herein described as unique, having a body densely covered with variously sized bucklers. It is also distinguished from congeners by the following combination of characters: body disk relatively small, disk width 59.7% SL; orbit small, its diameter 8.3% SL; interorbital moderately wide, 7.4% SL; tail length 47.7% SL; illicial trough opening wide and high; dorsal fin absent; pectoral-fin rays 13; uniformly creamy white when preserved; peritoneal membrane pale with dense melanophores and scattered black dots.
How I approach smoldering multiple myeloma
Authors: Vaxman Iuliana , Gertz Morie A.
Published: May 2022

The current standard of care in smoldering multiple myeloma (SMM) is close surveillance, outside of clinical trials. Efforts are being made to understand the pathobiologic process that leads to the progression of SMM to active MM. This review provides a critical description of available data, including risk factors and risk models of progression, as well as clinical trials investigating interventions for this patient population. We describe 2 cases in which patients were seen before the concept of a myeloma-defining event was established. Today, based on the International Myeloma Working Group criteria, both patients would have been identified as experiencing myeloma-defining events, and therapy would have been initiated. These cases show that occasionally, patients can undergo observation only, even when they exceed criteria for high-risk SMM.
Thrombolytic tPA-Induced Hemorrhagic Transformation of Ischemic Stroke is Mediated by PKCβ phosphorylation of Occludin
Authors: Goncalves Andreia , Su Enming J , Muthusamy Arivalagan , Zeitelhofer Manuel , Torrente Daniel , Nilsson Ingrid , Protzmann Jil , Fredriksson Linda , Eriksson Ulf , Antonetti David A , Lawrence Daniel A
Published: May 2022

The current standard of care for moderate to severe ischemic stroke is thrombolytic therapy with tissue plasminogen activator (tPA). Treatment with tPA can significantly improve neurological outcomes; however, thrombolytic therapy is associated with an increased risk of intracerebral hemorrhage (ICH). The risk of hemorrhage significantly limits the use of thrombolytic therapy and identifying pathways induced by tPA that increase this risk could provide new therapeutic options to extend thrombolytic therapy to a wider patient population. Here, we investigate the role of protein kinase (PK)Cβ phosphorylation of the tight junction protein occludin during ischemic stroke and its role in cerebrovascular permeability. We demonstrate that activation of this pathway by tPA is associated with an increased risk of ICH. Middle cerebral artery occlusion (MCAO) increased occludin serine 490 (S490) phosphorylation in the ischemic penumbra in a tPA-dependent manner, as tPA-/- mice were significantly protected from MCAO-induced occludin phosphorylation. Intra-ventricular injection of tPA in the absence of ischemia was sufficient to induce occludin phosphorylation and vascular permeability in a PKCb-dependent manner. Blocking occludin phosphorylation either by targeted expression of a non-phosphorylatable form of occludin (S490A) or by pharmacologic inhibition of PKCβ, reduced MCAO-induced permeability and improved functional outcome. Further, inhibiting PKCβ after MCAO prevented ICH associated with delayed thrombolysis. These results reveal that PKCβ phosphorylation of occludin is a downstream mediator of tPA-induced cerebrovascular permeability and suggest that PKCb inhibitors could improve stroke outcome and prevent ICH associated with delayed thrombolysis, potentially extending the window for thrombolytic therapy in stroke.
A phase 1 dose escalation study of the pyruvate kinase activator mitapivat (AG-348) in sickle cell disease
Authors: Xu Julia Z. , Conrey Anna , Frey Ingrid , Gwaabe Eveline , Menapace Laurel A. , Tumburu Laxminath , Lundt Maureen , Lequang Timothy , Li Quan , Glass Kristen , Dunkelberger Emily B. , Iyer Varsha , Mangus Heidi , Kung Charles , Dang Lenny , Kosinski Penelope A. , Hawkins Peter , Jeffries Neal , Eaton William A. , Lay Thein Swee
Published: May 2022

Polymerization of deoxygenated hemoglobin S underlies the pathophysiology of sickle cell disease (SCD). In activating red blood cell pyruvate kinase and glycolysis, mitapivat (AG-348) increases adenosine triphosphate (ATP) levels and decreases the 2,3-diphosphoglycerate (2,3-DPG) concentration, an upstream precursor in glycolysis. Both changes have therapeutic potential for patients with SCD. Here, we evaluated the safety and tolerability of multiple ascending doses of mitapivat in adults with SCD with no recent blood transfusions or changes in hydroxyurea or l-glutamine therapy. Seventeen subjects were enrolled; 1 subject was withdrawn shortly after starting the study. Sixteen subjects completed 3 ascending dose levels of mitapivat (5, 20, and 50 mg, twice daily [BID]) for 2 weeks each; following a protocol amendment, the dose was escalated to 100 mg BID in 9 subjects. Mitapivat was well tolerated at all dose levels, with the most common treatment-emergent adverse events (AEs) being insomnia, headache, and hypertension. Six serious AEs (SAEs) included 4 vaso-occlusive crises (VOCs), non–VOC-related shoulder pain, and a preexisting pulmonary embolism. Two VOCs occurred during drug taper and were possibly drug related; no other SAEs were drug related. Mean hemoglobin increase at the 50 mg BID dose level was 1.2 g/dL, with 9 of 16 (56.3%) patients achieving a hemoglobin response of a ≥1 g/dL increase compared with baseline. Mean reductions in hemolytic markers and dose-dependent decreases in 2,3-DPG and increases in ATP were also observed. This study provides proof of concept that mitapivat has disease-modifying potential in patients with SCD. This trial was registered at www.clinicaltrials.gov as #NCT04000165.
Famotidine activates the vagus nerve inflammatory reflex to attenuate cytokine storm
Authors: Yang Huan , George Sam J. , Thompson Dane A. , Silverman Harold A. , Tsaava Téa , Tynan Aisling , Pavlov Valentin A. , Chang Eric H. , Andersson Ulf , Brines Michael , Chavan Sangeeta S. , Tracey Kevin J.
Published: May 2022

Background

Severe COVID-19 is characterized by pro-inflammatory cytokine release syndrome (cytokine storm) which causes high morbidity and mortality. Recent observational and clinical studies suggest famotidine, a histamine 2 receptor (H2R) antagonist widely used to treat gastroesophageal reflux disease, attenuates the clinical course of COVID-19. Because evidence is lacking for a direct antiviral activity of famotidine, a proposed mechanism of action is blocking the effects of histamine released by mast cells. Here we hypothesized that famotidine activates the inflammatory reflex, a brain-integrated vagus nerve mechanism which inhibits inflammation via alpha 7 nicotinic acetylcholine receptor (α7nAChR) signal transduction, to prevent cytokine storm.

Methods

The potential anti-inflammatory effects of famotidine and other H2R antagonists were assessed in mice exposed to lipopolysaccharide (LPS)-induced cytokine storm. As the inflammatory reflex is integrated and can be stimulated in the brain, and H2R antagonists penetrate the blood brain barrier poorly, famotidine was administered by intracerebroventricular (ICV) or intraperitoneal (IP) routes.

Results

Famotidine administered IP significantly reduced serum and splenic LPS-stimulated tumor necrosis factor (TNF) and IL-6 concentrations, significantly improving survival. The effects of ICV famotidine were significantly more potent as compared to the peripheral route. Mice lacking mast cells by genetic deletion also responded to famotidine, indicating the anti-inflammatory effects are not mast cell-dependent. Either bilateral sub-diaphragmatic vagotomy or genetic knock-out of α7nAChR abolished the anti-inflammatory effects of famotidine, indicating the inflammatory reflex as famotidine’s mechanism of action. While the structurally similar H2R antagonist tiotidine displayed equivalent anti-inflammatory activity, the H2R antagonists cimetidine or ranitidine were ineffective even at very high dosages.

Conclusions

These observations reveal a previously unidentified vagus nerve-dependent anti-inflammatory effect of famotidine in the setting of cytokine storm which is not replicated by high dosages of other H2R antagonists in clinical use. Because famotidine is more potent when administered intrathecally, these findings are also consistent with a primarily central nervous system mechanism of action.
Identification and validation of an eight-lncRNA signature that predicts prognosis in patients with esophageal squamous cell carcinoma
Authors: Zhang Jinfeng , Ling Xiaodong , Fang Chengyuan , Ma Jianqun
Published: May 2022

Background

Esophageal squamous cell carcinoma (ESCC) is correlated with worse clinical prognosis and lacks available targeted therapy. Thus, identification of reliable biomarkers is required for the diagnosis and treatment of ESCC.

Methods

We downloaded the GSE53625 dataset as a training dataset to screen differentially expressed RNAs (DERs) with the criterion of false discovery rate (FDR) < 0.05 and |log2fold change (FC)| > 1. A support vector machine classifier was used to find the optimal feature gene set that could conclusively distinguish different samples. An eight-lncRNA signature was identified by random survival forest algorithm and multivariate Cox regression analysis. The RNA sequencing data from The Cancer Genome Atlas (TCGA) database were used for external validation. The predictive value of the signature was assessed using Kaplan–Meier test, time-dependent receiver operating characteristic (ROC) curves, and dynamic area under the curve (AUC). Furthermore, a nomogram to predict patients’ 3-year and 5-year prognosis was constructed. CCK-8 assay, flow cytometry, and transwell assay were conducted in ESCC cells.

Results

A total of 1136 DERs, including 689 downregulated mRNAs, 318 upregulated mRNAs, 74 downregulated lncRNAs and 55 upregulated lncRNAs, were obtained in the GES53625 dataset. From the training dataset, we identified an eight-lncRNA signature, (ADAMTS9-AS1, DLX6-AS1, LINC00470, LINC00520, LINC01497, LINC01749, MAMDC2-AS1, and SSTR5-AS1). A nomogram based on the eight-lncRNA signature, age, and pathologic stage was developed and showed good accuracy for predicting 3-year and 5-year survival probability of patients with ESCC. Functionally, knockdown of LINC00470 significantly suppressed cell proliferation, G1/S transition, and migration in two ESCC cell lines (EC9706 and TE-9). Moreover, knockdown of LINC00470 downregulated the protein levels of PCNA, CDK4, and N-cadherin, while upregulating E-cadherin protein level in EC9706 and TE-9 cells.

Conclusion

Our eight-lncRNA signature and nomogram can provide theoretical guidance for further research on the molecular mechanism of ESCC and the screening of molecular markers.
Mechanism-aware imputation: a two-step approach in handling missing values in metabolomics
Authors: Dekermanjian Jonathan P. , Shaddox Elin , Nandy Debmalya , Ghosh Debashis , Kechris Katerina
Published: May 2022

When analyzing large datasets from high-throughput technologies, researchers often encounter missing quantitative measurements, which are particularly frequent in metabolomics datasets. Metabolomics, the comprehensive profiling of metabolite abundances, are typically measured using mass spectrometry technologies that often introduce missingness via multiple mechanisms: (1) the metabolite signal may be smaller than the instrument limit of detection; (2) the conditions under which the data are collected and processed may lead to missing values; (3) missing values can be introduced randomly. Missingness resulting from mechanism (1) would be classified as Missing Not At Random (MNAR), that from mechanism (2) would be Missing At Random (MAR), and that from mechanism (3) would be classified as Missing Completely At Random (MCAR). Two common approaches for handling missing data are the following: (1) omit missing data from the analysis; (2) impute the missing values. Both approaches may introduce bias and reduce statistical power in downstream analyses such as testing metabolite associations with clinical variables. Further, standard imputation methods in metabolomics often ignore the mechanisms causing missingness and inaccurately estimate missing values within a data set. We propose a mechanism-aware imputation algorithm that leverages a two-step approach in imputing missing values. First, we use a random forest classifier to classify the missing mechanism for each missing value in the data set. Second, we impute each missing value using imputation algorithms that are specific to the predicted missingness mechanism (i.e., MAR/MCAR or MNAR). Using complete data, we conducted simulations, where we imposed different missingness patterns within the data and tested the performance of combinations of imputation algorithms. Our proposed algorithm provided imputations closer to the original data than those using only one imputation algorithm for all the missing values. Consequently, our two-step approach was able to reduce bias for improved downstream analyses.
Molecular docking analysis reveals the functional inhibitory effect of Genistein and Quercetin on TMPRSS2: SARS-COV-2 cell entry facilitator spike protein
Authors: Manjunathan Reji , Periyaswami Vijayalakshmi , Mitra Kartik , Rosita Arokiaraj Sherlin , Pandya Medha , Selvaraj Jayaraman , Ravi Lokesh , Devarajan Nalini , Doble Mukesh
Published: May 2022

Background

The Transmembrane Serine Protease 2 (TMPRSS2) of human cell plays a significant role in proteolytic cleavage of SARS-Cov-2 coronavirus spike protein and subsequent priming to the receptor ACE2. Approaching TMPRSS2 as a therapeutic target for the inhibition of SARS-Cov-2 infection is highly promising. Hence, in the present study, we docked the binding efficacy of ten naturally available phyto compounds with known anti-viral potential with TMPRSS2. The aim is to identify the best phyto compound with a high functional affinity towards the active site of the TMPRSS2 with the aid of two different docking software. Molecular Dynamic Simulations were performed to analyse the conformational space of the binding pocket of the target protein with selected molecules.

Results

Docking analysis using PyRx version 0.8 along with AutoDockVina reveals that among the screened phyto compounds, Genistein shows the maximum binding affinity towards the hydrophobic substrate-binding site of TMPRSS2 with three hydrogen bonds interaction ( − 7.5 kcal/mol). On the other hand, molecular docking analysis using Schrodinger identified Quercetin as the most potent phyto compound with a maximum binding affinity towards the hydrophilic catalytic site of TMPRSS2 ( − 7.847 kcal/mol) with three hydrogen bonds interaction. The molecular dynamics simulation reveals that the Quercetin-TMPRSS complex is stable until 50 ns and forms stable interaction with the protein ( − 22.37 kcal/mol of MM-PBSA binding free energy). Genistein creates a weak interaction with the loop residues and hence has an unstable binding and exits from the binding pocket.

Conclusion

The compounds, Quercetin and Genistein, can inhibit the TMPRSS2 guided priming of the spike protein. The compounds could reduce the interaction of the host cell with the type I transmembrane glycoprotein to prevent the entry of the virus. The critical finding is that compared to Genistein, Quercetin exhibits higher binding affinity with the catalytic unit of TMPRSS2 and forms a stable complex with the target. Thus, enhancing our innate immunity by consuming foods rich in Quercetin and Genistein or developing a novel drug in the combination of Quercetin and Genistein could be the brilliant choices to prevent SARS-Cov-2 infection when we consider the present chaos associated with vaccines and anti-viral medicines.
Transcriptomic and genomic analysis provides new insights in molecular and genetic processes involved in zucchini ZYMV tolerance
Authors: Amoroso C. G. , Andolfo G. , Capuozzo C. , Di Donato A. , Martinez C. , Tomassoli L. , Ercolano M. R.
Published: May 2022

Background

Cucurbita pepois highly susceptible to Zucchini yellow mosaic virus (ZYMV) and the resistance found in several wild species cannot be considered as complete or broad-spectrum resistance. In this study, a source of tolerance introgressed inC. pepo(381e) fromC. moschata,in True French (TF) background, was investigated 12 days post-inoculation (DPI) at transcriptomic and genomic levels.

Results

The comparative RNA-sequencing (RNA-Seq) of TF (susceptible to ZYMV) and 381e (tolerant to ZYMV) allowed the evaluation of about 33,000 expressed transcripts and the identification of 146 differentially expressed genes (DEGs) in 381e, mainly involved in photosynthesis, transcription, cytoskeleton organization and callose synthesis. By contrast, the susceptible cultivar TF triggered oxidative processes related to response to biotic stimulus and activated key regulators of plant virus intercellular movement. In addition, the discovery of variants located in transcripts allowed the identification of two chromosome regions rich in Single Nucleotide Polymorphisms (SNPs), putatively introgressed fromC. moschata,containing genes exclusively expressed in 381e.

Conclusion

381e transcriptome analysis confirmed a global improvement of plant fitness by reducing the virus titer and movement. Furthermore, genes implicated in ZYMV tolerance inC. moschataintrogressed regions were detected. Our work provides new insight into the plant virus recovery process and a better understanding of the molecular basis of 381e tolerance.