bluuebunny/crossref_metadata_2025 huggingface dataset:
Peri-operative myocardial performance in infants with Down syndrome undergoing CHD repair
Authors: Zakharchenko Lyudmyla , EL-Khuffash Afif , Molloy Eleanor J. , Breatnach Colm , Franklin Orla
Published: August 2021

Background:

We aimed to characterise the impact of Down syndrome on myocardial performance and loading conditions in infants with Down syndrome and CHD over the peri-operative period by comparing them with infants matched for cardiac lesion with a normal microarray.

Methods:

Left ventricular global longitudinal strain, right ventricular free wall longitudinal strain, left ventricular end-systolic wall stress, and right ventricular systolic pressure were measured in the two groups over the peri-operative period.

Results:

Fifty-five infants had a diagnosis of Down syndrome and these were compared with 29 control infants. Left ventricular global longitudinal strain decreased in both groups post-operatively with the Down syndrome group demonstrating some recovery pre-discharge (18 ± 3 versus 16 ± 3 %, p = 0.01). Right ventricular longitudinal strain significantly decreased in both groups post-operatively with the control group demonstrating better recovery by hospital discharge (14 ± 4 versus 18 ± 6 %, p < 0.01). End-systolic wall stress was lower and right ventricular systolic pressure was higher in the Down syndrome group throughout the study period (all p < 0.05). Down syndrome was an independent predictor of the duration of ventilation, post-operative use of inotropes, and intensive care stay. Right ventricular longitudinal strain was an independent predictor of duration of intensive care stay.

Conclusion:

This study demonstrates the difference between the two groups in relation to left and right ventricular function, particularly prior to discharge, and outlines the additional impact a diagnosis of Down syndrome has on myocardial performance during the peri-operative period.
Influence of fenestration on long-term Fontan survival
Authors: Materna Ondřej , Illinger Vojtěch , Jičínská Denisa , Koubský Karel , Kovanda Jan , Ložek Miroslav , Tax Petr , Reich Oleg , Chaloupecký Václav , Janoušek Jan
Published: August 2021

Introduction:

Fenestration in the total cavopulmonary connection system may improve the outcome of patients with significant risk factors for Fontan haemodynamics. Our study aims to analyse the difference in long-term survival between non-fenestrated and fenestrated patients.

Methods:

All consecutive patients (n = 351) who underwent total cavopulmonary connection between 1992 and 2016 were identified. Six early deaths were excluded resulting in a group of 345 patients. Median (interquartile range,) length of follow-up was 14.4 (7.1–19.7) years. Freedom from the composite endpoint of death, total cavopulmonary connection take-down or indication for a heart transplant was analysed.

Results:

Fenestration was absent in 237 patients (68.7%, Group 1), was created and closed later in 79 patients (22.9%, Group 2), and remained open in 29 patients (8.4%, Group 3). Mean survival probability until composite endpoint was 97.1 and 92.9% at 10 and 20 years, respectively. Patients with patent fenestration had worse survival (p < 0.001) as compared to both the non-fenestrated and fenestration closure groups. Despite a similar outcome, exercise capacity was lower in Group 2 than 1 (p = 0.013). In 58 patients with interventional fenestration closure, Nakata index was lower at the time of closure than pre-operatively, and both the pressure in the circuit and oxygen saturation in the aorta increased significantly (p < 0.001).

Conclusions:

Patients with persisting risk factors preventing fenestration closure are at higher risk of reaching the composite endpoint. Patients after fenestration closure have the worse functional outcome; their survival is, however, not different from the non-fenestrated group.
Impact of the community eligibility provision program on school meal participation in Texas
Authors: Schneider Kate R , Oslund Jennifer , Liu Tiffany
Published: August 2021

Objective:

To estimate the impact of opting into the community eligibility provision (CEP) on school meal participation among students in Texas.

Design:

A quasi-experimental design using a two-way fixed effects panel difference-in-difference model and the variation in adoption timing to estimate the impact of opting into CEP on student breakfast and lunch participation in eligible, ever-adopting schools.

Setting:

All public and charter K-12 schools in Texas participating in national school meals (breakfast and/or lunch) from 2013 to 2019 who are eligible for the CEP program in at least 1 year and choose to opt into the program in at least 1 year (n 2797 unique schools and 16 103 school-years).

Participants:

School-level administrative data from the Texas Department of Agriculture on meal counts, enrollment and summary characteristics of students merged with district-level educational and socio-demographic data from the Texas Education Authority.

Results:

We find opting into CEP increased school breakfast participation by 4·59 percentage points (P < 0·001) and lunch participation by 4·32 percentage points (P < 0·001), on average. The effect is slightly larger (4·64 and 4·61, respectively) and still statistically significant when excluding summer months.

Conclusion:

Our findings suggest that opting into CEP modestly increases school meal participation in Texas, with a similar impact on breakfast and lunch.
Students’ Attitudes and Intention to Work with Older Adults in the Era of COVID-19
Authors: Shea Adam , Woolverton Cindy , Biccum Katelind , Yu Aiping , Strong Jessica V.
Published: August 2021

Abstract. We surveyed 377 undergraduates, half in the spring (i.e., before COVID-19) and half in the fall (i.e., during COVID-19) term of 2020 on explicit attitudes toward and intention to work with older adults (OAs). We asked open-ended questions about their attitudes toward OAs resulting from COVID-19. We found significant differences with small effect sizes between the cohorts on explicit ageism. Thematic content analyses found that most students themselves did not perceive a change in their explicit attitudes toward OAs. Negative ageism predicted intention to work with OAs for the spring cohort, but this shifted to positive ageism for the fall cohort.
Addressing the Mental Health of Black Older Adults During the COVID-19 Pandemic
Authors: McDuffie Danielle L.
Published: August 2021

Abstract. The COVID-19 pandemic continues to disrupt the world. However, a particular group has felt the effects of the pandemic to an extraordinarily greater degree: Black older adults. This conceptual paper applies the law of small effects theory to the COVID-19 pandemic and its effects on the mental health and well-being of Black older adults. It explores factors such as health and healthcare disparities, geographic factors, cultural factors, and other components of the Black older adult experience in the context of COVID-19. The conclusions and implications address how the subfields within gerontology and geropsychology can aid Black older adults moving forward, things to consider as the pandemic persists, and considerations following its conclusion.
Perceived Stress of Cypriot College Students During COVID-19
Authors: Panteli Maria , Vaiouli Potheini , Leonidou Chrysanthi , Panayiotou Georgia
Published: August 2021

Abstract. Background: Increased perceived stress is associated with physical and mental health problems. However, little is known about the social factors that influenced perceived stress during the COVID-19 pandemic. In this study, we examined the relationship between social skills, perceived support from family and friends, and perceived stress during the COVID-19 pandemic, through a two-wave design. Methods: A group of 106 college students completed measures of social skills during the prepandemic period as well as of perceived social support and perceived stress 1 month into the implementation of the first lockdown in Cyprus. Results: Preexisting social skills and concurrent family support the predicted negatively perceived stress during the lockdown. Although several aspects of social skills were correlated negatively with perceived stress, only the ability to manage interpersonal conflicts and to effectively resolve disagreements negatively predicted perceived stress, suggesting that this skill may constitute a protective factor against perceived stress during stressful events. Perceived support during the pandemic, on the other hand, was not overall significantly predicted by one’s social skills. Conclusions: Our study provides preliminary evidence about the relationship between interpersonal skills and perceived stress during the COVID-19 pandemic. Interventions targeting the development of conflict resolution skills seem to be promising in ameliorating the psychological stress associated with the pandemic.
Context-Specific Interpersonal Problem-Solving and Suicidal Thoughts and Behaviors
Authors: Park Yeonsoo , McCloskey Michael S. , Ammerman Brooke A.
Published: August 2021

Abstract. Background: Interpersonal problem-solving difficulties constitute a suicide risk factor that may be particularly relevant among college students. Most studies have examined general interpersonal problem-solving; however, context-specific abilities may have greater clinical implications. Aim: This study examined whether individuals with and without a history of suicidal thoughts and behaviors differed in context-specific interpersonal problem-solving. Method: Undergraduate students ( n = 112) completed a brief interview and interpersonal problem-solving tasks with positive (e.g., initiating romantic relationship) and negative (i.e., physical revenge) resolutions. Results: Individuals with a history of suicide ideation generated more effective solutions and more alternatives in the negative-resolution scenario; no significant differences were identified for the positive-resolution scenarios. No group differences were found based on suicide attempt status. Limitations: Our results do not account for the mechanisms that influence problem-solving abilities in negative-resolution scenarios. Conclusion: Clinical efforts may benefit from targeting the translation of interpersonal problem-solving abilities to situations with positive resolutions.
Pet Attachment and the Interpersonal Theory of Suicide
Authors: Douglas Valerie J. , Kwan Mun Yee , Gordon Kathryn H.
Published: August 2021

Abstract. Background: Pet ownership is often assumed to have mental health benefits, but the effect of pets on suicide risk has a scant literature. Aims: Using the interpersonal theory of suicide, we examined the relationships between perceived burdensomeness (PB), thwarted belongingness (TB), overall attachment to one's pet, pet attachment avoidance or anxiety, and suicide risk. The following three hypotheses were investigated: (1) Higher attachment would be indirectly associated with lower suicide risk via lower TB and lower PB; (2) attachment would be associated with higher suicide risk, as conditioned on attachment avoidance/anxiety; and (3) attachment avoidance/anxiety would be associated with higher suicide risk via higher TB/PB. Method: Undergraduates ( N = 187) completed surveys, and indirect effect and conditional effect analyses were utilized. Results: Overall attachment was associated with lower PB, which was associated with lower suicide risk. The relationship between overall attachment and suicide risk was not conditional upon attachment anxiety/avoidance. Attachment avoidance was associated with increased levels of TB, which was associated with increased suicide risk. Attachment anxiety was associated with increased suicide risk via TB and PB. Limitations: We used a university sample that had limited access to pets. Conclusions: Findings suggest that pet ownership may provide mixed associations with suicide risk.
PM2.5 Influence on Urban Heat Island (UHI) Effect in Beijing and the Possible Mechanisms
Authors: Yang Guowei , Ren Guoyu , Zhang Panfeng , Xue Xiaoying , Tysa Suonam Kealdrup , Jia Wenqian , Qin Yun , Zheng Xiang , Zhang Siqi
Published: August 2021

Whether the urban heat island (UHI) is affected by air pollution in urban areas has attracted much attention. By analyzing the observation data of automatic weather stations and environmental monitoring stations in Beijing from 2016 to 2018, we found a seasonally dependent interlink of the UHI intensity (UHII) and PM2.5 concentration in urban areas. PM2.5 pollution weakens the UHII in summer and winter night, but strengthens it during winter daytime. The correlation between the UHI and PM2.5 concentration has been regulated by the interaction of aerosol with radiation, evaporation and planetary boundary layer (PBL) height. The former two change the surface energy balance via sensible and latent heat fluxes, while the latter affects atmospheric stability and energy exchange. In summer daytime, aerosol‐radiation interaction plays an important role, and the energy balance in urban areas is more sensitive to PM2.5 concentration than in rural areas, thereby weakening UHII. In winter daytime, aerosol‐PBL interaction is dominant, because aerosols lower the PBL height and stabilize atmosphere, weaken the heat exchange with the surrounding, with more heat accumulated in the urban areas and the increased UHII. Changes in evaporation and radiation strengthen the relationship. At night, the change of UHII more depends on the energy stored in the urban canopy. Aerosols effectively reduce the incident energy during daytime, and the long‐wave radiation from the buildings of urban canopy at night becomes less, leading to a weakened UHII. Our analysis results can improve the understanding of climate‐aerosols interaction in megacities like Beijing.
UK Ammonia Emissions Estimated With Satellite Observations and GEOS‐Chem
Authors: Marais Eloise A. , Pandey Alok K. , Van Damme Martin , Clarisse Lieven , Coheur Pierre‐François , Shephard Mark W. , Cady‐Pereira Karen E. , Misselbrook Tom , Zhu Lei , Luo Gan , Yu Fangqun
Published: August 2021

Agricultural emissions of ammonia (NH3) impact air quality, human health, and the vitality of aquatic and terrestrial ecosystems. In the UK, there are few direct policies regulating anthropogenic NH3 emissions and development of sustainable mitigation measures necessitates reliable emissions estimates. Here, we use observations of column densities of NH3 from two space‐based sensors (IASI and CrIS) with the GEOS‐Chem model to derive top‐down NH3 emissions for the UK at fine spatial (∼10 km) and time (monthly) scales. We focus on March‐September when there is adequate spectral signal to reliably retrieve NH3. We estimate total emissions of 272 Gg from IASI and 389 Gg from CrIS. Bottom‐up emissions are 27% less than IASI and 49% less than CrIS. There are also differences in seasonality. Top‐down and bottom‐up emissions agree on a spring April peak due to fertilizer and manure application, but there is also a comparable summer July peak in the top‐down emissions that is not in the bottom‐up emissions and appears to be associated with dairy cattle farming. We estimate relative errors in the top‐down emissions of 11%–36% for IASI and 9%–27% for CrIS, dominated by column density retrieval errors. The bottom‐up versus top‐down emissions discrepancies estimated in this work impact model predictions of the environmental damage caused by NH3 emissions and warrant further investigation.
Geology and Geochemistry of Noachian Bedrock and Alteration Events, Meridiani Planum, Mars: MER Opportunity Observations
Authors: Mittlefehldt David W. , Gellert Ralf , vanBommel Scott , Arvidson Raymond E. , Ashley James W. , Clark Benton C. , Crumpler Larry S. , Farrand William H. , Golombek Matthew P. , Grant John A. , Morris Richard V. , Schröder Christian
Published: August 2021

We have used Mars Exploration Rover Opportunity data to investigate the origin and alteration of lithic types along the western rim of Noachian‐aged Endeavour crater on Meridiani Planum. Two geologic units are identified along the rim: the Shoemaker and Matijevic formations. The Shoemaker formation consists of two types of polymict impact breccia: clast‐rich with coarser clasts in upper units; clast‐poor with smaller clasts in lower units. Comparisons with terrestrial craters show that the lower units represent more distal ejecta from at least two earlier impacts, and the upper units are proximal ejecta from Endeavour crater. Both are mixtures of target rocks of basaltic composition with subtle compositional variations caused by differences in post‐impact alteration. The Matijevic formation and lower Shoemaker units represent pre‐Endeavour geology, which we equate with the regional Noachian subdued cratered unit. An alteration style unique to these rocks is formation of smectite and Si‐ and Al‐rich vein‐like structures crosscutting outcrops. Post‐Endeavour alteration is dominated by sulfate formation. Rim‐crossing fracture zones include regions of alteration that produced Mg‐sulfates as a dominant phase, plausibly closely associated in time with the Endeavour impact. Calcium‐sulfate vein formation occurred over extended time, including before the Endeavour impact and after the Endeavour rim had been substantially degraded, likely after deposition of the Burns formation that surrounds and embays the rim. Differences in Mg, Ca and Cl concentrations on rock surfaces and interiors indicate that mobilization of salts by transient water has occurred recently and may be ongoing.
Modeling Terrestrial Dissolved Organic Carbon Loading to Western Arctic Rivers
Authors: Rawlins Michael A. , Connolly Craig T. , McClelland James W.
Published: August 2021

The mobilization and land‐to‐ocean transfer of dissolved organic carbon (DOC) in Arctic watersheds is intricately linked with the region's climate and water cycle, and furthermore at risk of changes from climate warming and associated impacts. This study quantifies model‐simulated estimates of runoff, surface and active layer leachate DOC concentrations and loadings to western Arctic rivers, specifically for basins that drain into coastal waters between and including the Yukon and Mackenzie Rivers. Model validation leverages data from other field measurements, synthesis studies, and modeling efforts. The simulations effectively quantify DOC leaching in surface and subsurface runoff and broadly capture the seasonal cycle in DOC concentration and mass loadings reported from other studies that use river‐based measurements. A marked east‐west gradient in simulated spring and summer DOC concentrations of 24 drainage basins on the North Slope of Alaska is captured by the modeling, consistent with independent data derived from river sampling. Simulated loadings for the Mackenzie and Yukon show reasonable agreement with estimates of DOC export for annual totals and four of the six seasonal comparisons. Nearly equivalent loading occurs to rivers which drain north to the Beaufort Sea and west to the Bering and Chukchi Seas. The modeling framework provides a basis for understanding carbon export to coastal waters and for assessing impacts of hydrological cycle intensification and permafrost thaw with ongoing warming in the Arctic.
YBX1 mediates translation of oncogenic transcripts to control cell competition in AML
Authors: Perner Florian , Schnoeder Tina M. , Xiong Yijun , Jayavelu Ashok Kumar , Mashamba Nomusa , Santamaria Nuria Tubio , Huber Nicolas , Todorova Kristina , Hatton Charles , Perner Birgit , Eifert Theresa , Murphy Ciara , Hartmann Maximilian , Hoell Jessica I. , Schröder Nicolas , Brandt Sabine , Hochhaus Andreas , Mertens Peter R. , Mann Matthias , Armstrong Scott A. , Mandinova Anna , Heidel Florian H.
Published: August 2021

Persistence of malignant clones is a major determinant of adverse outcome in patients with hematologic malignancies. Despite the fact that the majority of patients with acute myeloid leukemia (AML) achieve complete remission after chemotherapy, a large proportion of them relapse as a result of residual malignant cells. These persistent clones have a competitive advantage and can re-establish disease. Therefore, targeting strategies that specifically diminish cell competition of malignant cells while leaving normal cells unaffected are clearly warranted. Recently, our group identified YBX1 as a mediator of disease persistence in JAK2-mutated myeloproliferative neoplasms. The role of YBX1 in AML, however, remained so far elusive. Here, inactivation of YBX1 confirms its role as an essential driver of leukemia development and maintenance. We identify its ability to amplify the translation of oncogenic transcripts, including MYC, by recruitment to polysomal chains. Genetic inactivation of YBX1 disrupts this regulatory circuit and displaces oncogenic drivers from polysomes, with subsequent depletion of protein levels. As a consequence, leukemia cells show reduced proliferation and are out-competed in vitro and in vivo, while normal cells remain largely unaffected. Collectively, these data establish YBX1 as a specific dependency and therapeutic target in AML that is essential for oncogenic protein expression.
The deubiquitinase USP15 modulates cellular redox and is a therapeutic target in acute myeloid leukemia
Authors: Niederkorn Madeline , Ishikawa Chiharu , M. Hueneman Kathleen , Bartram James , Stepanchick Emily , R. Bennett Joshua , E. Culver-Cochran Ashley , Bolanos Lyndsey C. , Uible Emma , Choi Kwangmin , Wunderlich Mark , Perentesis John P. , M. Chlon Timothy , Filippi Marie-Dominique , Starczynowski Daniel T.
Published: August 2021

Ubiquitin-specific peptidase 15 (USP15) is a deubiquitinating enzyme implicated in critical cellular and oncogenic processes. We report that USP15 mRNA and protein are overexpressed in human acute myeloid leukemia (AML) as compared to normal hematopoietic progenitor cells. This high expression of USP15 in AML correlates with KEAP1 protein and suppression of NRF2. Knockdown or deletion of USP15 in human and mouse AML models significantly impairs leukemic progenitor function and viability and de-represses an antioxidant response through the KEAP1-NRF2 axis. Inhibition of USP15 and subsequent activation of NRF2 leads to redox perturbations in AML cells, coincident with impaired leukemic cell function. In contrast, USP15 is dispensable for human and mouse normal hematopoietic cells in vitro and in vivo. A preclinical small-molecule inhibitor of USP15 induced the KEAP1-NRF2 axis and impaired AML cell function, suggesting that targeting USP15 catalytic function can suppress AML. Based on these findings, we report that USP15 drives AML cell function, in part, by suppressing a critical oxidative stress sensor mechanism and permitting an aberrant redox state. Furthermore, we postulate that inhibition of USP15 activity with small molecule inhibitors will selectively impair leukemic progenitor cells by re-engaging homeostatic redox responses while sparing normal hematopoiesis.
Verification of immunology-related genetic associations in BPD supports ABCA3 and five other genes
Authors: Blume Felix , Kirsten Holger , Ahnert Peter , Chakraborty Trinad , Gross Arnd , Horn Katrin , Toliat Mohammad Reza , Nürnberg Peter , Westenfelder Eva-Maria , Goepel Wolfgang , Scholz Markus
Published: August 2021

Background

Inflammatory processes are key drivers of bronchopulmonary dysplasia (BPD), a chronic lung disease in preterm infants. In a large sample, we verify previously reported associations of genetic variants of immunology-related genes with BPD.

Methods

Preterm infants with a gestational age ≤32 weeks from PROGRESS and the German Neonatal Network (GNN) were included. Through a consensus case/control definition, 278 BPD cases and 670 controls were identified. We identified 49 immunity-related genes and 55 single-nucleotide polymorphisms (SNPs) previously associated with BPD through a comprehensive literature survey. Additionally, a quantitative genetic association analysis regarding oxygen supplements, mechanical ventilation, and continuous positive air pressure (CPAP) was performed.

Results

Five candidate SNPs were nominally associated with BPD-related phenotypes with effect directions not conflicting the original studies: rs11265269-CRP, rs1427793-NUAK1, rs2229569-SELL, rs1883617-VNN2, and rs4148913-CHST3. Four of these genes are involved in cell adhesion. Extending our analysis to all well-imputed SNPs of all candidate genes, the strongest association was rs45538638-ABCA3 with CPAP (p = 4.9 × 10−7, FDR = 0.004), an ABC transporter involved in surfactant formation.

Conclusions

Most of the previously reported associations could not be replicated. We found additional support for SNPs in CRP, NUAK1, SELL, VNN2, and ABCA3. Larger studies and meta-analyses are required to corroborate these findings.

Impact

Larger cohort for improved statistical power to detect genetic associations with bronchopulmonary dysplasia (BPD).

Most of the previously reported genetic associations with BPD could not be replicated in this larger study.

Among investigated immunological relevant candidate genes, additional support was found for variants in genes CRP, NUAK1, SELL, VNN2, and CHST3, four of them related to cell adhesion.

rs45538638 is a novel candidate SNP in reported candidate gene ABC-transporter ABCA3.

Results help to prioritize molecular candidate pathomechanisms in follow-up studies.
Review of patient-reported outcomes in multiple myeloma registrational trials: highlighting areas for improvement
Authors: Fernandes Laura L. , Zhou Jiaxi , Kanapuru Bindu , Horodniceanu Erica , Gwise Thomas , Kluetz Paul G. , Bhatnagar Vishal
Published: August 2021

Over the past 13 years, there have been advances in characterizing the patient experience in oncology trials, primarily using patient-reported outcomes (PROs). This review aims to provide details on the PRO measures and analyses used in multiple myeloma (MM) registrational trials. We identified registrational trials supporting MM indications from 2007 to 2020 from FDA databases. Trial protocols, statistical analysis plans, and clinical study reports were reviewed for PRO measures used, collection methods, statistical analyses, baseline and instrument completion definitions, and thresholds for clinical meaningfulness. Twenty-five trials supporting 20 MM indications were identified; 17 (68%) contained submitted PRO data. Of the 17 trials, 14 were randomized controlled trials and the remainder were single-arm trials. All but one trial were open label trials. Seven trials collected data electronically and five in paper format. The majority of trials evaluated at least two PRO measures (82%) with two trials (12%) utilizing four measures. Nine unique PRO measures were used, most commonly the EORTC QLQ-30 (87%), EQ-5D (65%), and QLQ-MY20 (47%). All 17 (100%) trials provided descriptive summaries, 10 (59%) carried out longitudinal mixed model analysis, 9 (53%) conducted responder analysis, and 2 (12%) did a basic inferential test. We noted substantial heterogeneity in terms of PRO collection methods, measures, definitions, and analyses, which may hinder the ability to effectively capture and interpret patient experience in future MM clinical trials. Further research is needed to determine the most appropriate approaches for statistical and analytical methodologies for PRO data in MM trials.
Combined effects of hyperthermia and chemotherapy on the regulate autophagy of oral squamous cell carcinoma cells under a hypoxic microenvironment
Authors: Shi Fan , Luo Dan , Zhou Xuexiao , Sun Qiaozhen , Shen Pei , Wang Shengzhi
Published: August 2021

Autophagy has a complex dual role in tumor survival or cell death owning to that is an evolutionarily conserved catabolic mechanism and provides the cells with a sustainable source of biomolecules and energy for the maintenance of homeostasis under stressful conditions such as tumor microenvironment. Hyperthermia is a rapidly growing field in cancer therapy and many advances have been made in understanding and applying the mechanisms of hyperthermia. The shallow oral and maxillofacial position and its abundant blood supply are favorable for the use of hyperthermia. However, the relationship between hyperthermia and autophagy has not been examined of oral squamous cell carcinoma (OSCC) in the tumor hypoxia microenvironment. Here, the expression level of autophagy relative genes is examined to explore autophagy effect on the responses of hyperthermia, hypoxia, and innutrition tumor microenvironment. It is founded that hyperthermia and hypoxia cause autophagy in starvation conditions; further, in hypoxia and innutrition tumor microenvironment, hyperthermia combines YC-1 and 3-MA could inhibit HIF-1α/BNIP3/Beclin1 signal pathway and decrease the secretion of HMGB1; moreover, the cell apoptosis rate increases with an inhibited of cell migration capacity. Thus, the present study demonstrated that combined use of YC-1 and 3-MA might increase the death of tumor cells in physiological and hyperthermic conditions, which could be relevant with the inhibition of autophagy in OSCC tumor cells under hypoxia microenvironment in vitro, which offers new insight into the therapy of OSCC and its application in treating others study carcinomas.
Autologous transplantation of thecal stem cells restores ovarian function in nonhuman primates
Authors: Chen Hong , Xia Kai , Huang Weijun , Li Huijian , Wang Chao , Ma Yuanchen , Chen Jianhui , Luo Peng , Zheng Shuwei , Wang Jiancheng , Wang Yi , Dong Lin , Tan Zhipeng , Lai Xingqiang , Mao Frank Fuxiang , Li Weiqiang , Liang Xiaoyan , Wang Tao , Xiang Andy Peng , Ke Qiong
Published: August 2021

Premature ovarian insufficiency (POI) is defined as the loss of ovarian activity under the age of 40. Theca cells (TCs) play a vital role during folliculogenesis and TCs dysfunction participate in the pathogenesis of POI. Therefore, transplantation of thecal stem cells (TSCs), which are capable of self-renewal and differentiation into mature TCs, may provide a new strategy for treating POI. To investigate the feasibility, safety, and efficacy of TSCs transplantation in clinically relevant non-human primate (NHP) models, we isolate TSCs from cynomolgus monkeys, and these cells are confirmed to expand continuously and show potential to differentiate into mature TCs. In addition, engraftment of autologous TSCs into POI monkeys significantly improves hormone levels, rescues the follicle development, promotes the quality of oocytes and boosts oocyte maturation/fertilization rate. Taken together, these results for the first time suggest that autologous TSCs can ameliorate POI symptoms in primate models and shed new light on developing stem cell therapy for POI.
Acquisition of aneuploidy drives mutant p53-associated gain-of-function phenotypes
Authors: Redman-Rivera Lindsay N. , Shaver Timothy M. , Jin Hailing , Marshall Clayton B. , Schafer Johanna M. , Sheng Quanhu , Hongo Rachel A. , Beckermann Kathryn E. , Wheeler Ferrin C. , Lehmann Brian D. , Pietenpol Jennifer A.
Published: August 2021

p53 is mutated in over half of human cancers. In addition to losing wild-type (WT) tumor-suppressive function, mutant p53 proteins are proposed to acquire gain-of-function (GOF) activity, leading to novel oncogenic phenotypes. To study mutant p53 GOF mechanisms and phenotypes, we genetically engineered non-transformed and tumor-derived WT p53 cell line models to express endogenous missense mutant p53 (R175H and R273H) or to be deficient for p53 protein (null). Characterization of the models, which initially differed only by TP53 genotype, revealed that aneuploidy frequently occurred in mutant p53-expressing cells. GOF phenotypes occurred clonally in vitro and in vivo, were independent of p53 alteration and correlated with increased aneuploidy. Further, analysis of outcome data revealed that individuals with aneuploid-high tumors displayed unfavorable prognoses, regardless of the TP53 genotype. Our results indicate that genetic variation resulting from aneuploidy accounts for the diversity of previously reported mutant p53 GOF phenotypes.
Neural signatures of hyperdirect pathway activity in Parkinson’s disease
Authors: Oswal Ashwini , Cao Chunyan , Yeh Chien-Hung , Neumann Wolf-Julian , Gratwicke James , Akram Harith , Horn Andreas , Li Dianyou , Zhan Shikun , Zhang Chao , Wang Qiang , Zrinzo Ludvic , Foltynie Tom , Limousin Patricia , Bogacz Rafal , Sun Bomin , Husain Masud , Brown Peter , Litvak Vladimir
Published: August 2021

Parkinson’s disease (PD) is characterised by the emergence of beta frequency oscillatory synchronisation across the cortico-basal-ganglia circuit. The relationship between the anatomy of this circuit and oscillatory synchronisation within it remains unclear. We address this by combining recordings from human subthalamic nucleus (STN) and internal globus pallidus (GPi) with magnetoencephalography, tractography and computational modelling. Coherence between supplementary motor area and STN within the high (21–30 Hz) but not low (13-21 Hz) beta frequency range correlated with ‘hyperdirect pathway’ fibre densities between these structures. Furthermore, supplementary motor area activity drove STN activity selectively at high beta frequencies suggesting that high beta frequencies propagate from the cortex to the basal ganglia via the hyperdirect pathway. Computational modelling revealed that exaggerated high beta hyperdirect pathway activity can provoke the generation of widespread pathological synchrony at lower beta frequencies. These findings suggest a spectral signature and a pathophysiological role for the hyperdirect pathway in PD.
Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma
Authors: Frontzek Fabian , Staiger Annette M. , Zapukhlyak Myroslav , Xu Wendan , Bonzheim Irina , Borgmann Vanessa , Sander Philip , Baptista Maria Joao , Heming Jan-Niklas , Berning Philipp , Wullenkord Ramona , Erdmann Tabea , Lutz Mathias , Veratti Pia , Ehrenfeld Sophia , Wienand Kirsty , Horn Heike , Goodlad John R. , Wilson Matthew R. , Anagnostopoulos Ioannis , Lamping Mario , Gonzalez-Barca Eva , Climent Fina , Salar Antonio , Castellvi Josep , Abrisqueta Pau , Menarguez Javier , Aldamiz Teresa , Richter Julia , Klapper Wolfram , Tzankov Alexandar , Dirnhofer Stefan , Rosenwald Andreas , Mate José Luis , Tapia Gustavo , Lenz Peter , Miething Cornelius , Hartmann Wolfgang , Chapuy Björn , Fend Falko , Ott German , Navarro José-Tomas , Grau Michael , Lenz Georg
Published: August 2021

Plasmablastic lymphoma (PBL) represents a rare and aggressive lymphoma subtype frequently associated with immunosuppression. Clinically, patients with PBL are characterized by poor outcome. The current understanding of the molecular pathogenesis is limited. A hallmark of PBL represents its plasmacytic differentiation with loss of B-cell markers and, in 60% of cases, its association with Epstein-Barr virus (EBV). Roughly 50% of PBLs harbor aMYCtranslocation. Here, we provide a comprehensive integrated genomic analysis using whole exome sequencing (WES) and genome-wide copy number determination in a large cohort of 96 primary PBL samples. We identify alterations activating the RAS-RAF, JAK-STAT, and NOTCH pathways as well as frequent high-level amplifications inMCL1andIRF4. The functional impact of these alterations is assessed using an unbiased shRNA screen in a PBL model. These analyses identify the IRF4 and JAK-STAT pathways as promising molecular targets to improve outcome of PBL patients.
B-SOiD, an open-source unsupervised algorithm for identification and fast prediction of behaviors
Authors: Hsu Alexander I. , Yttri Eric A.
Published: August 2021

Studying naturalistic animal behavior remains a difficult objective. Recent machine learning advances have enabled limb localization; however, extracting behaviors requires ascertaining the spatiotemporal patterns of these positions. To provide a link from poses to actions and their kinematics, we developed B-SOiD - an open-source, unsupervised algorithm that identifies behavior without user bias. By training a machine classifier on pose pattern statistics clustered using new methods, our approach achieves greatly improved processing speed and the ability to generalize across subjects or labs. Using a frameshift alignment paradigm, B-SOiD overcomes previous temporal resolution barriers. Using only a single, off-the-shelf camera, B-SOiD provides categories of sub-action for trained behaviors and kinematic measures of individual limb trajectories in any animal model. These behavioral and kinematic measures are difficult but critical to obtain, particularly in the study of rodent and other models of pain, OCD, and movement disorders.
Predicting post-operative right ventricular failure using video-based deep learning
Authors: Shad Rohan , Quach Nicolas , Fong Robyn , Kasinpila Patpilai , Bowles Cayley , Castro Miguel , Guha Ashrith , Suarez Erik E. , Jovinge Stefan , Lee Sangjin , Boeve Theodore , Amsallem Myriam , Tang Xiu , Haddad Francois , Shudo Yasuhiro , Woo Y. Joseph , Teuteberg Jeffrey , Cunningham John P. , Langlotz Curtis P. , Hiesinger William
Published: August 2021

Despite progressive improvements over the decades, the rich temporally resolved data in an echocardiogram remain underutilized. Human assessments reduce the complex patterns of cardiac wall motion, to a small list of measurements of heart function. All modern echocardiography artificial intelligence (AI) systems are similarly limited by design – automating measurements of the same reductionist metrics rather than utilizing the embedded wealth of data. This underutilization is most evident where clinical decision making is guided by subjective assessments of disease acuity. Predicting the likelihood of developing post-operative right ventricular failure (RV failure) in the setting of mechanical circulatory support is one such example. Here we describe a video AI system trained to predict post-operative RV failure using the full spatiotemporal density of information in pre-operative echocardiography. We achieve an AUC of 0.729, and show that this ML system significantly outperforms a team of human experts at the same task on independent evaluation.
Large uncertainties in trends of energy demand for heating and cooling under climate change
Authors: Deroubaix Adrien , Labuhn Inga , Camredon Marie , Gaubert Benjamin , Monerie Paul-Arthur , Popp Max , Ramarohetra Johanna , Ruprich-Robert Yohan , Silvers Levi G. , Siour Guillaume
Published: August 2021

The energy demand for heating and cooling buildings is changing with global warming. Using proxies of climate-driven energy demand based on the heating and cooling Degree-Days methodology applied to thirty global climate model simulations, we show that, over all continental areas, the climate-driven energy demand trends for heating and cooling were weak, changing by less than 10% from 1950 to 1990, but become stronger from 1990 to 2030, changing by more than 10%. With the multi-model mean, the increasing trends in cooling energy demand are more pronounced than the decreasing trends in heating. The changes in cooling, however, are highly variable depending on individual simulations, ranging from a few to several hundred percent in most of the densely populated mid-latitude areas. This work presents an example of the challenges that accompany future energy demand quantification as a result of the uncertainty in the projected climate.
Synergistic targeting of BRCA1 mutated breast cancers with PARP and CDK2 inhibition
Authors: Aziz Diar , Portman Neil , Fernandez Kristine J. , Lee Christine , Alexandrou Sarah , Llop-Guevara Alba , Phan Zoe , Yong Aliza , Wilkinson Ashleigh , Sergio C. Marcelo , Ferraro Danielle , Etemadmoghadam Dariush , Bowtell David D. ,   kConFab Investigators, Serra Violeta , Waring Paul , Lim Elgene , Caldon C. Elizabeth
Published: August 2021

Basal-like breast cancers (BLBC) are aggressive breast cancers that respond poorly to targeted therapies and chemotherapies. In order to define therapeutically targetable subsets of BLBC we examined two markers: cyclin E1 and BRCA1 loss. In high grade serous ovarian cancer (HGSOC) these markers are mutually exclusive, and define therapeutic subsets. We tested the same hypothesis for BLBC. Using a BLBC cohort enriched for BRCA1 loss, we identified convergence between BRCA1 loss and high cyclin E1 protein expression, in contrast to HGSOC in which CCNE1 amplification drives increased cyclin E1. In cell lines, BRCA1 loss was associated with stabilized cyclin E1 during the cell cycle, and BRCA1 siRNA led to increased cyclin E1 in association with reduced phospho-cyclin E1 T62. Mutation of cyclin E1 T62 to alanine increased cyclin E1 stability. We showed that tumors with high cyclin E1/BRCA1 mutation in the BLBC cohort also had decreased phospho-T62, supporting this hypothesis. Since cyclin E1/CDK2 protects cells from DNA damage and cyclin E1 is elevated in BRCA1 mutant cancers, we hypothesized that CDK2 inhibition would sensitize these cancers to PARP inhibition. CDK2 inhibition induced DNA damage and synergized with PARP inhibitors to reduce cell viability in cell lines with homologous recombination deficiency, including BRCA1 mutated cell lines. Treatment of BRCA1 mutant BLBC patient-derived xenograft models with combination PARP and CDK2 inhibition led to tumor regression and increased survival. We conclude that BRCA1 status and high cyclin E1 have potential as predictive biomarkers to dictate the therapeutic use of combination CDK inhibitors/PARP inhibitors in BLBC.
Superpixel image segmentation of VISTA expression in colorectal cancer and its relationship to the tumoral microenvironment
Authors: Wu Dongling , Hacking Sean , Vitkovski Taisia , Nasim Mansoor
Published: August 2021

Colorectal cancer (CRC) is the third most common cause of cancer related death in the United States (Jasperson et al. in Gastroenterology 138:2044–2058, https://doi.org/10.1053/j.gastro.2010.01.054, 2010). Many studies have explored prognostic factors in CRC. Today, much focus has been placed on the tumor microenvironment, including different immune cells and the extracellular matrix (ECM). The present study aims to evaluate the role of V-domain immunoglobulin suppressor of T cell activation (VISTA). We utilized QuPath for whole slides image analysis, performing superpixel image segmentation (SIS) on a 226 patient-cohort. High VISTA expression correlated with better disease-free survival (DFS), high tumor infiltrative lymphocyte, microsatellite instability, BRAF mutational status as well as lower tumor stage. High VISTA expression was also associated with mature stromal differentiation (SD). When cohorts were separated based on SD and MMR, only patients with immature SD and microsatellite stability were found to correlate VISTA expression with DFS. Considering raised VISTA expression is associated with improved survival, TILs, mature SD, and MMR in CRC; careful, well-designed clinical trials should be pursued which incorporate the underlying tumoral microenvironment.
The RhoA dependent anti-metastatic function of RKIP in breast cancer
Authors: Kalpana Gardiyawasam , Figy Christopher , Feng Jingwei , Tipton Claire , De Castro Julius N. , Bach Vu N. , Borile Clariza , LaSalla Alexandria , Odeh Hussain N. , Yeung Miranda , Garcia-Mata Rafael , Yeung Kam C.
Published: August 2021

Raf-1 kinase inhibitor protein was initially discovered as a physiological kinase inhibitor of the MAPK signaling pathway and was later shown to suppress cancer cell invasion and metastasis. Yet, the molecular mechanism through which RKIP executes its effects is not completely defined. RhoA has both a pro- and anti-metastatic cell-context dependent functions. Given that Rho GTPases primarily function on actin cytoskeleton dynamics and cell movement regulation, it is possible that one way RKIP hinders cancer cell invasion/metastasis is by targeting these proteins. Here we show that RKIP inhibits cancer cell invasion and metastasis by stimulating RhoA anti-tumorigenic functions. Mechanistically, RKIP activates RhoA in an Erk2 and GEF-H1 dependent manner to enhance E-cadherin membrane localization and inhibit CCL5 expression.
Risk-factors for re-admission and outcome of patients hospitalized with confirmed COVID-19
Authors: Green Hefziba , Yahav Dafna , Eliakim-Raz Noa , Karny-Epstein Nitzan , Kushnir Shiri , Shochat Tzippy , Tadmor Boaz , Grossman Alon
Published: August 2021

Burden of COVID-19 on Hospitals across the globe is enormous and has clinical and economic implications. In this retrospective study including consecutive adult patients with confirmed SARS-CoV-2 who were admitted between 3/2020 and 30/9/20, we aimed to identify post-discharge outcomes and risk factors for re-admission among COVID-19 hospitalized patients. Mortality and re-admissions were documented for a median post discharge follow up of 59 days (interquartile range 28,161). Univariate and multivariate analyses of risk factors for re-admission were performed. Overall, 618 hospitalized COVID-19 patients were included. Of the 544 patient who were discharged, 10 patients (1.83%) died following discharge and 50 patients (9.2%) were re-admitted. Median time to re-admission was 7 days (interquartile range 3, 24). Oxygen saturation or treatment prior to discharge were not associated with re-admissions. Risk factors for re-admission in multivariate analysis included solid organ transplantation (hazard ratio [HR] 3.37, 95% confidence interval [CI] 2.73–7.5, p = 0.0028) and higher Charlson comorbidity index (HR 1.34, 95% CI 1.23–1.46, p < 0.0001). Mean age of post discharge mortality cases was 85.0 (SD 9.98), 80% of them had cognitive decline or needed help in ADL at baseline. In conclusion, re-admission rates of hospitalized COVID-19 are fairly moderate. Predictors of re-admission are non-modifiable, including baseline comorbidities, rather than COVID-19 severity or treatment.
Prior intracerebral hemorrhage and white matter hyperintensity burden on recurrent stroke risk
Authors: Park Jong-Ho , Kwon Sun U. , Kwon Hyuk Sung , Heo Sung Hyuk
Published: August 2021

Prior intracerebral hemorrhage (ICH) is associated with increased risk of ischemic stroke. Since white matter hyperintensity (WMH) is associated with ischemic stroke and ICH, this study aimed to evaluate the relationship between ICH and the risk of recurrent stroke by WMH severity. From a prospective multicenter database comprising 1454 noncardioembolic stroke patients with cerebral small-vessel disease, patients were categorized by presence or absence of prior ICH and WMH severity: mild-moderate WMH (reference); advanced WMH; ICH with mild-moderate WMH; and ICH with advanced WMH. Among patients with ICH, the association with stroke outcomes by WMH burden was further assessed. The primary endpoint was ischemic stroke and hemorrhagic stroke. The secondary endpoint was major adverse cardiovascular events (MACE): stroke/coronary heart disease/vascular death. During the mean 1.9-year follow-up period, the ischemic stroke incidence rate per 100 person-years was 2.7, 4.0, 2.5, and 8.1 in increasing severity, and the rate of hemorrhagic stroke was 0.7, 1.3, 0.6, and 2.1, respectively. The risk of ischemic stroke was higher in ICH with advanced WMH (adjusted HR 2.62; 95% CI 1.22−5.60) than the reference group, while the risk of hemorrhagic stroke trended higher (3.75, 0.85–16.53). The risk of MACE showed a similar pattern in ICH with advanced WMH. Among ICH patients, compared with mild WMH, the risk of ischemic stroke trended to be higher in advanced WMH (HR 3.37; 95% CI 0.90‒12.61). Advanced WMH was independently associated with an increased risk of hemorrhagic stroke (HR 33.96; 95% CI 1.52−760.95). Given the fewer rate of hemorrhagic stroke, the risk of hemorrhagic stroke might not outweigh the benefits of antiplatelet therapy for secondary prevention.