bluuebunny/crossref_metadata_2025 huggingface dataset:
Cleavage of 14-3-3ε by the enteroviral 3C protease dampens RIG-I-mediated antiviral signaling
Authors: Andrews Daniel D. T. , Vlok Marli , Akbari Bani Dorssa , Hay Brenna N. , Mohamud Yasir , Foster Leonard J. , Luo Honglin , Overall Christopher M. , Jan Eric
Published: August 2023

Viruses have evolved diverse strategies to evade the host innate immune response and promote infection. The retinoic acid-inducible gene I (RIG-I)-like receptors RIG-I and MDA5 are antiviral factors that sense viral RNA and trigger downstream signal via mitochondrial antiviral-signaling protein (MAVS) to activate type I interferon expression. 14-3-3ε is a key component of the RIG-I translocon complex that interacts with MAVS at the mitochondrial membrane; however, the exact role of 14-3-3ε in this pathway is not well understood. In this study, we demonstrate that 14-3-3ε is a direct substrate of both the poliovirus and coxsackievirus B3 (CVB3) 3C proteases (3C
pro
) and that it is cleaved at Q236↓G237, resulting in the generation of N- and C-terminal fragments of 27.0 and 2.1 kDa, respectively. While the exogenous expression of wild-type 14-3-3ε enhances
IFNB
mRNA production during poly(I:C) stimulation, expression of the truncated N-terminal fragment does not. The N-terminal 14-3-3ε fragment does not interact with RIG-I in co-immunoprecipitation assays, nor can it facilitate RIG-I translocation to the mitochondria. Probing the intrinsically disordered C-terminal region identifies key residues responsible for the interaction between 14-3-3ε and RIG-I. Finally, overexpression of the N-terminal fragment promotes CVB3 infection in mammalian cells. The strategic enterovirus 3C
pro
-mediated cleavage of 14-3-3ε antagonizes RIG-I signaling by disrupting critical interactions within the RIG-I translocon complex, thus contributing to evasion of the host antiviral response.

IMPORTANCE

Host antiviral factors work to sense virus infection through various mechanisms, including a complex signaling pathway known as the retinoic acid-inducible gene I (RIG-I)-like receptor pathway. This pathway drives the production of antiviral molecules known as interferons, which are necessary to establish an antiviral state in the cellular environment. Key to this antiviral signaling pathway is the small chaperone protein 14-3-3ε, which facilitates the delivery of a viral sensor protein, RIG-I, to the mitochondria. In this study, we show that the enteroviral 3C protease cleaves 14-3-3ε during infection, rendering it incapable of facilitating this antiviral response. We also find that the resulting N-terminal cleavage fragment dampens RIG-I signaling and promotes virus infection. Our findings reveal a novel viral strategy that restricts the antiviral host response and provides insights into the mechanisms underlying 14-3-3ε function in RIG-I antiviral signaling.
Complete genome sequence of the archetype bile acid 7α-dehydroxylating bacterium,
Clostridium scindens
VPI12708, isolated from human feces, circa 1980
Authors: Olivos Caicedo Kelly Yovani , Fernandez-Materan Francelys V. , Hernandez Alvaro G. , Daniel Steven L. , Alves Joao M. P. , Ridlon Jason M.
Published: August 2023

Clostridium scindens
strain VPI12708 serves as model organism to study bile acid 7α-dehydroxylating pathways. The closed circular genome of
C. scindens
VPI12708 was obtained by PacBio sequencing. The genome is composed of 3,983,052 bp, with 47.59% G + C, and 3,707 coding DNA sequences are predicted.
Draft genome sequence of
Limosilactobacillus reuteri,
isolated from human breast milk
Authors: Tyagi Akanksha , Yeon Su-Jung , Chelliah Ramachandran , Oh Deog-Hwan
Published: August 2023

Limosilactobacillus reuteri
is a lactic acid bacterium with several probiotic properties. Here, we present the draft genome sequence of
L. reuteri
isolated from human breast milk. The average genome size was estimated as 2,087,202 bp, with a guanine-cytosine (GC) content of 51.6%. GC content is the percentage of nitrogenous bases in a DNA or RNA molecule that are either guanine (G) or cytosine (C). De Man, Rogosa and Sharpe, often abbreviated to MRS, is a selective culture medium designed to favor the luxuriant growth of lactobacilli for lab study.
The process of crustal thickening in the southern Lhasa terrane during India-Eurasia collision: Constraint from Eocene high Sr/Y rocks in the Quxu pluton
Authors: Wang Zhenzhen , Zhao Zhidan , Li Xuping , Liu Dong , Mo Xuanxue , Zhu Di-Cheng , Meng Yuanku , Tang Yan , Cong Fuyun
Published: August 2023

The crustal thickening process is the key to understanding global tectonic evolution and climatic patterns. The Sr/Y, (La/Yb)N ratios of granitoids can be used to quantitatively estimate crustal thickness and reconstruct the crustal thickening process. We present the geochemical characteristics, petrogenesis, and geodynamic implications of Eocene dioritic enclaves (monzodiorite), host granitoid rocks (monzonite), and granite dikes of southern Tibet to reveal the crustal thickening process underway during the collision of India and Asia. The Quxu dioritic enclaves were produced by magma mixing and represent mafic end member. The adakitic host rocks were generated by partial melting of lower crust with normal thickness. The high Sr/Y, (La/Yb)N ratios of the Quxu host rocks were inherited from their magma source region. The ∼40% fractional crystallization of amphibole from magma resembling Quxu host rocks formed the Quxu granite dikes. The continuous crustal thickening history determined by the locally weighted regression analysis shows that the crustal thickness of the Lhasa terrane during 50−45 Ma was no more than 36−46 km, and the crust thickened quickly during the syn-collisional period.
Supplemental Material: Role of volatiles in intrusion emplacement and sulfide deposition in the supergiant Norilsk-Talnakh Ni-Cu-PGE ore deposits
Authors: Barnes Stephen J. , al. et
Published: August 2023

Geological map (regional and local geology) and stratigraphic column of Paleozoic sedimentary sequence and of the individual ore-hosting intrusions.  
Administrative professionals’ quality of life in educational institutions: a systematic review protocol
Authors: Pereira Nicolli Godoi , Silva Regina Márcia Ferreira , Oliveira Isabela Fernanda Rodrigues de , Fernandes Michele da Silva Valadão , Costa Woska Pires da , Vitta Alberto de , Noll Priscilla Rayanne E Silva , Noll Matias
Published: August 2023

Introduction

Indicators of administrative professionals’ quality of life (QoL) in educational institutions are essential for planning improvements in their daily lives. QoL is a recurring topic in academic research, particularly in the healthcare sector. Therefore, this study aims to evaluate the perceptions of administrative professionals in educational institutions regarding their QoL and the implications of remote and in-person work. Additionally, we aim to compare the QoL before, during and after the COVID-19 pandemic.

Methods and analysis

Five electronic databases will be searched for this systematic review: CINAHL, LILACS, PubMed, Scopus and Web of Science. Original, peer-reviewed articles published in any language, without time limitations, will be included in this study. Two researchers will screen the articles and extract the data. The included articles will be evaluated for the quality of their evidence using Grading of Recommendations, Assessment, Development and Evaluations. The risk of bias will be assessed using the Critical Appraisal Skills Programme checklist and the Downs and Black scale. A third reviewer will resolve any discrepancies.

Ethics and dissemination

The systematic review results will be published in a peer-reviewed journal and presented at a relevant conference. The data will not include individual patient data; therefore, ethical approval is not required.

PROSPERO registration number

CRD42022365862.
Effectiveness of a comprehensive tele-empowerment programme on self-care behaviours, uncertainty and readmission of patients with heart failure: protocol for a randomised controlled trial
Authors: Khanipour-Kencha Ali , Ghiyasvandian Shahrzad , Mohammadi Somaye , Khabazkhoob Mehdi , Mirshahi Arvin , Wells Rachel , Zakerimoghadam Masoumeh
Published: August 2023

Introduction

Heart failure (HF) as a long-term clinical syndrome is associated with inadequate self-care behaviours, a feeling of uncertainty and frequent hospitalisation. In recent years, empowerment has evolved for improving chronic disease management. Nevertheless, there is a lack of studies investigating remote care interventions such as a tele-empowerment programme in patients with HF. Therefore, this protocol proposes a randomised controlled trial which aims to evaluate the effectiveness of a comprehensive tele-empowerment programme on self-care behaviours, uncertainty and readmission in patients with HF.

Methods and analysis

The study is a double-arm and parallel-group randomised controlled trial in which a 10-week intervention, including 6 weeks of a comprehensive tele-empowerment programme and 4 weeks of follow-up, will be compared with usual care. A total of 96 eligible patients with HF will be recruited and randomly assigned to the intervention or control group. The patients in the intervention group will join virtual groups and receive the five-step tele-empowerment programme through the internet. The primary outcomes include self-care behaviours and uncertainty which will be measured with valid instruments at baseline and 10th week. The secondary outcome is the number of patients’ hospital readmissions and will be assessed at the end of the study. Descriptive statistics will be used to describe variables. According to the types of variables, appropriate statistical tests including two-sample t-tests, Χ2, analysis of covariance or linear regression will be performed. In addition, standardised intervention effect sizes will be calculated for each outcome.

Ethics and dissemination

The trial has been approved by the Research Ethics Committee of School of Nursing and Midwifery & Rehabilitation at Tehran University of Medical Sciences. In this study, written consent will be obtained from all participants. The results will be presented to representative groups and published in peer-reviewed journals.

Trial registration number

Iranian Registry of Clinical Trials (IRCT20100725004443N30).
Videos of simulated after action reviews: a training resource to support social and inclusive learning from patient safety events
Authors: McCarthy Siobhán E , Hogan Catherine , Jenkins Loretta , Schwanberg Lorraine , Williams David J , Mellon Lisa , Walsh Aisling , Keane Theresa , Rafter Natasha
Published: August 2023

Innovation in the education and training of healthcare staff is required to support complementary approaches to learning from patient safety and everyday events in healthcare. Debriefing is a commonly used learning tool in healthcare education but not in clinical practice. Little is known about how to implement debriefing as an approach to safety learning across a health system. After action review (AAR) is a debriefing approach designed to help groups come to a shared mental model about what happened, why it happened and to identify learning and improvement. This paper describes a digital-based implementation strategy adapted to the Irish healthcare system to promote AAR uptake. The digital strategy aims to assist implementation of national level incident management policies and was collaboratively developed by the RCSI University of Medicine and Health Sciences and the National Quality and Patient Safety Directorate of the Health Service Executive. During the COVID-19 pandemic, a well-established in-person AAR training programme was disrupted and this led to the development of a series of open access videos on AAR facilitation skills (which accompany the online version of this paper). These provide: (1) an introduction to the AAR facilitation process; (2) a simulation of a facilitated formal AAR; (3) techniques for handling challenging situations that may arise in an AAR and a (4) reflection on the benefits of the AAR process. These have the potential to be used widely to support learning from patient safety and everyday events including excellent care.
Balanced resuscitation and earlier mortality end points: bayesian post hoc analysis of the PROPPR trial
Authors: Lammers Daniel , Rokayak Omar , Uhlich Rindi , Sensing Thomas , Baird Emily , Richman Joshua , Holcomb John B , Jansen Jan
Published: August 2023

Introduction

The Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial failed to demonstrate a mortality difference for hemorrhaging patients receiving a balanced (1:1:1) vs a 1:1:2 resuscitation at 24 hours and 30 days. Recent guidelines recommend earlier mortality end points for hemorrhage-control trials, and the use of contemporary statistical methods. The aim of this post hoc analysis of the PROPPR trial was to evaluate the impact of a balanced resuscitation strategy at early resuscitation time points using a Bayesian analytical framework.

Methods

Bayesian hierarchical models were created to assess mortality differences at the 1, 3, 6, 12, 18, and 24 hours time points between study cohorts. Posterior probabilities and Bayes factors were calculated for each time point.

Results

A 1:1:1 resuscitation displayed a 96%, 99%, 94%, 92%, 96%, and 94% probability for mortality benefit at 1, 3, 6, 12, 18, and 24 hours, respectively, when compared with a 1:1:2 approach. Associated Bayes factors for each respective time period were 21.2, 142, 14.9, 11.4, 26.4, and 15.5, indicating ‘strong’ to ‘decisive’ supporting evidence in favor of balanced transfusions.

Conclusion

This analysis provides evidence in support that a 1:1:1 resuscitation has a high probability of mortality benefit when compared with a 1:1:2 strategy, especially at the newly defined more proximate time points during the resuscitative period. Researchers should consider using Bayesian approaches, along with more proximate end points when assessing hemorrhage-related mortality, for the analysis of future clinical trials.

Level of evidence

Level III/Therapeutic.
Cardiac autonomic modulation in individuals with controlled and uncomplicated hypertension during exercise-heat stress
Authors: Carrillo Andres E. , Akerman Ashley P. , Notley Sean R. , Herry Christophe L. , Seely Andrew J.E. , Ruzicka Marcel , Boulay Pierre , Kenny Glen P.
Published: August 2023

Impaired cardiac autonomic modulation is implicated in the development of hypertension. Exercise improves sympathovagal balance and is often prescribed for hypertension management. Environmental conditions, however, are not considered during the development of these exercise recommendations. We examined cardiac autonomic modulation, assessed using heart rate variability (HRV), in individuals (49–77 years) with ( n = 20) and without ( n = 28) controlled, uncomplicated hypertension performing three 30 min bouts of exercise (light, moderate, and vigorous) in dry heat (40.2 ± 0.3 °C, 17% ± 7% relative humidity), each separated by 15 min breaks. Regardless of intensity, short bouts of exercise-heat stress did not significantly disrupt HRV in physically active individuals with hypertension relative to normotensives.

Take-home message

During short bouts of light-to-vigorous exercise in the heat, controlled and uncomplicated hypertension did not significantly modulate HRV in physically active individuals. These findings can be used to refine guidance on use of exercise for hypertension management in the heat.
Biological extinction and photic-zone anoxia across the Triassic–Jurassic transition: insights from the Qiangtang Basin, eastern Tethys
Authors: Hu Fangzhi , Fu Xiugen , Wang Jian , Wei Hengye , Nie Ying , Zhang Jian , Tian Kangzhi
Published: August 2023

The end-Triassic mass extinction (ETME) is one of the five catastrophic extinction events. However, the driving mechanisms of biodiversity loss during this interval remain controversial. In this study, we investigate the marine sediment geochemistry and fauna across the Triassic–Jurassic boundary in the Wenquan section of Qiangtang Basin, and the triggering mechanism of the Late Triassic extinction in the eastern Tethys Ocean. Our study shows that the main pulse of the ETME occurred in Bed 8, manifesting as the disappearance of four brachiopod species, a significant decrease of other faunas, and the ‘Lilliput effect’ on bivalves. Analyses of pyrite framboids and redox-sensitive trace elements suggest the development of photic zone anoxia near the T/J boundary and coincident with the Late Triassic extinction. Thus, the development of abrupt and intense photic-zone anoxia could play an important role in the end-Triassic extinction.

Supplementary material:
Supplementary tables giving element contents and palaeontological data are available at
https://doi.org/10.6084/m9.figshare.c.6771606
An Efficient Transfer Learning Method with Auxiliary Information
Authors: Liu Bo , Li Liangjiao , Xiao Yanshan , Wang Kai , Hu Jian , Liu Junrui , Chen Qihang , Huang Ruiguang
Published: August 2023

Transfer learning (TL) is an information reuse learning tool, which can help us learn better classification effect than traditional single task learning, because transfer learning can share information within the task-to-task model. Most TL algorithms are studied in the field of data improvement, doing some data extraction and transformation. However, it ignores that existing the additional information to improve the model’s accuracy, like Universum samples in the training data with privileged information. In this article, we focus on considering prior data to improve the TL algorithm, and the additional features also called privileged information are incorporated into the learning to improve the learning paradigm. In addition, we also carry out the Universum samples which do not belong to any indicated categories into the transfer learning paradigm to improve the utilization of prior knowledge. We propose a new TL Model (PU-TLSVM), in which each task with corresponding privileged features and Universum data is considered in the proposed model, so as to apply tasks with a priori data to the training stage. Then, we use Lagrange duality theorem to optimize our model to obtain the optimal discriminant for target task classification. Finally, we make a lot of predictions and tests to compare the actual effectiveness of the proposed method with the previous methods. The experiment results indicate that the proposed method is more effective and robust than other baselines.
Low Resource Language Analysis Using Deep Learning Algorithm for Gender Classification
Authors: Singhal Abhishek , Sharma Devendra Kumar
Published: August 2023

Voice signals are the essential input source for applications based on human and computer interaction technology. Gender identification through voice signals is one of the most challenging tasks. For voice signal based analysis, deep learning algorithms provide an alternative to traditional and conventional algorithms for classification. To identify the gender through voice signals of female, male and ‘first-time’ transgender, the deep learning algorithm is used to improve the robustness of the identification model with the Mel Frequency Cepstrum Coefficients (MFCC) as a feature of the voice signals. This article presents the identification accuracy of gender with the help of recorded live voice signals. The voice samples of the third gender are recorded in the Hindi language. These Hindi language voice samples of transgender are very low resources and are unavailable at any recognized sources. The simulation results do not depend on the duration of the signals and are text independent. The recurrent neural network – Bidirectional Long Short-term Memory (RNN – BiLSTM) algorithm has been simulated on the recorded voice signals. The simulation outcome is compared with the earlier reported results in the literature. The gender-wise average accuracy of the proposed model is achieved as 91.44%, 94.94%, and 96.11% for males, females, and transgender, respectively, using voice signals. The identification accuracy of transgender is high in comparison to other genders. On the other hand, the average accuracy of the proposed model is obtained as 94.16%.
Impacts of Land Use and Land Cover Change on Vegetation Diversity of Tropical Highland in Ethiopia
Authors: Hussein Abdulbasit
Published: August 2023

Ethiopia has undergone a substantial shift in land use and land cover (LULC), which is home to the majority of the human and animal population. Land degradation has occurred in the Ethiopian highlands as a result of modifications in LULC caused by poor farming methods, high livestock population, and human pressures. Most researchers identified the many LULC drivers and their impact on floristic composition. All of these manifestations have the potential to have major consequences for land users and individuals whose livelihoods rely on the products of a healthy environment. This change in LULC type, combined with poor land management practices in Ethiopia, puts land in jeopardy of erosion, resulting in accelerated soil degradation. All LULC variables, such as the spread of various agricultural activities, the production of fuelwood and charcoal, cutting trees for construction resources, settlements, and revenue growth, are associated with population increase and resettlement. In Ethiopia, the lack of a relevant forest policy implementation on the ground is recognized as a cause pushing deforestation and other landscape changes. This review paper aimed to compile the effects of land use land cover changes on Ethiopian vegetation.
The Composite Autonomic Symptom Score 31 Questionnaire: A Sensitive Test to Detect Risk for Autonomic Neuropathy
Authors: Meling Sondre , Tjora Erling , Eichele Heike , Ejskjaer Niels , Carlsen Siri , Njølstad Pål Rasmus , Brock Christina , Søfteland Eirik
Published: August 2023

Background and Aims. Autonomic neuropathy is a common but often neglected complication of diabetes, prediabetes, and even in individuals with an elevated risk of diabetes. The Composite Autonomic Symptom Score (COMPASS) 31 is a validated and easy-to-use questionnaire regarding autonomic symptoms. We aimed to use a digitally, Norwegian version of the COMPASS 31 in people with different durations of diabetes and healthy controls to consider feasibility and to investigate if scores could discriminate between positive and negative outcomes for established tests for diabetic neuropathy, including cardiovascular autonomic neuropathy (CAN) and a novel method of examining the gastrointestinal visceral sensitivity. Method. We included 21 participants with longstanding type 2 diabetes, 15 with early type 2 diabetes, and 30 matched controls. The mean age for all groups was 69 years. Participants were phenotyped by cardiovascular autonomic reflex tests, electrical skin conductance, sural nerve electrophysiology, and the monofilament test. As a proxy for gastrointestinal visceral and autonomic nerve function, evoked potentials were measured following rapid rectal balloon distention. Results. Participants with longstanding diabetes scored a median (IQR) of 14.9 (10.8-28.7) points, early diabetes of 7.3 (1.6-15.2), and matched controls of 8.6 (4.1-21.6),

p
=
0.04

. Women and men scored 14.4 (5.5-28.7) and 7.8 (3.6-14.6) points, respectively,

p
=
0.01

. Participants with definite or borderline CAN scored 14.3 (10.4-31.9) points, compared to participants with no CAN, 8.3 (3.2-21.5),

p
=
0.04

. Lowering the diagnostic cut-off from 16 to 10 points increased the sensitivity from 0.33 to 0.83, with a decreased specificity from 0.68 to 0.55. Conclusion. We successfully used COMPASS 31 in Norwegian. Thus, following the guidelines, we suggest clinical implementation for the assessment of autonomic neuropathy. Participants with longstanding diabetes had an increased likelihood of symptoms and signs of autonomic neuropathy. For screening purposes, the sensitivity was improved by lowering the cut-off to 10 points, with a lower score nearly excluding the diagnosis.
External Genitalia Myiasis in a 40-Year-Old Woman
Authors: Mansouri Ghazal , Allahqoli Leila , Salehiniya Hamid , Alkatout Ibrahim
Published: August 2023

Human myiasis is an infestation produced by fly larvae invading the tissues. We present a case of a 40-year-old virgin woman with vulvar myiasis. She reported at the gynecology clinic with a bloody discharge, severe pain, and swelling of the genital area for six days. Her menstrual history revealed the use of folded clothes. She had no specific gynecological disease. At the examination of the external genitalia, a tender mass measuring

6
 
cm
×
4
 
cm

and an ulcer measuring

1
 
cm
×
1
 
cm

on the surface of the labia majora were found. The patient was hospitalized. Serology, blood, and urine tests were requested; all laboratory tests were normal. The patient was transferred to the operating room (OR) with the diagnosis of necrotizing fasciitis. In the OR, we performed a longitudinal incision on the mass and removed nearly 30 visible maggots. After washing with normal saline, the patient was transferred to the ward without wound suturing. Debridement of the necrotic vulvar mass along with daily washing was performed for 7 days. The wound was sutured on the seventh day at the OR. Antibiotic therapy was continued for 4 days, and the patient was discharged with normal laboratory tests on the eleventh day after admission. We believe that poor sanitary hygiene was the cause of vulvar myiasis in our patient. We conclude that appropriate measures must be taken to reduce the risk of human myiasis, especially in tropical rural regions.
Basal and Bolus Insulin Distribution According to Treatment Modality: Data from SWEET Diabetes Registry
Authors: Evin Ferda , Tittel Sascha R. , Piccini Barbara , Cardona-Hernandez Roque , Mul Dick , Sheanon Nicole , von dem Berge Thekla , Neuman Vit , Tauschmann Martin , Gökşen Damla
Published: August 2023

Background and Aims. The optimal basal and bolus insulin distribution in type 1 diabetes (T1D) is still controversial. Herein, we aimed to determine the variability of basal to total daily insulin dose according to treatment modality and diabetes technologies from the Better Control in Pediatric and Adolescent Diabetes: Working to Create Centers of Reference (SWEET) registry. Methods. The study cohort was generated by using the SWEET database. Patients with T1D for at least 2 years, aged between 2.5 and 18 years, with at least one clinic visit between June 2010 and June 2021, were included in the study. Four groups were composed according to treatment modality as follows: multiple daily injections (MDI) without continuous glucose monitoring (CGM); MDI with CGM; subcutaneous insulin infusion (CSII) without CGM; and CSII with CGM. Data of the participants were analyzed and compared for each treatment modality separately. Results. A total of 38,956 children and adolescents were included in the study. Of the study sample, 48.6% were female, the median (range) age was 15.2 (11.9–17.2) years, and the median diabetes duration was 6.0 (3.8–9.0) years. The distribution of treatment modality was as follows: MDI without CGM, 32.9%; MDI with CGM, 18.0%; CSII without CGM, 11.7%; and CSII with CGM, 37.3%. In unadjusted data, regardless of treatment modality, all the analyses revealed a significant association between basal dose to total daily insulin dose (BD/TDD) with male gender, younger age group, and lower HbA1c, which were all related to a decreased ratio of BD/TDD (all

p
<
0.05

). There was no association between BD/TDD and different diabetes technologies after the age, gender, and diabetes duration were adjusted. Conclusions. Herein, we showed that there was an association between lower proportions of basal to total insulin and lower hemoglobin A1c in a large cross-sectional cohort of children who had T1D. There was also an association between lower BD/TDD and younger age. There was no significant difference between BD/TDD ratios under different diabetes technologies (CGM and/or CSII).
Mini-Aortic Valve Replacement versus Transcatheter Aortic Valve Implantation: A Propensity-Matched Study
Authors: Monteagudo-Vela María , Monguió-Santín Emilio , de Antonio Antón Nieves , Aguirre Fernanda , Bernal Gallego Begoña , Reyes-Copa Guillermo , Panoulas Vasileios
Published: August 2023

Background. Total sternotomy for aortic valve replacement has been superseded by less invasive approaches such as mini-sternotomy or transcatheter procedures. There has been an exponential uptake in transcatheter aortic valve implantation (TAVI) in younger and lower risk patients following recent randomized trials. This study aims to compare the outcomes of patients with aortic stenosis treated with minimally invasive approaches: mini-sternotomy for aortic valve replacement (mini-AVR) and TAVI implantation. Methods. Between January 2015 and December 2021, a total of 1437 TAVI and 176 mini-AVR patients from 2 tertiary centers fulfilled the criteria and were included in the propensity matching model. Results. A total of 256 TAVIs and 146 mini-AVR were included in the matched cohort. There was no significant difference in 30-day mortality in the two groups (TAVI vs. mini-AVR 2.7% vs. 2.8%,

p
=
0.935

). TAVI confers slightly lower gradients in the follow-up echo when compared with mini-AVR (peak gradient 20 ± 8.7 mmHg vs. 24.5 ± 10 mmHg,

p
 
<
0.001

; mean gradient 10.9 ± 5.6 mmHg vs. 13.2 ± 5.7 mmHg,

p
<
0.001

). On the other hand, mini-AVR exhibits remarkably lower rates of paravalvular leak (mild leak 8% vs. 41.5%,

p
<
0.001

; moderate leak 2.8% vs. 0%,

p
<
0.001

) and of need for permanent pacemaker implantation (2% vs. 12.2%,

p
<
0.001

). Unsurprisingly, TAVI has lower in-hospital stay 3 (2 to 6) days vs. 10 (8 to 13) days,

p
<
0.001

). Conclusions. For eligible aortic stenosis patients in the 7th decade of life, mini-AVR remains an excellent therapeutic option.
Targeting BCL6 in Gastrointestinal Stromal Tumor Promotes p53-Mediated Apoptosis to Enhance the Antitumor Activity of Imatinib
Authors: Zeng Xiangyu , Zhao Fei , Jia Jie , Ma Xianxiong , Jiang Qi , Zhang Ruizhi , Li Chengguo , Wang Tao , Liu Weizhen , Hao Yalan , Tao Kaixiong , Lou Zhenkun , Zhang Peng
Published: August 2023

Imatinib mesylate (IM) has revolutionized the treatment of gastrointestinal stromal tumor (GIST). However, most patients inevitably acquire IM resistance. Second- and third-line treatments exhibit modest clinical benefits with a median time to disease progression of 4 to 6 months, highlighting the urgency for novel therapeutic approaches. Here, we report that the expression of BCL6, a known oncogenic driver and transcriptional repressor, was significantly induced in GIST cells following IM treatment. Elevated BCL6 levels suppressed apoptosis and contributed to IM resistance. Mechanistically, BCL6 recruited SIRT1 to the TP53 promoter to modulate histone acetylation and transcriptionally repress TP53 expression. The reduction in p53 subsequently attenuated cell apoptosis and promoted tolerance of GIST cells to IM. Concordantly, treatment of GIST cells showing high BCL6 expression with a BCL6 inhibitor, BI-3802, conferred IM sensitivity. Furthermore, BI-3802 showed striking synergy with IM in IM-responsive and IM-resistant GIST cells in vitro and in vivo. Thus, these findings reveal a role for BCL6 in IM resistance and suggest that a combination of BCL6 inhibitors and IM could be a potentially effective treatment for GIST.

Significance:

BCL6 drives resistance to imatinib by inhibiting p53-mediated apoptosis and can be targeted in combination with imatinib to synergistically suppress tumor growth, providing a therapeutic strategy for treating gastrointestinal stromal tumor.
Supplementary Table S5 from Racial and Ethnic Variation in Diagnostic Mammography Performance among Women Reporting a Breast Lump
Authors: Nyante Sarah J. , Abraham Linn , Aiello Bowles Erin J. , Lee Christoph I. , Kerlikowske Karla , Miglioretti Diana L. , Sprague Brian L. , Henderson Louise M.
Published: August 2023

Model-based comparisons of diagnostic mammography performance by race and ethnicity, among women with nonmissing data for all covariates
Data from Association between outdoor light at night and prostate cancer in the Health Professionals Follow-Up Study
Authors: Chowdhury-Paulino Ilkania M. , Hart Jaime E. , James Peter , Iyer Hari S. , Wilt Grete E. , Booker Benjamin D. , Nethery Rachel C. , Laden Francine , Mucci Lorelei A. , Markt Sarah C.
Published: August 2023

Abstract
Background: Circadian disruption is a potential risk factor for advanced prostate cancer, and light at night (LAN) exposure may disrupt circadian rhythms. We evaluated whether outdoor LAN increases the risk of prostate cancer.
Methods: We prospectively followed 49,148 participants in the Health Professionals Follow-up Study from 1986 through 2016. We estimated baseline and cumulative time-varying outdoor LAN with ~1 km2 resolution using data from the US Defense Meteorological Satellite Program’s Operational Linescan System, which was assigned to participants’ geocoded addresses. Participants reside in all 50 US states and reported a work or home address. We used multivariable Cox models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between outdoor LAN and risk of overall (7,175 cases) and fatal (915 cases) prostate cancer adjusting for individual and contextual factors.
Results: There was no association between the interquartile range increase in cumulative LAN and total (HR:1.02, 95% CI 0.98, 1.06) or fatal (HR: 1.05, 95% CI: 0.96, 1.15) prostate cancer in adjusted models. However, there was a positive association between baseline LAN and total prostate cancer among non-movers (HR: 1.06, 95% CI:1.00,1.14) including among highly screened participants (HR: 1.11, 95% CI:1.01,1.23).
Conclusions: There was a suggestive positive association between baseline outdoor LAN and total prostate cancer. Additional studies with different measures of outdoor LAN and in more diverse populations are necessary.
Impact: To our knowledge, this is the first longitudinal cohort study exploring the relationship between outdoor LAN and prostate cancer.
Data from Racial and Ethnic Variation in Diagnostic Mammography Performance among Women Reporting a Breast Lump
Authors: Nyante Sarah J. , Abraham Linn , Aiello Bowles Erin J. , Lee Christoph I. , Kerlikowske Karla , Miglioretti Diana L. , Sprague Brian L. , Henderson Louise M.
Published: August 2023

AbstractBackground:
We evaluated diagnostic mammography among women with a breast lump to determine whether performance varied across racial and ethnic groups.
Methods:
This study included 51,014 diagnostic mammograms performed between 2005 and 2018 in the Breast Cancer Surveillance Consortium among Asian/Pacific Islander (12%), Black (7%), Hispanic/Latina (6%), and White (75%) women reporting a lump. Breast cancers occurring within 1 year were ascertained from cancer registry linkages. Multivariable regression was used to adjust performance statistic comparisons for breast cancer risk factors, mammogram modality, demographics, additional imaging, and imaging facility.
Results:
Cancer detection rates were highest among Asian/Pacific Islander [per 1,000 exams, 84.2 (95% confidence interval (CI): 72.0–98.2)] and Black women [81.4 (95% CI: 69.4–95.2)] and lowest among Hispanic/Latina women [42.9 (95% CI: 34.2–53.6)]. Positive predictive values (PPV) were higher among Black [37.0% (95% CI: 31.2–43.3)] and White [37.0% (95% CI: 30.0–44.6)] women and lowest among Hispanic/Latina women [22.0% (95% CI: 17.2–27.7)]. False-positive results were most common among Asian/Pacific Islander women [per 1,000 exams, 183.9 (95% CI: 126.7–259.2)] and lowest among White women [112.4 (95% CI: 86.1–145.5)]. After adjustment, false-positive and cancer detection rates remained higher for Asian/Pacific Islander and Black women (vs. Hispanic/Latina and White). Adjusted PPV was highest among Asian/Pacific Islander women.
Conclusions:
Among women with a lump, Asian/Pacific Islander and Black women were more likely to have cancer detected and more likely to receive a false-positive result compared with White and Hispanic/Latina women.
Impact:
Strategies for optimizing diagnostic mammography among women with a lump may vary by racial/ethnic group, but additional factors that influence performance differences need to be identified.
Memory-like Differentiation, Tumor-Targeting mAbs, and Chimeric Antigen Receptors Enhance Natural Killer Cell Responses to Head and Neck Cancer
Authors: Jacobs Miriam T. , Wong Pamela , Zhou Alice Y. , Becker-Hapak Michelle , Marin Nancy D. , Marsala Lynne , Foster Mark , Foltz Jennifer A. , Cubitt Celia C. , Tran Jennifer , Russler-Germain David A. , Neal Carly , Kersting-Schadek Samantha , Chang Lily , Schappe Timothy , Pence Patrick , McClain Ethan , Zevallos Jose P. , Rich Jason T. , Paniello Randal C. , Jackson Ryan S. , Pipkorn Patrik , Adkins Douglas R. , DeSelm Carl J. , Berrien-Elliott Melissa M. , Puram Sidharth V. , Fehniger Todd A.
Published: August 2023

Purpose:

Head and neck squamous cell carcinoma (HNSCC) is an aggressive tumor with low response rates to frontline PD-1 blockade. Natural killer (NK) cells are a promising cellular therapy for T cell therapy–refractory cancers, but are frequently dysfunctional in patients with HNSCC. Strategies are needed to enhance NK cell responses against HNSCC. We hypothesized that memory-like (ML) NK cell differentiation, tumor targeting with cetuximab, and engineering with an anti-EphA2 (Erythropoietin-producing hepatocellular receptor A2) chimeric antigen receptor (CAR) enhance NK cell responses against HNSCC.

Experimental Design:

We generated ML NK and conventional (c)NK cells from healthy donors, then evaluated their ability to produce IFNγ, TNF, degranulate, and kill HNSCC cell lines and primary HNSCC cells, alone or in combination with cetuximab, in vitro and in vivo using xenograft models. ML and cNK cells were engineered to express anti-EphA2 CAR-CD8A-41BB-CD3z, and functional responses were assessed in vitro against HNSCC cell lines and primary HNSCC tumor cells.

Results:

Human ML NK cells displayed enhanced IFNγ and TNF production and both short- and long-term killing of HNSCC cell lines and primary targets, compared with cNK cells. These enhanced responses were further improved by cetuximab. Compared with controls, ML NK cells expressing anti-EphA2 CAR had increased IFNγ and cytotoxicity in response to EphA2+ cell lines and primary HNSCC targets.

Conclusions:

These preclinical findings demonstrate that ML differentiation alone or coupled with either cetuximab-directed targeting or EphA2 CAR engineering were effective against HNSCCs and provide the rationale for investigating these combination approaches in early phase clinical trials for patients with HNSCC.
Figure S6 from CBF-Beta Mitigates PI3K-Alpha–Specific Inhibitor Killing through PIM1 in PIK3CA-Mutant Gastric Cancer
Authors: Stanland Lyla J. , Ang Hazel X. , Hoj Jacob P. , Chu Yunqiang , Tan Patrick , Wood Kris C. , Luftig Micah A.
Published: August 2023

Figure S6 shows down-regulation of RUNX1 in BYL719 resistant cells
Data from CBF-Beta Mitigates PI3K-Alpha–Specific Inhibitor Killing through PIM1 in PIK3CA-Mutant Gastric Cancer
Authors: Stanland Lyla J. , Ang Hazel X. , Hoj Jacob P. , Chu Yunqiang , Tan Patrick , Wood Kris C. , Luftig Micah A.
Published: August 2023

Abstract
PIK3CA is the second most mutated gene in cancer leading to aberrant PI3K/AKT/mTOR signaling and increased translation, proliferation, and survival. Some 4%–25% of gastric cancers display activating PIK3CA mutations, including 80% of Epstein–Barr virus–associated GCs. Small molecules, including pan-PI3K and dual PI3K/mTOR inhibitors, have shown moderate success clinically, due to broad on-target/off-tissue effects. Thus, isoform-specific and mutant selective inhibitors have been of significant interest. However, drug resistance is a problem and has affected success of new drugs. There has been a concerted effort to define mechanisms of resistance and identify potent combinations in many tumor types, though gastric cancer is comparatively understudied. In this study, we identified modulators of the response to the PI3Kα-specific inhibitor, BYL719, in PIK3CA-mutant GCs. We found that loss of NEDD9 or inhibition of BCL-XL conferred hypersensitivity to BYL719, through increased cell-cycle arrest and cell death, respectively. In addition, we discovered that loss of CBFB conferred resistance to BYL719. CBFB loss led to upregulation of the protein kinase PIM1, which can phosphorylate and activate several overlapping downstream substrates as AKT thereby maintaining pathway activity in the presence of PI3Kα inhibition. The addition of a pan-PIM inhibitor re-sensitized resistant cells to BYL719. Our data provide clear mechanistic insights into PI3Kα inhibitor response in PIK3CA-mutant gastric tumors and can inform future work as mutant-selective inhibitors are in development for diverse tumor types.
Implications:
Loss of either NEDD9 or BCL-XL confers hypersensitivity to PI3K-alpha inhibition whereas loss of CBFB confers resistance through a CBFB/PIM1 signaling axis.
Supplementary Video S12 from Dynamic Glycoprotein Hyposialylation Promotes Chemotherapy Evasion and Metastatic Seeding of Quiescent Circulating Tumor Cell Clusters in Breast Cancer
Authors: Dashzeveg Nurmaa K. , Jia Yuzhi , Zhang Youbin , Gerratana Lorenzo , Patel Priyam , Shajahan Asif , Dandar Tsogbadrakh , Ramos Erika K. , Almubarak Hannah F. , Adorno-Cruz Valery , Taftaf Rokana , Schuster Emma J. , Scholten David , Sokolowski Michael T. , Reduzzi Carolina , El-Shennawy Lamiaa , Hoffmann Andrew D. , Manai Maroua , Zhang Qiang , D'Amico Paolo , Azadi Parastoo , Colley Karen J. , Platanias Leonidas C. , Shah Ami N. , Gradishar William J. , Cristofanilli Massimo , Muller William A. , Cobb Brian A. , Liu Huiping
Published: August 2023

Supplementary Video S12 shows the clustering video of siICAM1 transfected ST6KO cells presented in Fig.5E.
Supplementary Video S10 from Dynamic Glycoprotein Hyposialylation Promotes Chemotherapy Evasion and Metastatic Seeding of Quiescent Circulating Tumor Cell Clusters in Breast Cancer
Authors: Dashzeveg Nurmaa K. , Jia Yuzhi , Zhang Youbin , Gerratana Lorenzo , Patel Priyam , Shajahan Asif , Dandar Tsogbadrakh , Ramos Erika K. , Almubarak Hannah F. , Adorno-Cruz Valery , Taftaf Rokana , Schuster Emma J. , Scholten David , Sokolowski Michael T. , Reduzzi Carolina , El-Shennawy Lamiaa , Hoffmann Andrew D. , Manai Maroua , Zhang Qiang , D'Amico Paolo , Azadi Parastoo , Colley Karen J. , Platanias Leonidas C. , Shah Ami N. , Gradishar William J. , Cristofanilli Massimo , Muller William A. , Cobb Brian A. , Liu Huiping
Published: August 2023

Supplementary Video S10 shows the clustering video of siCD97 transfected ST6KO cells presented in Fig.5E.
Data from MHC Class II is Induced by IFNγ and Follows Three Distinct Patterns of Expression in Colorectal Cancer Organoids
Authors: Pickles Oliver J. , Wanigasooriya Kasun , Ptasinska Anetta , Patel Akshay J. , Robbins Helen L. , Bryer Claire , Whalley Celina M. , Tee Louise , Lal Neeraj , Pinna Claudia M.A. , Elzefzafy Nahla , Taniere Philippe , Beggs Andrew D. , Middleton Gary M.
Published: August 2023

Tumor-specific MHC class II (tsMHC-II) expression impacts tumor microenvironmental immunity. tsMHC-II positive cancer cells may act as surrogate antigen-presenting cells and targets for CD4+ T cell–mediated lysis. In colorectal cancer, tsMHC-II negativity is common, in cell lines due to CIITA promoter methylation. To clarify mechanisms of tsMHC-II repression in colorectal cancer, we analyzed colorectal cancer organoids which are epigenetically faithful to tissue of origin. 15 primary colorectal cancer organoids were treated with IFNγ ± epigenetic modifiers: flow cytometry was used for tsMHC-II expression. qRT-PCR, total RNA sequencing, nanopore sequencing, bisulfite conversion/pyrosequencing, and Western blotting was used to quantitate CIITA, STAT1, IRF1, and JAK1 expression, mutations and promoter methylation and chromatin immunoprecipitation to quantitate H3K9ac, H3K9Me2, and EZH2 occupancy at CIITA.

We define three types of response to IFNγ in colorectal cancer: strong, weak, and noninducibility. Delayed and restricted expression even with prolonged IFNγ exposure was due to IFNγ-mediated EZH2 occupancy at CIITA. tsMHC-II expression was enhanced by EZH2 and histone deacetylase inhibition in the weakly inducible organoids. Noninducibility is seen in three consensus molecular subtype 1 (CMS1) organoids due to JAK1 mutation. No organoid demonstrates CIITA promoter methylation.

Providing IFNγ signaling is intact, most colorectal cancer organoids are class II inducible. Upregulation of tsMHC-II through targeted epigenetic therapy is seen in one of fifteen organoids. Our approach can serve as a blueprint for investigating the heterogeneity of specific epigenetic mechanisms of immune suppression across individual patients in other cancers and how these might be targeted to inform the conduct of future trials of epigenetic therapies as immune adjuvants more strategically in cancer.
Significance:
Cancer cell expression of MHC class II significantly impacts tumor microenvironmental immunity. Previous studies investigating mechanisms of repression of IFNγ-inducible class II expression using cell lines demonstrate epigenetic silencing of IFN pathway genes as a frequent immune evasion strategy. Unlike cell lines, patient-derived organoids maintain epigenetic fidelity to tissue of origin. In the first such study, we analyze patterns, dynamics, and epigenetic control of IFNγ-induced class II expression in a series of colorectal cancer organoids.
PARP Inhibitors Effectively Reduce MAPK Inhibitor Resistant Melanoma Cell Growth and Synergize with MAPK Inhibitors through a Synthetic Lethal Interaction In Vitro and In Vivo
Authors: Fröhlich Lisa Marie , Niessner Heike , Sauer Birgit , Kämereit Sofie , Chatziioannou Eftychia , Riel Simon , Sinnberg Tobias , Schittek Birgit
Published: August 2023

The efficacy of targeting the MAPK signaling pathway in patients with melanoma is limited by the rapid development of resistance mechanisms that result in disease relapse. In this article, we focus on targeting the DNA repair pathway as an antimelanoma therapy, especially in MAPK inhibitor resistant melanoma cells using PARP inhibitors. We found that MAPK inhibitor resistant melanoma cells are particularly sensitive to PARP inhibitor treatment due to a lower basal expression of the DNA damage sensor ataxia-telangiectasia mutated (ATM). As a consequence, MAPK inhibitor resistant melanoma cells have decreased homologous recombination repair activity leading to a reduced repair of double-strand breaks caused by the PARP inhibitors. We validated the clinical relevance of our findings by ATM expression analysis in biopsies from patients with melanoma before and after development of resistance to MAPK inhibitors. Furthermore, we show that inhibition of the MAPK pathway induces a homologous recombination repair deficient phenotype in melanoma cells irrespective of their MAPK inhibitor sensitivity status. MAPK inhibition results in a synthetic lethal interaction of a combinatorial treatment with PARP inhibitors, which significantly reduces melanoma cell growth in vitro and in vivo. In conclusion, this study shows that PARP inhibitor treatment is a valuable therapy option for patients with melanoma, either as a single treatment or as a combination with MAPK inhibitors depending on ATM expression.

Significance:

We show that MAPK inhibitor resistant melanoma cells exhibit low ATM expression increasing their sensitivity toward PARP inhibitors and that a combination of MAPK/PARP inhibitors act synthetically lethal in melanoma cells. Our study shows that PARP inhibitor treatment is a valuable therapy option for patients with melanoma, either as a single treatment or as a combination with MAPK inhibitors depending on ATM expression, which could serve as a novel biomarker for treatment response.