bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibitory effect of natural flavone luteolin on
Streptococcus mutans
biofilm formation
Authors: Rudin Lucille , Roth Noelle , Kneubühler Julien , Dubey Badri Nath , Bornstein Michael M. , Shyp Viktoriya
Published: September 2023

Streptococcus mutans
is one of the key pathogens responsible for dental caries, which is known to be one of the most prevalent biofilm-associated diseases worldwide.
S. mutans
virulence strongly depends on its biofilm formation and enamel demineralization abilities due to the production of surface adhesins, exopolysaccharides, and acid in the presence of sugar. Luteolin is an abundant natural flavone with a prominent anti-bacterial function. However, it remains unclear how luteolin affects
S. mutans
pathogenicity including its acidogenicity and biofilm formation. In this study, the effect of luteolin on
S. mutans
growth, acid production, and its early and late biofilm formation and biofilm disruption was tested. Luteolin shows strong anti-biofilm activity, while it remains non-toxic for bacterial cell viability. In the biofilm, luteolin reduces the expression of
S. mutans
virulence genes such as
gbpC
,
spaP
,
gtfBCD
, and
ftf
encoding for surface adhesins and extracellular polysaccharides (EPS)-producing enzymes, which reflects in the strong reduction of bacteria and EPS. Further, it reduces water-insoluble glucan production in the biofilm, potentially, via direct interference with glucosyltransfereases (Gtfs). Moreover, at biofilm inhibitory concentrations, luteolin significantly reduces acid production by
S. mutans
. Finally, luteolin could target
S. mutans
amyloid proteins to disrupt the biofilm based on the observation that it inhibits the uptake of the amyloid dye, thioflavin T, by
S. mutans
extracellular proteins and failed to inhibit biofilm formation by the mutant strain lacking three main amyloid proteins. In conclusion, luteolin appears to be a potent natural compound with pleiotropic anti-biofilm properties against one of the main cariogenic human pathogens,
S. mutans
.

IMPORTANCE

Flavonoids are natural compounds with proven anti-bacterial and anti-biofilm properties. Here, we describe the anti-biofilm properties of natural flavone luteolin against the main cariogenic bacteria,
S. mutans
. Luteolin inhibited gene expression of cell surface adhesins, fructosyltransferases, and glucosyltransferases, which promotes a significant reduction of bacterial and EPS biomass in early and late biofilms. Moreover, luteolin could directly target
S. mutans
Gtfs and functional amyloids to modulate pathogenic biofilms. These observations provide important insights into the anti-biofilm properties of luteolin while laying out a framework for future therapeutic strategies targeting biofilm-associated virulence factors of oral pathogens.
New paleomagnetic and geochronologic results from late Paleozoic rocks in the Turfan-Hami block (NW China) and implications for the geodynamic evolution of the western Altaids
Authors: Xu Wei , Song Bo , Wang Baowen , Shi Jizhong , Zhao Yue , Zhang Huiyuan , Wei Jianshe , Han Xiaofeng , Ye Xiaozhou , Wei Xiaoyan
Published: September 2023

How and when the ocean-continent transition started in the western Altaids remain controversial. The paleomagnetic signals recorded by late Paleozoic rocks in the Turpan-Hami block can provide critical constraints on this issue. We conducted a new combined paleomagnetic and geochronologic study on the late Paleozoic rocks from the Turpan-Hami block. Laser ablation−inductively coupled plasma−mass spectrometry zircon U-Pb dating of volcanic beds from the Upper Carboniferous Qijiaojing and Julideneng Formations yielded ages of 313.1 ± 4.3 Ma and 309.6 ± 1.9 Ma to 308.1 ± 3.6 Ma, respectively. Meanwhile, the U-Pb age of the granite intruding the Julideneng Formation is 300.3 ± 2.4 Ma. Passing a series of fold tests, the characteristic remanent magnetization (ChRM) directions of the Qijiaojing Formation are likely primary and consistent with the Kiaman reversed superchron (ca. 319−267 Ma). However, the ChRM values of the Dananhu (Middle Devonian) and Julideneng Formations all represent reverse polarity with negative fold tests, which indicate remagnetizations related to the magmatic thermal events during the late Carboniferous. Thus, two high-quality paleomagnetic poles were obtained for the periods ca. 313−308 Ma at 44.4°N, 177.3°E (K = 22.1, A95 = 8.0°) and ca. 300 Ma at 47.8°N, 173.9°E (K = 116.0, A95 = 4.8°), respectively. Comparison with published coeval paleomagnetic poles of the blocks on both sides of the Tianshan sutures suggests that the central oceanic basin of the western Paleo-Asian Ocean (between the Siberian and Tarim blocks) had been closed since the late Carboniferous (ca. 310 Ma), apart from remnant seas. In addition, a sizeable clockwise rotation (∼58°) of the Turpan-Hami block had taken place during the early Permian, with a scissor-style shrinking of the remnant Bogda marine basin in the meantime. This study provides a new perspective for understanding the tectonic evolution of the western Altaids.
Trichotillomania: a perspective synthesised from neuroscience and lived experience
Authors: Mackay Clare E
Published: September 2023

Trichotillomania, or hair-pulling disorder, is one of a family of disorders called body-focused repetitive behaviours (BFRBs), which also include disordered skin-picking (dermotillomania) and nail-biting (onychophagia). The disorders affect 1%–2% of the population, cause high levels of distress and have high levels of comorbidity with other psychiatric diagnoses. The key facts and figures are briefly reviewed and some important points are further explored: (1) BFRBs are associated with psychological distress, but are distinct from other diagnoses, (2) The pathological behaviours mirror excessive self-grooming behaviours in other species, and may relate to immune-system mediated feedback loops, and (3) The resulting behaviours are stigmatised and cause intense shame and isolation for those who suffer, which might in itself maintain the feedback loop. These observations lead to the hypothesis that the core disorder is one of pathological grooming, which may have a basis in an immune response, with shame being both a consequence and a maintainer of the disorder. The major barrier to testing the hypotheses and potential interventions remains the stigma that keeps these disorders, and those who suffer from them, in the shadows.
Socioeconomic inequalities in physical activity among older adults before and during the COVID-19 pandemic: evidence from the English Longitudinal Study of Ageing
Authors: Malkowski Olivia S , Townsend Nick P , Kelson Mark J , Foster Charlie E M , Western Max J
Published: September 2023

Introduction

The influence of the COVID-19 pandemic on physical activity behaviour in older adults is of particular concern. However, little is yet known about how pre-existing socioeconomic inequalities in older adults’ physical activity have been affected by the COVID-19 pandemic. The aim of this study was to explore socioeconomic disparities in physical activity levels and change over time among older adults in England, using data collected before and during the COVID-19 pandemic.

Methods

This longitudinal cohort study analysed data from 3720 older adults (aged 60+ years) who participated in wave 9 (2018/2019) of the main English Longitudinal Study of Ageing (ELSA) survey and wave 2 of the ELSA COVID-19 substudy (November/December 2020). Using multilevel ordinal logistic models, we investigated associations between socioeconomic variables (education, occupational class and wealth) and physical activity, adjusting for potential confounders. We also examined interactions between socioeconomic variables and time (prepandemic vs intrapandemic) to investigate changes in the magnitude of inequalities in physical activity across the two survey periods.

Results

The proportion of participants considered ‘inactive’ rose from 5.7% before the COVID-19 pandemic to 12.5% in November and December 2020. Higher education, occupational class and wealth were positively associated with physical activity before the lockdown. These socioeconomic disparities generally persisted during the COVID-19 pandemic. There was some evidence that differences in physical activity based on education and occupational class reduced during the COVID-19 pandemic, relative to prepandemic data. However, these associations were no longer statistically significant when the three socioeconomic variables and their interactions with time corrected for one another (p>0.05).

Conclusion

Our results suggest there was no additional influence of the COVID-19 pandemic on pre-existing socioeconomic inequalities in older adults’ physical activity levels.
Topological solitons in the sigma-cuscuton model
Authors: Lima F. C. E. , Almeida C. A. S.
Published: September 2023

Building a multi-field theory with canonical and non-canonical contributions, one studies the topological solitons of the O(3)-sigma model. We propose a model constituted by the O(3)-sigma field, the cuscuton-like neutral scalar field, and Maxwell’s field. We investigate BPS properties considering a theory without interaction. One performs this study by adopting the first-order formalism in a model with contribution non-canonical. Thus, these contributions will preserve the spontaneous symmetry breaking of the system. Concurrently, a non-minimal coupling between the sigma and the Maxwell field is assumed. In this scenario, interesting results arise, i.e., one notes that the solitons have an internal structure and ring-like profile. Furthermore, one observes that the ring-like configurations that emerge are directly related to the contribution of the cuscuton-like term.
Finite distributive lattices, polyominoes and ideals of König type
Authors: Herzog Jürgen , Hibi Takayuki
Published: September 2023

Finite distributive lattices whose join-meet ideals are of König type will be classified. Furthermore, a class of polyominoes whose polyomino ideals are of König type will be studied.
Linear half-space problems in kinetic theory: Abstract formulation and regime transitions
Authors: Bernhoff Niclas
Published: September 2023

In this work, a general formulation, which is based on steady boundary layer problems for the Boltzmann equation, of a half-space problem is considered. The number of conditions on the indata at the interface needed to obtain well-posedness is investigated. The solutions will converge exponentially fast “far away” from the interface. For linearized kinetic half-space problems similar to the one of evaporation and condensation in kinetic theory, slowly varying modes might occur near regime transitions where the number of conditions needed to obtain well-posedness changes (corresponding to transition between evaporation and condensation, or subsonic and supersonic evaporation/condensation), preventing uniform exponential speed of convergence. However, those modes might be eliminated by imposing extra conditions on the indata at the interface. Flow velocities at the far end for which regime transitions occur are presented for Boltzmann equations: for monatomic and polyatomic single species and mixtures; as well as bosons and fermions.
Modulations for Quantum Electronic Material Transports by Vacuum Annealing Methods
Authors: Ci Ji-Wei , Chen Bo-Yu , Hung Yuan-Chih , Wang Huan-Chien , Tsai Dung-Sheng , Uen Wu-Yih , Zhong Yuan-Liang , Wang Jyh-Shyang , Liang Chi-Te , Chuang Chiashain
Published: September 2023

Gapless linear band structure quantum electronic materials play important roles in quantum computing developments due to their novel superb electronic transport properties and two-dimensional (2D) gateable device possibility. However, the sensitive surface of quantum electronic materials easily reacted with ambient air molecules so as to change their intrinsic transport properties. We review a series of our works to show the importance of surface reactions in quantum electronic materials, such as graphene. By using different electronic transport facilities and in situ vacuum annealing methods, we are able to gently clean the absorbed air molecules on graphene so as to change the carrier densities and the electronic transport properties, which is a great improvement for 2D-quantum material-based quantum chips and computing devices.
Mobilising Workers via Digital Means: Reinventing Trade Unions for the Digital Age
Authors: Trenerry Brigid , Chng Samuel , Wang Yang , Lim Sun Sun , Oh Peng Ho
Published: September 2023

Singapore’s economy has witnessed successive waves of transformation with its highly skilled and competent workforce serving as a backbone to continuing economic growth. Tripartism is a key feature of Singapore’s economy and underpins workforce participation and the mediation of employer-employee relations through collaboration between trade unions, employers, and the government. As with other unions around the world, changing social and economic realities are putting pressure on trade unions in Singapore to digitalise and adapt to new forms of worker engagement. Social norms are also rapidly changing parallel to the new forms of work and opportunities afforded by digital technologies. Amidst challenges such as membership declines, institutional changes and the rise of the gig economy and precarious labour, some unions have struggled to transform, while others have thrived and grown by adopting modern tools and technologies to engage with and organise emerging groups of workers. This article explores how the organisation of workers through digital means can benefit Singapore’s trade unions in light of its economic and employment climate, and the historical trajectory of trade unions. We focus on how engagement, which is of paramount importance for trade unions, can be complemented or enhanced through the adoption of digital tools. We also present several examples from different parts of the world demonstrating how traditional unions are digitalising through transnational collaborations and collectives, and through the adoption of communication technologies, digital platforms, and campaigns to support worker organising. In so doing, we distil key lessons for trade unions in Singapore that are contemplating and exploring organising workers through digital means.
The Journey of Engaging and Organising Workers Through Digital Means
Authors: Cheong Horson
Published: September 2023

This practitioner note examines the motivations that the Singapore Supply Chain Employees’ Union (SCEU) had in embarking on their journey of engaging and organising workers through digital means. The advent of new, digital tools and the evolution of communication methods amid changing work and workforce landscapes meant that new and effective ways to reach out to more workers needed to be devised. SCEU’s foray into digital platforms as a means of communication, engagement and organising of workers was thus borne out of a desire for progressivity as much as it was an existential necessity. There remain challenges that must be addressed to ensure that the use of digital platforms translates into successful organising. This practitioner note draws from SCEU’s experiences and outlines its digital organising strategy in response to these challenges, as it works towards its aim of establishing a strong foundation and community of supply chain and logistics workers for the next generation of SCEU leaders to continue building upon.
Knowing What You Need to Know
Authors: Limoncelli Thomas A.
Published: September 2023

Blockers can take a tiny task and stretch it over days or weeks. Taking a moment at the beginning of a project to look for and prevent possible blockers can improve productivity. These examples of personal, team, and organizational levels show how gathering the right information and performing preflight checks can save hours of wasted time later.
Understanding and Predicting User Satisfaction with Conversational Recommender Systems
Authors: Siro Clemencia , Aliannejadi Mohammad , De Rijke Maarten
Published: September 2023

User satisfaction depicts the effectiveness of a system from the user’s perspective. Understanding and predicting user satisfaction is vital for the design of user-oriented evaluation methods forconversational recommender systems (CRSs). Current approaches rely on turn-level satisfaction ratings to predict a user’s overall satisfaction with CRS. These methods assume that all users perceive satisfaction similarly, failing to capture the broader dialogue aspects that influence overall user satisfaction.

We investigate the effect of several dialogue aspects on user satisfaction when interacting with a CRS. To this end, we annotate dialogues based on six aspects (i.e.,relevance,interestingness,understanding,task-completion,interest-arousal, andefficiency) at the turn and dialogue levels. We find that the concept of satisfaction varies per user. At the turn level, a system’s ability to make relevant recommendations is a significant factor in satisfaction. We adopt these aspects as features for predicting response quality and user satisfaction. We achieve an F1-score of 0.80 in classifying dissatisfactory dialogues, and a Pearson’srof 0.73 for turn-level response quality estimation, demonstrating the effectiveness of the proposed dialogue aspects in predicting user satisfaction and being able to identify dialogues where the system is failing.

With this article, we release our annotated data.1
High levels of uric acid inhibit BAT thermogenic capacity through regulation of AMPK
Authors: Dong Meijuan , An Kun , Mao Li
Published: September 2023

To investigate the effect and mechanism of UA on BAT thermogenic capacity, we established HUA models in vitro and in vivo, and performed RNA sequencing analysis. Our results revealed that HUA suppresses mitochondrial biogenesis by regulating AMPK, thereby inhibiting BAT thermogenic capacity. Taken together, our study identifies UA as a novel regulator of BAT thermogenic capacity, providing a new strategy to combat obesity.
Mapping the Landscape of Magnetic Field Effects on Neural Regeneration and Repair: A Combined Systematic Review, Mathematical Model, and Meta-Analysis
Authors: McGraw Meghan , Gilmer Gabrielle , Bergmann Juliana , Seshan Vishnu , Wang Kai , Pekker David , Modo Michel , Ambrosio Fabrisia
Published: September 2023

Magnetic field exposure is a well-established diagnostic tool. However, its use as a therapeutic in regenerative medicine is relatively new. To better understand how magnetic fields affect neural repair in vitro, we started by performing a systematic review of publications that studied neural repair responses to magnetic fields. The 38 included articles were highly heterogeneous, representing 13 cell types, magnetic field magnitudes of 0.0002–10,000 mT with frequencies of 0–150 Hz, and exposure times ranging from one hour to several weeks. Mathematical modeling based on data from the included manuscripts revealed higher magnetic field magnitudes enhance neural progenitor cell (NPC) viability. Finally, for those regenerative processes not influenced by magnitude, frequency, or time, we integrated the data by meta-analyses. Results revealed that magnetic field exposure increases NPC proliferation while decreasing astrocytic differentiation. Collectively, our approach identified neural repair processes that may be most responsive to magnetic field exposure.
Investigation of Risk Factors Associated with the African Swine Fever Outbreaks in the Nizhny Novgorod Region of Russia, 2011–2022
Authors: Zakharova Olga I. , Blokhin Andrey A. , Yashin Ivan V. , Burova Olga A. , Kolbasov Denis V. , Korennoy Fedor I.
Published: September 2023

African swine fever (ASF) is a transboundary viral disease that affects both domestic pigs and wild boar, causing enormous damage to the pig production. Numerous studies are devoted to elucidating the role of domestic and wild pigs in ASF outbreaks. The identification of the risk factors contributing to the spread of disease in previously unaffected regions is of special interest. We conducted a retrospective analysis of sporadic ASF outbreaks in the Nizhny Novgorod region of the Russian Federation from 2011 to 2022 among both domestic pig and wild boar populations. Methods of spatiotemporal cluster analysis, mathematical modeling with logistic and negative binomial regressions, as well as the cross-correlation analysis of time series, were used to identify the most significant factors associated with the ASF outbreaks’ presence and intensity. Regression analysis did not reveal a statistically significant correlation between ASF outbreaks in wild boar and their population density over the entire study period. However, the spatial and temporal coincidence between outbreaks and increased wild boar density was observed at the beginning of the ASF epidemic in the region. We identified the significant environmental and sociodemographic factors contributing to the spread of ASF in both domestic pig and wild boar populations. The number of small-scale farms (backyards) and summary road length were determined as the main factors contributing to the spread of ASF among domestic pigs in the Nizhny Novgorod region. The regression model for ASF outbreaks in the wild boar population revealed the presence of water bodies, number of hunting farms, and the occurrence of ASF outbreaks in the domestic pig population to be the main explanatory factors. A statistically significant coincidence was identified between the monthly volume of pork products imported to the region from the rest of Russia and the occurrence of ASF outbreaks in both domestic and wild populations. Thus, the identified spatiotemporal patterns may be useful to determine areas with an elevated risk of ASF outbreaks emergence for better resource management, disease control, and prevention. The importance of intensified monitoring and control measures in the pig products supply chain is strongly needed. The obtained models can be applied not only by the veterinary service of the Nizhny Novgorod region but to other regions with similar environmental and sociodemographic conditions.
Associations between Executive Functions and Sensorimotor Performance in Children at Risk for Learning Disabilities
Authors: Tószegi Cecília , Zsido Andras N. , Lábadi Beatrix
Published: September 2023

Executive functions (EF) and sensorimotor skills play a critical role in children’s goal-directed behavior and school readiness. The aim of the current study is to provide new insights into the relationship between executive functions and sensorimotor development by considering the risks associated with learning difficulties. Therefore, we investigate the predictive role of EF and sensorimotor skills in the development of learning difficulties during preschool years. Ninety-five preschool children (5–7 years old) were tested, comparing the performance of children that are at risk of learning difficulties (

n
=
55

) to the performance of typically developing children (

n
=
40

). Participants completed a battery for the assessment of sensorimotor skills (i.e., Southern California Sensory Integration Test: postural imitation, body midline crossing, bilateral motor coordination, and standing balance with eyes open) and executive functions (i.e., inhibition, cognitive flexibility, and verbal working memory). Our results show that children at risk for learning difficulties exhibited more impairments on sensorimotor and EF measures (inhibition and verbal working memory) when compared with TD children. We ran three separate binary logistic regression analyses to assess the relative influence of EF and sensorimotor functions on predicting risk for learning difficulties. Our findings demonstrated that verbal working memory as EF function (odd ratio

OR

=
0.91

, 95% CI 0.78-0.91,

P
=
0.05

) and standing balance skills as a sensorimotor skill (odd ratio

OR

=
0.86

, 95% CI 0.81-0.98,

P
=
0.01

) were the strongest predictors of risk for learning difficulties. The findings point to the importance of supporting children’s executive function development and promoting sensorimotor development, as both fundamentally influence school readiness.
Preliminary Study on the Antibacterial Activities and Antibacterial Guided Fractionation of Some Common Medicinal Plants Practices in Itum Bahal, Kathmandu Valley of Nepal
Authors: Bhandari Ravin , Pant Dhakaraj , Kathayat Kamal Singh , Bhattarai Ramesh , Barakoti Himal , Pandey Jitendra , Jamarkatel-Pandit Nirmala
Published: September 2023

The aim of this study was to evaluate the antibacterial activities of selected medicinal plant practices by a traditional healer of the Newar community in Itum Bahal, Kathmandu, Nepal. The antibacterial activities of the methanolic extract (1 mg/disc) of fifteen medicinal plants were screened against two Gram-positive bacteria (Staphylococcus aureus ATCC 25923 and Bacillus subtilis ATCC 6633) and two Gram-negative bacteria (Escherichia coli ATCC 25922 and Salmonella typhi CCM 5445) using the disc diffusion method. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were calculated for the different fractions (hexane, chloroform, ethyl acetate, acetonitrile, and acetone) of the plants having a significant antimicrobial effect. Only Quercus infectoria G. Olivier (galls) and Mallotus repandus (Willd.) Müll.Arg. (seeds) exhibited prominent antibacterial effects. The acetone fraction from Q. infectoria had the strongest antibacterial effect, with a 41.00 mm inhibition zone against S. aureus. In contrast, the ethyl acetate fraction in M. repandus exhibited the highest efficacy, producing a 29.00 mm inhibition zone against S. typhi. In a similar manner, in the case of Q. infectoria, the acetoe fraction depicted the lowest MIC (0.19 mg/mL) and MBC (0.98 mg/mL) values against S. aureus, whereas the ethyl acetate fraction of M. repandus was most significant, showing the lowest MIC and MBC of 0.25 and 0.53 mg/mL, respectively, against S. typhi. This study suggested that the acetone extract of Q. infectoria galls can be used as a potential source against Gram-positive bacteria, whereas the ethyl acetate extract of M. repandus seeds could serve as a useful source to inhibit Gram-negative bacteria. Furthermore, extensive scientific investigation is mandatory to ensure the proper use of folk medicines.
High-Performance Method for Brain Tumor Feature Extraction in MRI Using Complex Network
Authors: Han Trong Thanh , Nguyen Van Hinh , Vu Dang Luu
Published: September 2023

Objective. To localize and distinguish between benign and malignant tumors on MRI. Method. This work proposes a high-performance method for brain tumor feature extraction using a combination of complex network and U-Net architecture. And then, the common machine-learning algorithms are used to discriminate between benign and malignant tumors. Experiments and Results. The dataset of brain MRI of a total of 230 brain tumor patients in which 77 high-grade glioma patients and 153 low-grade glioma patients were processed. The results of classifying benign and malignant tumors achieved an accuracy of 99.84%. Conclusion. The high accuracy of experiment results demonstrates that the use of the complex network and U-Net architecture can significantly improve the accuracy of brain tumor classification. This method could potentially be useful for clinicians in aiding diagnosis and treatment planning for brain tumor patients.
A Compact Broad Circularly Polarized Cross-Dipole Antenna with Grounded Parasitic Elements
Authors: Yang Dong , Hao Lichao , Wang Lei
Published: September 2023

A new wideband cross-dipole antenna (CDA) with a circularly polarized (CP) characteristic is proposed in this article. The antenna consists of four L-shaped patches, two modified trapezoid-microstrip lines as an impedance tuner, a pair of vacant-quarter feeding loops as a continuous-phase feeding network, and four grounded inverted L-shaped strips as parasitic elements. It is noticed that the grounded inverted L-shaped strips are inserted directly below the L-shaped patches to increase the CP bandwidth and enhance the gains of the antenna, which is different from the conventional parasitic elements. First, a pair of vacant-quarter feeding loops is used as a feeding structure to provide a sequential phase characteristic. Second, four L-shaped patches as driven elements are connected to the feeding structure to excite two CP resonant modes. Third, two modified trapezoid-microstrip lines are inserted into the feeding structure to adjust the impedance match. Moreover, four grounded inverted L-shaped strips are introduced into the square reflector to achieve wider CP operation by utilizing a gap capacitive coupling feeding way. Finally, the proposed antenna is simulated, manufactured, and measured to verify the design rationality. The measured results indicate the proposed antenna has a broad 3-dB ARBW of 82.5% (1.38–3.32 GHz, 2.35 GHz) and a wide −10-dB IBW of 81.2% (1.18–3.04 GHz, 2.29 GHz). Furthermore, the measured and simulated CP bandwidths are 75.1% (1.38–3.04 GHz, 2.21 GHz) and 74.7% (1.36–2.98 GHz, 2.17 GHz), which is suitable for CP applications in WiBro (2.3–2.39 GHz) and GPS (L1 1.575 GHz) bands.
Fertility-Preserving Surgery in a Young Nulligravid Woman with Bilateral Coexistence of a Granulosa Cell Tumor with a Teratoma
Authors: Nha Pham Ba , Tuyen Pham Van , Ha Nguyen Viet , Phuong Nguyen Thi Thu
Published: September 2023

Background. The coexistence of a granulosa cell tumor with a teratoma is extremely rare and impossible to diagnose preoperatively. For most patients with advanced age and stage, the standard treatment is hysterectomy and bilateral salpingo-oophorectomy; however, fertility-preserving surgery should be considered for young nulligravid women. Case. We present a case of a 24-year-old nulligravid female with bilateral adnexal masses, imaging findings of ovarian teratomas, and normal levels of tumor markers. A laparotomy revealed bilateral dermoid cysts, and solid tissue invaded most of the remaining ovarian parenchyma with no signs of malignancy in the uterus and peritoneum space. Consequently, a bilateral oophorectomy was performed to preserve her fertility. Histopathology examination showed mature cystic teratomas coexisting with granulosa cell tumors on both ovaries. Within six months, there were no signs of recurrence on ultrasonography and tumor makers. Combined oral contraceptive pills were prescribed as hormone replacement therapy. Conclusion. Fertility-preserving surgery can be performed in young women with an ovarian granulosa cell tumor coexisting with a teratoma. Long-term examination, hormone replacement therapy, and in vitro fertilization are required.
Supplementary Data: Figures S1-S6 and Tables S1-S6 from Inferred Immune-Cell Activity Is an Independent Predictor of HER2-Negative Breast Cancer Prognosis and Response to Paclitaxel-Based Therapy in the GeparSepto Trial
Authors: Fasching Peter A. , Szeto Christopher , Denkert Carsten , Benz Stephen , Weber Karsten , Spilman Patricia , Budczies Jan , Schneeweiss Andreas , Stickeler Elmar , Schmatloch Sabine , Jackisch Christian , Karn Thomas , Sinn Hans Peter , Warm Mathias , van Mackelenbergh Marion , Rabizadeh Shahrooz , Schem Christian , Heinmöller Ernst , Mueller Volkmar , Marmé Frederik , Soon-Shiong Patrick , Nekljudova Valentina , Untch Michael , Loibl Sibylle
Published: September 2023

G7 trial design; demographics; tissue types; gene names; displayed data from additional analyses; statistical data
ATM Mutations Associate with Distinct Co-Mutational Patterns and Therapeutic Vulnerabilities in NSCLC
Authors: Vokes Natalie I. , Galan Cobo Ana , Fernandez-Chas Margarita , Molkentine David , Treviño Santiago , Druker Vitaly , Qian Yu , Patel Sonia , Schmidt Stephanie , Hong Lingzhi , Lewis Jeff , Rinsurongkawong Waree , Rinsurongkawong Vadeerat , Lee J. Jack , Negrao Marcelo V. , Gibbons Don L. , Vaporciyan Ara , Le Xiuning , Wu Jia , Zhang Jianjun , Rigney Una , Iyer Sonia , Dean Emma , Heymach John V.
Published: September 2023

Purpose:

Ataxia-telangiectasia mutated (ATM) is the most frequently mutated DNA damage repair gene in non–small cell lung cancer (NSCLC). However, the molecular correlates of ATM mutations and their clinical implications have not been fully elucidated.

Experimental Design:

Clinicopathologic and genomic data from 26,587 patients with NSCLC from MD Anderson, public databases, and a de-identified nationwide (US-based) NSCLC clinicogenomic database (CGDB) were used to assess the co-mutation landscape, protein expression, and mutational processes in ATM-mutant tumors. We used the CGDB to evaluate ATM-associated outcomes in patients treated with immune checkpoint inhibitors (ICI) with or without chemotherapy, and assessed the effect of ATM loss on STING signaling and chemotherapy sensitivity in preclinical models.

Results:

Nonsynonymous mutations in ATM were observed in 11.2% of samples (2,980/26,587) and were significantly associated with mutations in KRAS, but mutually exclusive with EGFR (q < 0.1). KRAS mutational status constrained the ATM co-mutation landscape, with strong mutual exclusivity with TP53 and KEAP1 within KRAS-mutated samples. Those ATM mutations that co-occurred with TP53 were more likely to be missense mutations and associate with high mutational burden, suggestive of non-functional passenger mutations. In the CGDB cohort, dysfunctional ATM mutations associated with improved OS only in patients treated with ICI-chemotherapy, and not ICI alone. In vitro analyses demonstrated enhanced upregulation of STING signaling in ATM knockout cells with the addition of chemotherapy.

Conclusions:

ATM mutations define a distinct subset of NSCLC associated with KRAS mutations, increased TMB, decreased TP53 and EGFR co-occurrence, and potential increased sensitivity to ICIs in the context of DNA-damaging chemotherapy.
PERK Inhibition by HC-5404 Sensitizes Renal Cell Carcinoma Tumor Models to Antiangiogenic Tyrosine Kinase Inhibitors
Authors: Stokes Michael E. , Calvo Veronica , Fujisawa Sho , Dudgeon Crissy , Huang Sharon , Ballal Nupur , Shen Leyi , Gasparek Jennifer , Betzenhauser Matthew , Taylor Simon J. , Staschke Kirk A. , Rigby Alan C. , Mulvihill Mark J. , Bose Nandita , Lightcap Eric S. , Surguladze David
Published: September 2023

Purpose:

Tumors activate protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK, also called EIF2AK3) in response to hypoxia and nutrient deprivation as a stress-mitigation strategy. Here, we tested the hypothesis that inhibiting PERK with HC-5404 enhances the antitumor efficacy of standard-of-care VEGF receptor tyrosine kinase inhibitors (VEGFR-TKI).

Experimental Design:

HC-5404 was characterized as a potent and selective PERK inhibitor, with favorable in vivo properties. Multiple renal cell carcinoma (RCC) tumor models were then cotreated with both HC-5404 and VEGFR-TKI in vivo, measuring tumor volume across time and evaluating tumor response by protein analysis and IHC.

Results:

VEGFR-TKI including axitinib, cabozantinib, lenvatinib, and sunitinib induce PERK activation in 786-O RCC xenografts. Cotreatment with HC-5404 inhibited PERK in tumors and significantly increased antitumor effects of VEGFR-TKI across multiple RCC models, resulting in tumor stasis or regression. Analysis of tumor sections revealed that HC-5404 enhanced the antiangiogenic effects of axitinib and lenvatinib by inhibiting both new vasculature and mature tumor blood vessels. Xenografts that progress on axitinib monotherapy remain sensitive to the combination treatment, resulting in ∼20% tumor regression in the combination group. When tested across a panel of 18 RCC patient-derived xenograft (PDX) models, the combination induced greater antitumor effects relative to monotherapies. In this single animal study, nine out of 18 models responded with ≥50% tumor regression from baseline in the combination group.

Conclusions:

By disrupting an adaptive stress response evoked by VEGFR-TKI, HC-5404 presents a clinical opportunity to improve the antitumor effects of well-established standard-of-care therapies in RCC.
PD-1 Blockade Induces Reactivation of Nonproductive T-Cell Responses Characterized by NF-κB Signaling in Patients with Pancreatic Cancer
Authors: Ali Lestat R. , Lenehan Patrick J. , Cardot-Ruffino Victoire , Dias Costa Andressa , Katz Matthew H.G. , Bauer Todd W. , Nowak Jonathan A. , Wolpin Brian M. , Abrams Thomas A. , Patel Anuj , Clancy Thomas E. , Wang Jiping , Mancias Joseph D. , Reilley Matthew J. , Stucky Chee-Chee H. , Bekaii-Saab Tanios S. , Elias Rawad , Merchant Nipun , Slingluff Craig L. , Rahma Osama E. , Dougan Stephanie K.
Published: September 2023

Purpose:

Pancreatic ductal adenocarcinoma (PDAC) trials have evaluated CTLA-4 and/or PD-(L)1 blockade in patients with advanced disease in which bulky tumor burden and limited time to develop antitumor T cells may have contributed to poor clinical efficacy. Here, we evaluated peripheral blood and tumor T cells from patients with PDAC receiving neoadjuvant chemoradiation plus anti–PD-1 (pembrolizumab) versus chemoradiation alone. We analyzed whether PD-1 blockade successfully reactivated T cells in the blood and/or tumor to determine whether lack of clinical benefit could be explained by lack of reactivated T cells versus other factors.

Experimental Design:

We used single-cell transcriptional profiling and TCR clonotype tracking to identify TCR clonotypes from blood that match clonotypes in the tumor.

Results:

PD-1 blockade increases the flux of TCR clonotypes entering cell cycle and induces an IFNγ signature like that seen in patients with other GI malignancies who respond to PD-1 blockade. However, these reactivated T cells have a robust signature of NF-κB signaling not seen in cases of PD-1 antibody response. Among paired samples between blood and tumor, several of the newly cycling clonotypes matched activated T-cell clonotypes observed in the tumor.

Conclusions:

Cytotoxic T cells in the blood of patients with PDAC remain sensitive to reinvigoration by PD-1 blockade, and some have tumor-recognizing potential. Although these T cells proliferate and have a signature of IFN exposure, they also upregulate NF-κB signaling, which potentially counteracts the beneficial effects of anti–PD-1 reinvigoration and marks these T cells as non-productive contributors to antitumor immunity.

See related commentary by Lander and DeNardo, p. 474
Supplementary Data from miR-146a Exerts Differential Effects on Melanoma Growth and Metastatization
Authors: Raimo Monica , Orso Francesca , Grassi Elena , Cimino Daniela , Penna Elisa , De Pittà Cristiano , Stadler Michael B. , Primo Luca , Calautti Enzo , Quaglino Pietro , Provero Paolo , Taverna Daniela
Published: September 2023

 This file contains supplementary Materials and Methods, Supplementary Figure Legends and Supplementary Bibliography.
Figure S2 from miR-146a Exerts Differential Effects on Melanoma Growth and Metastatization
Authors: Raimo Monica , Orso Francesca , Grassi Elena , Cimino Daniela , Penna Elisa , De Pittà Cristiano , Stadler Michael B. , Primo Luca , Calautti Enzo , Quaglino Pietro , Provero Paolo , Taverna Daniela
Published: September 2023

miR-146a expression correlates with melanoma thickness and recurrence.
TABLE 1 from Treatment Beyond Progression After Anti-PD-1 Blockade in Hepatocellular Carcinoma
Authors: Lim Mir , Muquith Maishara , Miramontes Bernadette , Espinoza Magdalena , Hsiehchen David
Published: September 2023

Characteristics of patients with HCC treated beyond progression, treated with subsequent therapies, and received no subsequent therapies
Chromatin Accessibility Landscape of Human Triple-negative Breast Cancer Cell Lines Reveals Variation by Patient Donor Ancestry
Authors: Harris Alexandra R. , Panigrahi Gatikrushna , Liu Huaitian , Koparde Vishal N. , Bailey-Whyte Maeve , Dorsey Tiffany H. , Yates Clayton C. , Ambs Stefan
Published: September 2023

African American (AA) women have an excessive risk of developing triple-negative breast cancer (TNBC). We employed Assay for Transposase-Accessible Chromatin using sequencing to characterize differences in chromatin accessibility between nine commonly used TNBC cell lines derived from patients of European and African ancestry. Principal component and chromosome mapping analyses of accessibility peaks with the most variance revealed separation of chromatin profiles by patient group. Motif enrichment and footprinting analyses of disparate open chromatin regions revealed differences in transcription factor activity, identifying 79 with ancestry-associated binding patterns (FDR < 0.01). AA TNBC cell lines exhibited increased accessibility for 62 transcription factors associated with epithelial-to-mesenchymal transition, cancer stemness/chemotherapeutic resistance, proliferation, and aberrant p53 regulation, as well as KAISO, which has been previously linked to aggressive tumor characteristics in AA patients with cancer. Differential Assay for Transposase-Accessible Chromatin signal analysis identified 1,596 genes located within promoters of differentially open chromatin regions in AA-derived TNBC, identifying DNA methyltransferase 1 as the top upregulated gene associated with African ancestry. Pathway analyses with these genes revealed enrichment in several pathways, including hypoxia. Culturing cells under hypoxia showed ancestry-specific stress responses that led to the identification of a core set of AA-associated transcription factors, which included members of the Kruppel-like factor and Sp subfamilies, as well as KAISO, and identified ZDHHC1, a gene previously implicated in immunity and STING activation, as the top upregulated AA-specific gene under hypoxia. Together, these data reveal a differential chromatin landscape in TNBC associated with donor ancestry. The open chromatin structure of AA TNBC may contribute to a more lethal disease.

Significance:

We identify an ancestry-associated open chromatin landscape and related transcription factors that may contribute to aggressive TNBC in AA women. Furthermore, this study advocates for the inclusion of diversely sourced cell lines in experimental in vitro studies to advance health equity at all levels of scientific research.
Positive Selbsteinschätzung als Resilienzfaktor und motivationaler Moderator im integrativen motivational-volitionalen Modell suizidalen Verhaltens
Authors: Tegethoff Jan-Luca , Forkmann Thomas , Höller Inken
Published: September 2023

Hintergrund: Das integrative motivational-volitionale (IMV) Modell suizidalen Verhaltens beschreibt die Konstrukte Defeat und Entrapment als Kernkomponenten der Entstehung von Suizidgedanken. Trotz der Berücksichtigung weiterer Risikofaktoren zeigen Studien uneinheitliche Befunde, was an der fehlenden Beachtung protektiver Einflussfaktoren auf die Entstehung von Suizidgedanken liegen könnte. Als ein solcher Resilienzfaktor wird eine positive Selbsteinschätzung diskutiert. Die vorliegende Arbeit untersucht die postulierten Pfade des IMV-Modells unter Berücksichtigung des Resilienzfaktors an Menschen mit aktuellen Suizidgedanken. Material und Methoden: N = 338 Beschäftigte im Gesundheitswesen mit aktuellen Suizidgedanken zwischen 19 und 81 Jahren (M = 29,48, SD = 8,33; 97,6% weiblich) wurden in einer Online-Studie zu Defeat, Entrapment und positiver Selbsteinschätzung befragt. Berechnet wurden zwei von positiver Selbsteinschätzung moderierte lineare Regressionsmodelle – Entrapment zu Suizidgedanken sowie Defeat zu Entrapment – und jeweils zwei an denselben Stellen moderierte Mediationsmodelle unter Berücksichtigung aller Faktoren. Ergebnisse: Die moderierten Regressionsmodelle ergaben Interaktionseffekte positiver Selbsteinschätzung. Die komplexeren moderierten Mediationsmodelle zeigten wider Erwarten keine durch positive Selbsteinschätzung moderierten indirekten Effekte über Entrapment, sondern einen direkten Effekt von Defeat auf Suizidgedanken. Diskussion: Der untersuchte Resilienzfaktor scheint erst spät im Modell eine protektive Wirkung zu entfalten, hierbei fallen mögliche strukturelle Schwächen der motivationalen Phase des IMV-Modells auf. Schlussfolgerung: Diese Arbeit liefert, basierend auf dem IMV-Modell, wichtige Erkenntnisse zum Einfluss von Resilienzfaktoren auf Suizidgedanken.
Transbronchial Cryobiopsy Is Superior to Forceps Biopsy for Diagnosing both Fibrotic and Non-Fibrotic Interstitial Lung Diseases
Authors: Freund Ophir , Wand Ori , Schneer Sonia , Barel Nevo , Shalmon Tamar , Borsekofsky Sarah , Hershko Tzlil , Gershman Evgeni , Adir Yochai , Bar-Shai Amir , Shitrit David , Unterman Avraham
Published: September 2023

Background: Interstitial lung disease (ILD) evaluation often requires lung biopsy for definite diagnosis. In recent years, transbronchial cryobiopsy (TBCB) emerged as a procedure with higher diagnostic yield than transbronchial forceps biopsy (TBFB), especially for fibrotic ILDs. Nonetheless, studies comparing these modalities in non-fibrotic ILDs and for specific ILD diagnoses are scarce. Objectives: The aim of this study was to evaluate the diagnostic yield and safety of TBCB and TBFB in patients with fibrotic and non-fibrotic ILDs. Method: An observational retrospective multicenter study including patients with ILD diagnosis by multidisciplinary discussion that underwent TBCB or TBFB between 2017 and 2021. Chest CT scans were reviewed by a chest radiologist. Biopsy specimens were categorized as diagnostic (with specific histological pattern), nondiagnostic, or without lung parenchyma. Nondiagnostic samples were reassessed by a second lung pathologist. TBCB and TBFB diagnostic yields were analyzed by multivariate regression. Procedural complications were evaluated as well. Results: 276 patients were included, 116 (42%) underwent TBCB and 160 (58%) TBFB. Fibrotic ILDs were present in 148 patients (54%). TBCB diagnostic yield was 78% and TBFB 48% (adjusted odds ratio [AOR] 4.2, 95% CI: 2.4–7.6, p < 0.01). The diagnostic yield of TBCB was higher than TBFB among patients with fibrotic ILD (AOR 3.8, p < 0.01), non-fibrotic ILD (AOR 5.8, p < 0.01), and across most ILD diagnoses. TBCB was associated with higher risk for significant bleeding (10% vs. 3%, p < 0.01), but similar risk for pneumothorax. Conclusions: Diagnostic yield of TBCB was superior to that of TBFB for both fibrotic and non-fibrotic ILDs, and across most diagnoses.
Canagliflozin Ameliorates Ventricular Remodeling through Apelin/Angiotensin-Converting Enzyme 2 Signaling in Heart Failure with Preserved Ejection Fraction Rats
Authors: Zhang Tingting , Wang Xinyu , Wang Zhongli , Zhai Jianlong , He Lili , Wang Yan , Zuo Qingjuan , Ma Sai , Zhang Guorui , Guo Yifang
Published: September 2023

Introduction: The aim of this study was to investigate the effect of canagliflozin (CANA) on ventricular remodeling in patients with preserved ejection fraction (HFpEF) heart failure and to further investigate its possible molecular mechanisms. Methods: A high-salt diet was used to induce the formation of HFpEF model in salt-sensitive rats. The rats were fed with CANA and irbesartan, respectively. The mice were divided into control group, model group, CANA group, irbesartan group, and combined drug group. After 12 weeks of feeding, the rats were evaluated by measuring the relevant indexes and echocardiography for cardiac function. Histological analysis was performed using Masson trichrome staining and immunohistochemical staining. RT-qPCR and Western blot were used to quantify the relevant genes and proteins. Results: In this study, CANA exhibited diuresis, decreased blood pressure, weight loss, and increased food and water intake. Following a high-salt diet, Dahl salt-sensitive rats developed hypertension followed by left ventricular diastolic dysfunction, myocardial fibrosis, and left ventricular remodeling. Myocardial hypertrophy and fibrosis were reduced, and left ventricular diastolic function and ventricular remodeling improved after CANA treatment. The combination of CANA and irbesartan was superior to monotherapy in reducing blood pressure and improving cardiac insufficiency and left ventricular diastolic dysfunction in rats. CANA improves myocardial fibrosis, left ventricular diastolic dysfunction, and ventricular remodeling by upregulating apelin, activating angiotensin-converting enzyme 2 (ACE2), and increasing ACE2/Ang (1–7)/MASR axis levels. Conclusion: CANA improves myocardial fibrosis, left ventricular diastolic dysfunction, and ventricular remodeling in HFpEF rats through upregulation of apelin/ACE2 signaling.