bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of tramadol via a µ-opioid receptor on pancreatic ductal adenocarcinoma in vitro and in vivo
Authors: Kuramochi Tomoya , Sano Makoto , Kajiwara Ichie , Oshima Yukino , Itaya Tomoaki , Kim Jinsuk , Ichimaru Yoshimi , Kitajima Osamu , Masamune Atsushi , Ijichi Hideaki , Suzuki Takahiro 
Published: June 2023

IntroductionTramadol, a weak opioid anesthetic, is used for pain management in patients with cancer, but the effects of tramadol on cancer via µ-opioid receptor are still unknown. We assessed the effects of tramadol on pancreatic ductal adenocarcinoma using transgenic mice (LSL-KrasG12D/+; Trp53flox/flox; Pdx-1cre/+).MethodsSix-week-old transgenic mice were orally administered 10 mg/kg/day tramadol (n=12), 10 mg/kg/day tramadol and 1 mg/kg/day naltrexone (n=9), or vehicle water (n=14) until the humane endpoint. Cancer-related pain and plasma cytokine levels were assessed by the mouse grimace scale and cytokine array, respectively. Tumor status was determined histopathologically. Tramadol’s effects on proliferation and invasion in pancreatic ductal adenocarcinoma cell lines were studied in vitro.ResultsTramadol with/without naltrexone improved mouse grimace scale scores while decreasing inflammatory cytokines such as tumor necrosis factor-α and interleukin-6. Proliferative Ki-67 and cyclins decreased by tramadol, while local M1-like tumor-associated macrophages increased by tramadol, which was blocked by naltrexone. Meanwhile, tramadol with/without naltrexone reduced juxta-tumoral cancer-associated fibroblasts and M2-like tumor-associated macrophages. Tumor-associated neutrophils, natural killers, and cytotoxic T cells were not altered. Tramadol decreased the proliferative and invasive potentials of pancreatic ductal adenocarcinoma cell lines via decreasing cyclins/cyclin-dependent kinases, which was partially reversed by naltrexone.ConclusionsThese findings imply that tramadol might be a useful anesthetic for pancreatic ductal adenocarcinoma: inhibiting the proliferation and invasion along with increasing antitumor M1-like tumor-associated macrophages via the µ-opioid receptor, while improving cancer-associated pain possibly through the antitumor effects with the decrease of inflammatory cytokines.
Non-supersymmetric SO(10) models with Gauge and Yukawa coupling unification
Authors: Djouadi Abdelhak , Fonseca Renato , Ouyang Ruiwen , Raidal Martti 
Published: June 2023

AbstractWe study a non-supersymmetric SO(10) Grand Unification Theory with a very high energy intermediate symmetry breaking scale in which not only gauge but also Yukawa coupling unification are enforced via suitable threshold corrections and matching conditions. For gauge unification, we focus on a few symmetry breaking patterns with the intermediate gauge groups$$\text {SU}(4)_{\textrm{C}} \times \text {SU}(2)_{\textrm{L}} \times \text {SU}(2)_{\textrm{R}}$$SU(4)C×SU(2)L×SU(2)R(Pati–Salam) and$$\text {SU}(3)_{\textrm{C}} \times \text {SU}(2)_{\textrm{L}} \times \text {SU}(2)_{\textrm{R}}\times \text {U}(1)_{{\textrm{B}}-{\textrm{L}}}$$SU(3)C×SU(2)L×SU(2)R×U(1)B-L(minimal left-right symmetry) assuming an additional global U(1) Peccei–Quinn symmetry, and having the Standard Model supplemented by a second Higgs doublet field at the electroweak scale. We derive the conditions as well as the approximate analytical solutions for the unification of the gauge coupling constants at the two-loop level and discuss the constraints from proton decay on the resulting high scale. Specializing to the case of the Pati–Salam intermediate breaking pattern, we then impose also the unification of the Yukawa couplings of third generation fermions at the high scale, again at the two-loop level. In the considered context, Yukawa unification implies a relation between the fermion couplings to the 10- and 126-dimensional scalar representations of the SO(10) group. We consider one such possible relation which is obtainable in an$$\text {E}_6$$E6model where the previous two scalar fields are part of a single multiplet. Taking into account some phenomenological features such as the absence of flavor changing neutral currents at tree-level, we derive constraints on the parameters of the low energy model, in particular on the ratio of the two Higgs doublets vacuum expectation values$$\tan \beta $$tanβ.
Transformer-Based Relational Inference Network for Complex Visual Relational Reasoning
Authors: Tan Mingkui , Wen Zhiquan , Fang Leyuan , Wu Qi 
Published: June 2023

Visual Relational Reasoning is the basis of many vision-and-language based tasks (e.g., visual question answering and referring expression comprehension). In this article, we regard the complex referring expression comprehension (c-REF) task as the reasoning basis, in which c-REF seeks to localise a target object in an image guided by a complex query. Such queries often contain complex logic and thus impose two critical challenges for reasoning: (i) Comprehending the complex queries is difficult since these queries usually refer to multiple objects and their relationships; (ii) Reasoning among multiple objects guided by the queries and then localising the target correctly are non-trivial. To address the above challenges, we propose a Transformer-based Relational Inference Network (Trans-RINet). Specifically, to comprehend the queries, we mimic the language-comprehending mechanism of humans, and devise a language decomposition module to decompose the queries into four types, i.e., basic attributes, absolute location, visual relationship and relative location. We further devise four modules to address the corresponding information. In each module, we consider the intra-(i.e., between the objects) and inter-modality relationships(i.e., between the queries and objects) to improve the reasoning ability. Moreover, we construct a relational graph to represent the objects and their relationships, and devise a multi-step reasoning method to progressively understand the complex logic. Since each type of the queries is closely related, we let each module interact with each other before making a decision. Extensive experiments on the CLEVR-Ref+, Ref-Reasoning, and CLEVR-CoGenT datasets demonstrate the superior reasoning performance of our Trans-RINet.
Cultivation of Microalgae Spirulina platensis Biomass Using Palm Oil Mill Effluent for Phycocyanin Productivity and Future Biomass Refinery Attributes
Authors: Palanisamy Karthick Murugan , Bhuyar Prakash , Ab. Rahim Mohd Hasbi , Govindan Natanamurugaraj , Maniam Gaanty Pragas 
Published: June 2023

Palm oil mill effluent is a type of wastewater which contains a high concentration of organic nitrogen, phosphorus, and different supplement substances. These substances support and enhance the growth of microalgae. Cyanobacteria Spirulina platensis is a blue-green microalga with two phycobiliproteins as its primary constituents. Phycocyanin is a natural blue colourant used in biomedicines, cosmetics, diagnostics, treatments, and environmental protection. Chlorophyll pigment plays a significant role in photosynthesis where the photosynthetic process uses atmospheric carbon to produce starch and lipid which can eventually be converted into desirable products such as biodiesel. Therefore, in this study, Spirulina platensis was cultivated in different concentrations of diluted POME (10-50%,

v
/
v

) at

26
±
1

°C room temperature, 90 μmol photon m-2 s-1, and aerated for 24 h continuously. The growth of Spirulina platensis was monitored through optical density at 680 nm for 15 days. The highest biomass yield obtained in the control medium and 30% POME medium were

1.27
±
0.02

and

1.16
±
0.01

g/L, respectively. The highest phycocyanin yield obtained from the biomass harvested from 30% nutrient media was

175.12
±
22.32

mg and followed by

163.55
±
20.15

mg from control media with purified phycocyanin of

87.11
±
5.20

mg and

85.31
±
4.33

mg, respectively. The peak properties of phycocyanin such as the amide group at 1655.17 cm-1 (C=O stretching), FT-IR analysis revealed well-formed Spirulina platensis with all characteristic peaks and distinct fingerprints of phycocyanin. The ultrasound method produces the highest lipid yield (

28.6
±
0.7

%) which consists of stearic (38.45%), palmitoleic (

25.72
±
0.02

), and palmitic (

17.71
±
0.04

) fatty acid methyl esters. The FAME produced from the extracted lipid has the potential to be used in biodiesel applications. Since POME contains the essential nutrients which can support the growth of Spirulina platensis in the optimum environment for biomass and lipid productivity, it revealed the potential for biodiesel production.
Whole Slide Imaging-Based Prediction of TP53 Mutations Identifies an Aggressive Disease Phenotype in Prostate Cancer
Authors: Pizurica Marija , Larmuseau Maarten , Van der Eecken Kim , de Schaetzen van Brienen Louise , Carrillo-Perez Francisco , Isphording Simon , Lumen Nicolaas , Van Dorpe Jo , Ost Piet , Verbeke Sofie , Gevaert Olivier , Marchal Kathleen 
Published: June 2023

Abstract

In prostate cancer, there is an urgent need for objective prognostic biomarkers that identify the metastatic potential of a tumor at an early stage. While recent analyses indicated TP53 mutations as candidate biomarkers, molecular profiling in a clinical setting is complicated by tumor heterogeneity. Deep learning models that predict the spatial presence of TP53 mutations in whole slide images (WSI) offer the potential to mitigate this issue. To assess the potential of WSIs as proxies for spatially resolved profiling and as biomarkers for aggressive disease, we developed TiDo, a deep learning model that achieves state-of-the-art performance in predicting TP53 mutations from WSIs of primary prostate tumors. In an independent multifocal cohort, the model showed successful generalization at both the patient and lesion level. Analysis of model predictions revealed that false positive (FP) predictions could at least partially be explained by TP53 deletions, suggesting that some FP carry an alteration that leads to the same histological phenotype as TP53 mutations. Comparative expression and histologic cell type analyses identified a TP53-like cellular phenotype triggered by expression of pathways affecting stromal composition. Together, these findings indicate that WSI-based models might not be able to perfectly predict the spatial presence of individual TP53 mutations but they have the potential to elucidate the prognosis of a tumor by depicting a downstream phenotype associated with aggressive disease biomarkers.

Significance:
Deep learning models predicting TP53 mutations from whole slide images of prostate cancer capture histologic phenotypes associated with stromal composition, lymph node metastasis, and biochemical recurrence, indicating their potential as in silico prognostic biomarkers.
See related commentary by Bordeleau, p. 2809
SENP1 Decreases RNF168 Phase Separation to Promote DNA Damage Repair and Drug Resistance in Colon Cancer
Authors: Wei Min , Huang Xinping , Liao Liming , Tian Yonglu , Zheng Xiaofeng 
Published: June 2023

AbstractThe DNA damage response (DDR) is essential for the maintenance of genomic stability. Protein posttranslational modifications play pivotal roles in regulating the DDR process. Here, we found that SUMOylated RNF168 undergoes liquid–liquid phase separation (LLPS), which restricts the recruitment of RNF168 to DNA damage sites, reduces RNF168-catalyzed H2A ubiquitination, restrains 53BP1 in nuclear condensates, and ultimately impairs nonhomologous DNA end joining repair efficiency. Sentrin/SUMO-specific protease 1 (SENP1) was identified as a specific deSUMOylase of RNF168, and it was highly expressed in colorectal adenocarcinoma. In response to DNA damage, SENP1 decreased RNF168 SUMOylation and prevented RNF168 from forming nuclear condensates, thus promoting damage repair efficiency and cancer cell resistance to DNA damaging agents. Moreover, high SENP1 expression correlated with poor prognosis in patients with cancer, and SENP1 depletion sensitized cancer cells to chemotherapy. In summary, these findings reveal DDR is suppressed by SUMOylation-induced LLPS of RNF168 and suggest that SENP1 is a potential target for cancer therapy.Significance:Sentrin/SUMO-specific protease 1 decreases RNF168 SUMOylation and liquid–liquid phase separation to promote DNA damage repair, safeguarding genomic integrity and driving chemotherapy resistance.
Targeting Upregulated cIAP2 in SOX10-Deficient Drug Tolerant Melanoma
Authors: Glasheen McKenna Q. , Caksa Signe , Young Amelia G. , Wilski Nicole A. , Ott Connor A. , Chervoneva Inna , Flaherty Keith T. , Herlyn Meenhard , Xu Xiaowei , Aplin Andrew E. , Capparelli Claudia 
Published: June 2023

Abstract
Drug tolerance and minimal residual disease (MRD) are likely to prelude acquired resistance to targeted therapy. Mechanisms that allow persister cells to survive in the presence of targeted therapy are being characterized but selective vulnerabilities for these subpopulations remain uncertain. We identified cellular inhibitor of apoptosis protein 2 (cIAP2) as being highly expressed in SOX10-deficient drug tolerant persister (DTP) melanoma cells. Here, we show that cIAP2 is sufficient to induce tolerance to MEK inhibitors, likely by decreasing the levels of cell death. Mechanistically, cIAP2 is upregulated at the transcript level in SOX10-deficient cells and the AP-1 complex protein, JUND, is required for its expression. Using a patient-derived xenograft model, we demonstrate that treatment with the cIAP1/2 inhibitor, birinapant, during the MRD phase delays the onset of resistance to BRAF inhibitor and MEK inhibitor combination therapy. Together, our data suggest that cIAP2 upregulation in SOX10-deficient subpopulations of melanoma cells induces drug tolerance to MAPK targeting agents and provides a rationale to test a novel therapeutical approach to target MRD.
HCK Promotes High-Grade Serous Ovarian Cancer Tumorigenesis through CD44 and NOTCH3 Signaling
Authors: Khella Christen A. , Franciosa Lucyann , Rodirguez-Rodriguez Lorna , Rajkarnikar Resha , Mythreye Karthikeyan , Gatza Michael L. 
Published: June 2023

Abstract

High-grade serous ovarian cancer (HGSOC) is a highly aggressive and lethal subtype of ovarian cancer. While most patients initially respond to standard-of-care treatment, the majority will eventually relapse and succumb to their disease. Despite significant advances in our understanding of this disease, the mechanisms that govern the distinctions between HGSOC with good and poor prognosis remain unclear. In this study, we implemented a proteogenomic approach to analyze gene expression, proteomic and phosphoproteomic profiles of HGSOC tumor samples to identify molecular pathways that distinguish HGSOC tumors relative to clinical outcome. Our analyses identify significant upregulation of hematopoietic cell kinase (HCK) expression and signaling in poor prognostic HGSOC patient samples. Analyses of independent gene expression datasets and IHC of patient samples confirmed increased HCK signaling in tumors relative to normal fallopian or ovarian samples and demonstrated aberrant expression in tumor epithelial cells. Consistent with the association between HCK expression and tumor aggressiveness in patient samples, in vitro phenotypic studies showed that HCK can, in part, promote cell proliferation, colony formation, and invasive capacity of cell lines. Mechanistically, HCK mediates these phenotypes, partly through CD44 and NOTCH3-dependent signaling, and inhibiting CD44 or NOTCH3 activity, either genetically or through gamma-secretase inhibitors, can revert HCK-driven phenotypes.

Implications:
Collectively, these studies establish that HCK acts as an oncogenic driver of HGSOC through aberrant activation of CD44 and NOTCH3 signaling and identifies this network as a potential therapeutic opportunity in a subset of patients with aggressive and recurrent HGSOC.
Experiential Learning and Self-Efficacy in Physical Education of the Senior High School Students
Authors: Calubayan John Carlo T. , Ofrin Darwin O. 
Published: June 2023

This study aimed to determine the level of involvement of senior high school students in experiential learning and also to determine of their described self-efficacy in physical education. This employed the research and descriptive correlation design of quantitative method as participated by three hundred fifty (350) senior high school respondents in San Isidro National High School who were chosen using purposive sampling procedures. The data were gathered using survey questionnaires which are validated with the help of the experts. Data communication was established before data gathering procedures and was analyzed using weighted mean, standard deviation, and Pearson’s r.
Findings revealed that senior high school students agreed that they were involved in experiential learning. Students enhanced and boosted their self-efficacy through the use of mastery experiences, social modeling, social persuasions, and psychological responses. It was concluded that there’s a significant and strong positive correlation between experiential learning and students’ self-efficacy. It implied that as the students engage more in experiential learning, the higher the chance the students’ self-efficacy developed. Otherwise, the lesser engagement in experiential learning, the lower of chance developing self-efficacy. Based on the conclusion, it was recommended that the teachers are also recommended to motivate their students in involving experiential for them to mold and described their self-efficacy in engaging in physical activities.
Management of Patients With Patent Foramen Ovale and Stroke: A National Survey of Interventional Cardiologists and Vascular Neurologists
Authors: Khan Farhan , Derbas Laith A. , Messé Steven R. , Kavinsky Clifford , Kasner Scott E. , Favilla Christopher G. 
Published: June 2023

Background
Results from multiple clinical trials support patent foramen ovale closure after cryptogenic stroke in select patients, but it remains unclear how new data and updated professional society guidelines have impacted clinical practice. Here, we aimed to compare how stroke neurologists and interventional cardiologists approach patients with cryptogenic stroke with patent foramen ovale and how critical anatomic and clinical factors influence decision making.

Methods and Results

An electronic survey was administered to 1556 vascular neurologists and 1057 interventional cardiologists throughout the United States. The survey addressed factors such as patient age, preclosure workup, and postclosure antithrombotics. Clinical vignettes highlighted critical variables and used a 5‐point Likert scale to assess the providers' level of support for closure. There were 491 survey responses received from 301 (of 1556) vascular neurologists and 190 (of 1057) interventional cardiologists, with an overall response rate of 19%. Vascular neurologists were more likely to recommend against closure on the basis of older age (
P
<0.001). Interventional cardiologists are more supportive of closure across a range of clinical vignettes, including a very carefully selected patient with cryptogenic stroke (
P
<0.001), a patient with a high‐risk alternative stroke cause (
P
<0.001), and a range of cases highlighting clinical variables where data are lacking. The majority of interventionalists (88%) seek neurology consultation before pursuing patent foramen ovale closure.

Conclusions
lnterventional cardiologists are more likely than vascular neurologists to support patent foramen ovale closure across a range of situations. This emphasizes the importance of collaboration and shared decision making, but also reveals an opportunity for professional society educational outreach.
Keeping Promises? Democracies’ Ability to Harmonize Their International and National Climate Commitments
Authors: Baker Jack Kessel 
Published: June 2023

Abstract
Since the adoption of the Paris Agreement, global emissions have put the world beyond its goals. While there are calls for increasing ambition, countries must match their current international commitments at the national level. Democracies were assumed to comply with their own international commitments, yet their ability to adopt national mitigation policies that are consistent with their nationally determined contributions (NDCs) varies. This study applies the Vertical Policy Harmonization Index to quantify the extent to which countries’ mitigation commitments are vertically harmonized in their NDCs and national policies. Using qualitative comparative analysis, I investigate the role of institutions, interests, and ideas in shaping the vertical (dis)harmony of twenty-four democracies. I find that fossil fuel dependency constrains the harmonization of mitigation commitments, even in the face of high vulnerability and low abatement costs. Moreover, the results support the previous findings of an ambiguous relationship between veto points and mitigation commitment. However, the roles of an established green party and public opinion in shaping disharmony remain unclear.
Articulating Design Thinking and Integrative STEM Learning through Virtual Dissection Activity
Authors: Tan Da Yang , Koh Li Ling Apple , Kwan Wei Lek , Pee Gim-Yang Maggie 
Published: June 2023

Abstract
This article chronicles the implementation of virtual dissection and redesign activity as part of a special summer programme for a undergraduate year 1 engineering course on thermodynamics and energy systems. Students were tasked to perform a virtual dissection of a mosquito trap to identify the components and establish their functionalities, then ideated areas of improvement of the existing design through the 3D CAD model. Thereafter, students spent the remainder of the programme deriving and building possible designs, where they rapid prototyped their own version of the mosquito trap. The activity culminated with a challenge where their prototypes were subjected to actual site testing to establish the prototype’s efficacy. This case study explores the cohesion between design thinking, design processes and integrated STEM learning through the analysis of the field notes, video artefacts, online collaborative worksheets, and completed prototypes, shedding light on the affordance of the design activity on integrated STEM learning.