bluuebunny/crossref_metadata_2025 huggingface dataset:
Living without Beth and Craig: Definitions and Interpolants in Description and Modal Logics with Nominals and Role Inclusions
Authors: Artale Alessandro , Jung Jean Christoph , Mazzullo Andrea , Ozaki Ana , Wolter Frank
Published: June 2023

The Craig interpolation property (CIP) states that an interpolant for an implication exists iff it is valid. The projective Beth definability property (PBDP) states that an explicit definition exists iff a formula stating implicit definability is valid. Thus, the CIP and PBDP reduce potentially hard existence problems to entailment in the underlying logic. Description (and modal) logics with nominals and/or role inclusions do not enjoy the CIP nor the PBDP, but interpolants and explicit definitions have many applications, in particular in concept learning, ontology engineering, and ontology-based data management. In this article, we show that, even without Beth and Craig, the existence of interpolants and explicit definitions is decidable in description logics with nominals and/or role inclusions such as 𝒜ℒ𝒞𝒪, 𝒜ℒ𝒞ℋ, and 𝒜ℒ𝒞ℋ𝒪ℐ and corresponding hybrid modal logics. However, living without Beth and Craig makes these problems harder than entailment: the existence problems become
2ExpTime
-complete in the presence of an ontology or the universal modality, and
coNExpTime
-complete otherwise. We also analyze explicit definition existence if all symbols (except the one that is defined) are admitted in the definition. In this case, the complexity depends on whether one considers individual or concept names. Finally, we consider the problem of computing interpolants and explicit definitions if they exist and turn the complexity upper bound proof into an algorithm computing them, at least for description logics with role inclusions.
Side-channel and Fault-injection attacks over Lattice-based Post-quantum Schemes (Kyber, Dilithium): Survey and New Results
Authors: Ravi Prasanna , Chattopadhyay Anupam , D’Anvers Jan Pieter , Baksi Anubhab
Published: June 2023

In this work, we present a systematic study of Side-Channel Attacks (SCA) and Fault Injection Attacks (FIA) on structured lattice-based schemes, with main focus on Kyber Key Encapsulation Mechanism (KEM) and Dilithium signature scheme, which are leading candidates in the NIST standardization process for Post-Quantum Cryptography (PQC). Through our study, we attempt to understand the underlying similarities and differences between the existing attacks while classifying them into different categories. Given the wide variety of reported attacks, simultaneous protection against all the attacks requires to implement customized protections/countermeasures for both Kyber and Dilithium. We therefore present a range of customized countermeasures, capable of providing defenses/mitigations against existing SCA/FIA, and incorporate several SCA and FIA countermeasures within a single design of Kyber and Dilithium. Among the several countermeasures discussed in this work, we present novel countermeasures that offer simultaneous protection against several SCA- and FIA-based chosen-ciphertext attacks for Kyber KEM. We implement the presented countermeasures within two well-known public software libraries for PQC: (1)
pqm4
library for the ARM Cortex-M4-based microcontroller and (2)
liboqs
library for the Raspberry Pi 3 Model B Plus based on the ARM Cortex-A53 processor. Our performance evaluation reveals that the presented custom countermeasures incur reasonable performance overheads on both the evaluated embedded platforms. We therefore believe our work argues for usage of custom countermeasures within real-world implementations of lattice-based schemes, either in a standalone manner or as reinforcements to generic countermeasures such as masking.
Making Sense of Citizens’ Input through Artificial Intelligence: A Review of Methods for Computational Text Analysis to Support the Evaluation of Contributions in Public Participation
Authors: Romberg Julia , Escher Tobias
Published: June 2023

Public sector institutions that consult citizens to inform decision-making face the challenge of evaluating the contributions made by citizens. This evaluation has important democratic implications but at the same time, consumes substantial human resources. However, until now the use of artificial intelligence such as computer-supported text analysis has remained an under-studied solution to this problem. We identify three generic tasks in the evaluation process that could benefit from natural language processing (NLP). Based on a systematic literature search in two databases on computational linguistics and digital government, we provide a detailed review of existing methods and their performance. While some promising approaches exist, for instance to group data thematically and to detect arguments and opinions, we show that there remain important challenges before these could offer any reliable support in practice. These include the quality of results, the applicability to non-English language corpuses and making algorithmic models available to practitioners through software. We discuss a number of avenues that future research should pursue that can ultimately lead to solutions for practice. The most promising of these bring in the expertise of human evaluators, for example through active learning approaches or interactive topic modeling.
Autocrine proteinase-activated receptor signaling in PC3 prostate cancer cells
Authors: Chandrabalan Arundhasa , Ramachandran Rithwik
Published: June 2023

Proteinase-activated receptors (PARs) are G protein-coupled receptors (GPCRs) activated by limited n-terminal proteolysis. PARs are highly expressed in many cancer cells, including prostate cancer (PCa), and regulate various aspects of tumor growth and metastasis. Specific activators of PARs in different physiological and pathophysiological contexts remain poorly defined. In this study, we examined the androgen-independent human prostatic cancer cell line PC3 and find the functional expression of PAR1 and PAR2, but not PAR4. Using genetically encoded PAR cleavage biosensors, we showed that PC3 cells secrete proteolytic enzymes that cleave PARs and trigger autocrine signaling. CRISPR/Cas9 targeting of PAR1 and PAR2 combined with microarray analysis revealed genes that are regulated through this autocrine signaling mechanism. We found several genes that are known PCa prognostic factors or biomarker to be differentially expressed in the PAR1-knockout (KO) and PAR2-KO PC3 cells. We further examined PAR1 and PAR2 regulation of PCa cell proliferation and migration and found that absence of PAR1 promotes PC3 cell migration and suppresses cell proliferation, whereas PAR2 deficiency showed opposite effects. Overall, these results demonstrate that autocrine signaling through PARs is an important regulator of PCa cell function.
Hematoloechus sp. attachment shifts endothelium in vivo from pro- to anti-inflammatory profile in Rana pipiens: evidence from systemic and capillary physiology
Authors: Williams Donna A. , Flood Mary H.
Published: June 2023

This prospective, descriptive study focused on lung flukes ( Hematoloechus sp., H) and their impact on systemic and individual capillary variables measured in pithed Rana pipiens, a long-standing model for studies of capillary physiology. Three groups were identified based on Hematoloechus attachment: no Hematoloechus (No H), Hematoloechus not attached ( H Not Att), and Hematoloechus attached ( H Att). Among 38 descriptive, cardiovascular, and immunological variables, 18 changed significantly with H. Symptoms of H included weight loss, elevated immune cells, heart rate variability, faster coagulation, lower hematocrit, and fluid accumulation. Important capillary function discoveries included median baselines for hydraulic conductivity ( Lp) of 7.0 (No H), 12.4 ( H Not Att), and 4.2 ( H Att) × 10−7 cm·s−1·cmH2O−1 ( P < 0.0001) plus seasonal adaptation of sigma delta pi [σ(πc–πi), P = 0.03]. Pro- and anti-inflammatory phases were revealed for Lp and plasma nitrite/nitrate concentration ([NOx]) in both H Not Att and H Att, whereas capillary wall tensile strength increased in the H Att. H attachment was advantageous for the host due to lower edema and for the parasite via a sustained food source illustrating an excellent example of natural symbiosis. However, H attachment also resulted in host weight loss: in time, a conundrum for the highly dependent parasite. The study increases overall knowledge of Rana pipiens by revealing intriguing effects of H and previously unknown, naturally occurring seasonal changes in many variables. The data improve Rana pipiens as a general scientific and capillary physiology model. Diseases of inflammation and stroke are among the clinical applications.
Acute Hepatitis A and Hepatitis B Coinfection in a Young Female: A Case Report and Literature Review
Authors: Lashkarbolouk Narges , Khodabakhshi Behnaz , Mazandarani Mahdi
Published: June 2023

Background. Hepatitis is one of the common infectious diseases that can infect patients in various forms. Based on their characteristics and clinical features, they can cause irreparable complications in patients. Coinfections and superinfections between its variant have been reported, but the coinfection of acute HAV and HBV is rarely reported. Case Presentation. In this case report, we presented a case with severe malaise, nausea, vomiting, generalized jaundice, and a history of recent tattooing and travel to the HAV endemic area. In our evaluation, she had a positive HBsAg, HBeAg, anti-HBs IgM, anti-HAV IgM, and negative result in HCV antibody, HIV antibody, and anti-HAV IgG. The coinfection of HAV/HBV was confirmed for her. Conclusion. Physicians should differentiate hepatitis A and hepatitis B superinfection or coinfection, based on history and laboratory testing, to prevent complications with appropriate treatment.
A Function Area Division Approach for Autonomous Transportation System Based on Text Similarity
Authors: Huang Ke , Chen Caiting , Xiao Yao , Cai Ming
Published: June 2023

Along with emerging technologies and increasing demands, autonomation has become a significant trend in current transportation systems. Within this context, the autonomous transportation system (ATS) framework hinges on functions that serve as fundamental units to support its operation. Recognizing the divisions among these function areas can enhance our understanding of their meanings and interrelationships. This study introduces a method for dividing function areas within the ATS framework, grounded in text similarity, to mitigate reliance on subjective experience. Precisely, this method quantifies the similarity between functions based on their textual descriptions, and implements hierarchical clustering to delineate them into distinct function areas. To validate the effectiveness of this proposed method, a case study analyzing a vehicle automatic driving scenario was conducted. The results demonstrate that our approach can efficiently divide function areas, producing clustering outcomes that possess superior accuracy and purity when juxtaposed with reference classifications. Consequently, this method has the potential to facilitate the formulation of function areas within ATS, thereby supporting the autonomous operation and construction of ATS. Moreover, its applicability extends beyond ATS, showing promise for other clustering problems that involve multiple texts, such as in text classification.
Effects of CAR-T Cell Therapy on Immune Cells and Related Toxic Side Effect Analysis in Patients with Refractory Acute Lymphoblastic Leukemia
Authors: Li Lianlian , Gao Jie , Sun Zhaojun , Li Xiaolei , Wang Ning , Zhang Rui
Published: June 2023

Objective. To observe the effects of chimeric antigen receptor T (CAR-T) cell immunotherapy on immune cells and related toxic side effects in patients with refractory acute lymphoblastic leukemia (ALL). Methods. A retrospective study was conducted in 35 patients with refractory ALL. The patients were treated with CAR-T cell therapy in our hospital from January 2020 to January 2021. The efficacy was evaluated at one and three months post treatments. The venous blood of the patients was collected before treatment, 1 month after treatment, and 3 months after treatment. The percentage of regulatory T cells (Treg cells), natural killer (NK) cells, and T lymphocyte subsets (CD3+, CD4+, and CD8+ T cells) was detected by flow cytometry. The ratio of CD4+/CD8+ was calculated. Patient’s toxic side effects such as fever, chills, gastrointestinal bleeding, nervous system symptoms, digestive system symptoms, abnormal liver function, and blood coagulation dysfunction were monitored and recorded. The incidence of toxic and side effects was calculated, and the incidence of infection was recorded. Results. After one month of CAR-T cell therapy in 35 patients with ALL, the efficacy evaluation showed that complete response (CR) patients accounted for 68.57%, CR with incomplete hematological recovery (CRi) patients accounted for 22.86%, and partial disease (PD) patients accounted for 8.57%, and the total effective rate was 91.43%. In addition, compared with that before treatment, the Treg cell level in CR+CRi patients treated for 1 month and 3 months decreased prominently, and the NK cell level increased dramatically (

P
<
0.05

). Compared with that before treatment, the levels of CD3+, CD4+, and CD4+/CD8+ in patients with CR+CRi in the 1-month and 3-month groups were markedly higher, and the levels of CD4+/CD8+ in the 3-month group were memorably higher than those in the 1-month group (

P
<
0.05

). During CAR-T cell therapy in 35 patients with ALL, fever accounted for 62.86%, chills for 20.00%, gastrointestinal bleeding for 8.57%, nervous system symptoms for 14.29%, digestive system symptoms for 28.57%, abnormal liver function for 11.43%, and coagulation dysfunction for 8.57%. These side effects were all relieved after symptomatic treatment. During the course of CAR-T therapy in 35 patients with ALL, 2 patients had biliary tract infection and 13 patients had lung infection. No correlations were found between the infection and age, gender, CRS grade, usage of glucocorticoids or tocilizumab, and laboratory indicators such as WBC, ANC, PLT, and Hb (

P
>
0.05

). Conclusion. CAR-T cell therapy had a good effect on patients with refractory ALL by regulating the immune function of the body via mediating the content of immune cells. CAR-T cell therapy may have therapeutic effect on refractory ALL patients with mild side effects and high safety.
An Empirical Analysis of the Impact of the China Free Trade Zone on the Level of Human Capital Based on the Asymptotic PSM-DID Model
Authors: Xie Ruijun , Wang Rong , Zhang Duolei
Published: June 2023

The article selects relevant data from 283 cities in China from 2000 to 2020 and verifies the impact of the establishment of free trade zones on human capital levels based on the asymptotic PSM-DID model. It is found that the establishment of FTZs can significantly contribute to the improvement of regional human capital levels, but the promotion effect has a certain lag. Finally, the article gives constructive suggestions based on the empirical results.
In Situ Compositional Analysis of Tomato Plants and Cell Wall Using Fiber Optic Fourier-Transform Near-Infrared Spectroscopy
Authors: Tewari Raghav , Joshi Ritu
Published: June 2023

This research was intended to define and interpret cell wall attributes and other chemical composition of eight different varieties of tomato plants by utilizing fiber optic Fourier-transform near-infrared spectroscopy (FT-NIR) to acquire in situ chemical signatures of leaf, flower, fruit, and stem of tomato plant and cell wall at different developmental stages. Chemical spectral signatures of the tomato’s leaf, flower, fruit, and stem were only acquired during its session and in live mode such as green, yellow, and red in cell wall color. The spectral signature analysis of each tomato plant was performed to see substantial differences in chemical compositions using chemometric data modeling of FT-NIR spectra. In addition, principal component analysis (PCA) was performed to discriminate leaf, flower, fruit, and stem from the same variety. PCA was also performed to differentiate eight different varieties of tomato plants. The study showed how in situ FT-NIR could distinguish eight types of tomato leaf, flower, fruit, and stem chemical composition at different developmental stages related to cell wall and other attributes. This study has also demonstrated how in situ FT-NIR can discriminate between rusty vs. healthy leaf and intact fruit vs. off-the-plant fruit. The main objective of this study is to present the chemical signature differences in the live and developing tomato plants to improve crucial factors of tomatoes that would benefit plant breeding, tomato cell wall study, and ultimately human health.
The Effect of Sweeping Media and Temperature on Aqueous CO2 Removal Using Hollow Fiber Membrane Contactor (HFMC): An Experimental Determination
Authors: Tabesh Hadi , Gholami Mohammad Hossein , Marefat Marjan
Published: June 2023

Transport phenomena through hollow fiber membrane contactors (HFMCs) indicate the exchange of a component between the two phases, inside and outside of hollow fibers. In this research, we designed and fabricated lab-made HFMCs to assess the difference between water and air as sweeping media for CO2 exchange. The effects of flow rates and temperature ratios on aqueous CO2 absorption were investigated accordingly. A semiclosed circuit incorporating our fabricated HFMCs was set up to regulate the operating parameters and evaluate the aqueous CO2 concentration using an initiative pH-based method. The results of our experiments remarkably reveal that air tends to remove aqueous CO2 more than water when aqueous CO2 concentration is higher than 3.53 × 10−6 mlCO2/l. However, water would surpass air in lower concentrations. Nevertheless, tripling the flow rate of sweeping media from 500 to 1500 ml/min shifts up this cutoff point 50 times to around 1.66 × 10−4 mlCO2/l. The experiments performed at three different temperature ratios of 22 : 22, 44 : 12, and 22 : 12°C (CO2-rich liquid: sweeping medium) demonstrated that a higher temperature gradient deteriorates the CO2 absorption capacity of sweeping media. Nonetheless, temperature gradient becomes highly effective in aqueous CO2 concentrations lower than 1.57 × 10−6 CO2/l. The results of this research could be applied in performance optimization of aqueous CO2 absorbing HFMCs, even in sophisticated medical procedures such as arterio-venous and veno-venous CO2 removal systems where both water and air could be used as blood’s CO2 sweeping media.
DIBR–DOMBI–FUZZY MAIRCA Model for Strategy Selection in the System of Defense
Authors: Tešić Duško , Božanić Darko , Stojković Dejan , Puška Adis , Stojanović Ilija
Published: June 2023

Strategic management has applications in many areas of social life. One of the basic steps in the process of strategic management is formulating a strategy by choosing the optimal strategy. Improving the process of selecting the optimal strategy with MCDM methods and theories that treat uncertainty well in this process, as well as the application of other and different selection criteria, is the basic idea and goal of this research. The improvement of the process of the aforementioned selection in the defense system was carried out by applying a hybrid model of multicriteria decision-making based on methods defining interrelationships between ranked criteria (DIBR) and multiattributive ideal-real comparative analysis (MAIRCA) modified by triangular fuzzy numbers–“DIBR–DOMBI–Fuzzy MAIRCA model.” The DIBR method was used to determine the weight coefficients of the criteria, while the selection of the optimal strategy, from the set of offered methods, was carried out by the MAIRCA method. This was done in a fuzzy environment with the aim of better treatment of imprecise information and better translation of quantitative data into qualitative data. In the research, an analysis of the model’s sensitivity to changes in weight coefficients was performed. Additionally, a comparison of the obtained results with the results obtained using other multicriteria decision-making methods was conducted, which validated the model and confirmed stable results. In the end, it was concluded that the proposed MCDM methodology can be used for choosing a strategy in the defense system, that the results of the MCDM model are stable and valid, and that the process has been improved by making the choice easier for decision makers and by defining new and more comprehensive criteria for selection.
Association of COMT Val158Met Polymorphism with Fibromyalgia in Khartoum State, Sudan
Authors: Mamoun Abdelmageid Safaa , Mousa Alamir Faisal , Yousif Abdelrahman Hassan , Mohamed Abushama Hind
Published: June 2023

Fibromyalgia (FM) is a disorder characterized by chronic musculoskeletal pain, fatigue, and cognitive problems. Neurotransmitters, mainly catecholamines, appear to be involved in regulating the etiology of FM. Catechol-O-methyltransferase (COMT) is involved in catabolizing catecholamines such as norepinephrine. The most common variant studied in the COMT gene is the valine (Val) to methionine (Met) substitution at codon 158. This is the first study in Sudan addressing FM cases and genetic susceptibility to the disease. We aimed in this study to investigate the frequency of COMT Val 158 Met polymorphism among patients with FM, rheumatoid arthritis, and in healthy individuals. Genomic DNA from forty female volunteers was analyzed: twenty were from primary and secondary FM patients, ten were from rheumatoid arthritis patients, and ten were from healthy control. FM patients’ age was ranging from 25 years to 55 with a mean of 41.14 ± 8.90. The mean age of the rheumatoid arthritis patients and healthy individuals was 31.3 ± 7.5 and 38.6 ± 11.2, respectively. Samples were genotyped for COMT single nucleotide polymorphism rs4680 (Val158Met), using the amplification-refractory mutation system (ARMS-PCR). Genotyping data have been analyzed using the Chi-square and Fisher exact test. The most common genotype among the study participants was the heterozygous Val/Met found in all participants. It was the only genotype found in the healthy participants. The genotype Met/Met was found only in FM patients. The genotype Val/Val was found only in rheumatoid patients. Analyses have shown no association between the Met/Met genotype and FM, and this could be due to a small sample size. In a larger sample size, a significant association could be found as this genotype was shown only by FM patients. Moreover, the Val/Val genotype, which is shown only among rheumatoid patients, might protect them from developing FM symptoms.
Diagnostic Accuracy of p16INK4a/Ki‐67 Dual Immunostaining for Detection of High‐Grade Cervical Intraepithelial Neoplasia in Women Involved in Cervical Cancer Screening in Georgia
Authors: Kakaliashvili-Dzagnidze Sopio , Khardzeishvili Omar , Tabagari Sergo
Published: June 2023

Background. Despite the widespread introduction of primary and secondary preventative measures, death rates for cervical cancer are still significantly high among females, especially in developing countries. Pap cytology and human papillomavirus‐based screening often lead to unnecessary additional testing. The aim of this study is to analyze diagnostic accuracy of p16INK4a/Ki‐67 dual immunostaining (DS) in cervical smear for identifying high‐grade cervical intraepithelial neoplasia (CIN2+). Materials and Methods. We studied the diagnostic performance of p16INK4a/Ki‐67 DS in cervical smear of those women, who enrolled in cervical cancer screening due to abnormal previous screening results and compared it with Pap test results in identifying CIN2+. The reference standard was histopathology results. p16INK4a/Ki‐67 DS and Pap test results for 162 women and histopathology results for 29 women were available, respectively. Results. In our study, sensitivity, specificity, positive predictive value, and negative predictive value of p16INK4a/Ki‐67 DS, irrespective of the morphology of stained cells to detect CIN2+ were 100%, 89%, 85%, and 100% (p < 0.01), respectively. The diagnostic accuracy of p16INK4a/Ki‐67 DS is superior to that of existing cervical screening tests in the detection of CIN2+. Conclusion. The findings of cervical cancer screening based on Pap cytology highlight the importance of assessing the cost‐effectiveness of integrating p16INK4a/Ki‐67 biomarkers in cervical cancer cytology. Furthermore, these findings emphasize the need to enhance support for preventive programs for cervical cancer in Georgia.
The Interannual Relationship between the Diabatic Heating over the South Asia and the Snow Depth over the Southern Tibetan Plateau in Late Spring to Early Summer: Roles of the Air Temperature
Authors: Zhang Chengyang , Zheng Zhihai , Ou Yi , Zhang Tuantuan , Xiao Zhixiang , Lai Sheng , Cai Yuexing , Chen Sirong , Qin Weijian , He Hui
Published: June 2023

The southern Tibetan Plateau (TP) is snow covered during cold season but exhibits faster snow melting in early summer. Using in situ observations and improved satellite-derived data, the present study indicates that the snow depth (SD) over the southern TP exhibits distinction characteristics between late spring (i.e., P1: April 16th–May 15th) and early summer (i.e., P2: May 16th–June 14th). In terms of climate states, the snow melting rate over the southern TP in P2 is faster than that in P1. The acceleration of snow melting during P2 is mainly found over high elevation areas caused by the increase of local air temperature. Diagnoses of the thermodynamic equation further demonstrate that the warming over the southern TP during the two periods is mainly attributed to the meridional temperature advection and diabatic heating in situ. On the interannual time scale, the SD over the southern TP is closely related to diabatic heating over South Asia. During P1, the diabatic cooling from the southern Bay of Bengal eastward to the western South China Sea suppresses convection over the Bay of Bengal and southern TP and has resulted in an upper-level anomalous cyclone and cold temperature anomalies from the surface to 200 hPa over the southern TP, favoring the above-normal SD over the southern TP. On the other hand, SD over the southern TP in P2 is closely related to diabatic cooling over the northern Indochina Peninsula and diabatic heating over the southern China. But we could not prove that these diabatic heating anomalies can affect the SD over the southern TP by modulating local surface air temperature. This may be limited by the quality of the data and the simulation capability of the simple model.
Oxidative Phosphorylation Fueled by Fatty Acid Oxidation Sensitizes Leukemic Stem Cells to Cold
Authors: Griessinger Emmanuel , Pereira-Martins Diego , Nebout Marielle , Bosc Claudie , Saland Estelle , Boet Emiline , Sahal Ambrine , Chiche Johanna , Debayle Delphine , Fleuriot Lucile , Pruis Maurien , De Mas Véronique , Vergez François , Récher Christian , Huls Gerwin , Sarry Jean-Emmanuel , Schuringa Jan Jacob , Peyron Jean-François
Published: June 2023

Dependency on mitochondrial oxidative phosphorylation (OxPhos) is a potential weakness for leukemic stem cells (LSC) that can be exploited for therapeutic purposes. Fatty acid oxidation (FAO) is a crucial OxPhos-fueling catabolic pathway for some acute myeloid leukemia (AML) cells, particularly chemotherapy-resistant AML cells. Here, we identified cold sensitivity at 4°C (cold killing challenge; CKC4), commonly used for sample storage, as a novel vulnerability that selectively kills AML LSCs with active FAO-supported OxPhos while sparing normal hematopoietic stem cells. Cell death of OxPhos-positive leukemic cells was induced by membrane permeabilization at 4°C; by sharp contrast, leukemic cells relying on glycolysis were resistant. Forcing glycolytic cells to activate OxPhos metabolism sensitized them to CKC4. Lipidomic and proteomic analyses showed that OxPhos shapes the composition of the plasma membrane and introduces variation of 22 lipid subfamilies between cold-sensitive and cold-resistant cells. Together, these findings indicate that steady-state energy metabolism at body temperature predetermines the sensitivity of AML LSCs to cold temperature, suggesting that cold sensitivity could be a potential OxPhos biomarker. These results could have important implications for designing experiments for AML research to avoid cell storage at 4°C.

Significance:

Mitochondrial metabolism fueled by FAO alters the membrane composition and introduces membrane fragility upon cold exposure in OxPhos-driven AML and in LSCs.

See related commentary by Jones, p. 2441
Table S7 from SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy
Authors: Drilon Alexander , Sharma Manish R. , Johnson Melissa L. , Yap Timothy A. , Gadgeel Shirish , Nepert Dale , Feng Gang , Reddy Micaela B. , Harney Allison S. , Elsayed Mohamed , Cook Adam W. , Wong Christina E. , Hinklin Ronald J. , Jiang Yutong , Brown Eric N. , Neitzel Nickolas A. , Laird Ellen R. , Wu Wen-I , Singh Anurag , Wei Ping , Ching Keith A. , Gaudino John J. , Lee Patrice A. , Hartley Dylan P. , Rothenberg S. Michael
Published: June 2023

Supplementary Table 7: Adverse events for Dose Level 1 patients
Table S6 from SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy
Authors: Drilon Alexander , Sharma Manish R. , Johnson Melissa L. , Yap Timothy A. , Gadgeel Shirish , Nepert Dale , Feng Gang , Reddy Micaela B. , Harney Allison S. , Elsayed Mohamed , Cook Adam W. , Wong Christina E. , Hinklin Ronald J. , Jiang Yutong , Brown Eric N. , Neitzel Nickolas A. , Laird Ellen R. , Wu Wen-I , Singh Anurag , Wei Ping , Ching Keith A. , Gaudino John J. , Lee Patrice A. , Hartley Dylan P. , Rothenberg S. Michael
Published: June 2023

Supplementary Table 6: Disposition of all patients enrolled to Dose Level 1
Supplementary Methods from SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy
Authors: Drilon Alexander , Sharma Manish R. , Johnson Melissa L. , Yap Timothy A. , Gadgeel Shirish , Nepert Dale , Feng Gang , Reddy Micaela B. , Harney Allison S. , Elsayed Mohamed , Cook Adam W. , Wong Christina E. , Hinklin Ronald J. , Jiang Yutong , Brown Eric N. , Neitzel Nickolas A. , Laird Ellen R. , Wu Wen-I , Singh Anurag , Wei Ping , Ching Keith A. , Gaudino John J. , Lee Patrice A. , Hartley Dylan P. , Rothenberg S. Michael
Published: June 2023

Supplementary Data Title Page, Methods, References
Figure S7 from SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy
Authors: Drilon Alexander , Sharma Manish R. , Johnson Melissa L. , Yap Timothy A. , Gadgeel Shirish , Nepert Dale , Feng Gang , Reddy Micaela B. , Harney Allison S. , Elsayed Mohamed , Cook Adam W. , Wong Christina E. , Hinklin Ronald J. , Jiang Yutong , Brown Eric N. , Neitzel Nickolas A. , Laird Ellen R. , Wu Wen-I , Singh Anurag , Wei Ping , Ching Keith A. , Gaudino John J. , Lee Patrice A. , Hartley Dylan P. , Rothenberg S. Michael
Published: June 2023

Supplementary Figure 7: PF-07284892 sensitizes a patient with GOPC-ROS1 fusion-positive pancreatic cancer to lorlatinib
Figure S6 from SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy
Authors: Drilon Alexander , Sharma Manish R. , Johnson Melissa L. , Yap Timothy A. , Gadgeel Shirish , Nepert Dale , Feng Gang , Reddy Micaela B. , Harney Allison S. , Elsayed Mohamed , Cook Adam W. , Wong Christina E. , Hinklin Ronald J. , Jiang Yutong , Brown Eric N. , Neitzel Nickolas A. , Laird Ellen R. , Wu Wen-I , Singh Anurag , Wei Ping , Ching Keith A. , Gaudino John J. , Lee Patrice A. , Hartley Dylan P. , Rothenberg S. Michael
Published: June 2023

Supplementary Figure 6: PK profiles for patients
Data from SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy
Authors: Drilon Alexander , Sharma Manish R. , Johnson Melissa L. , Yap Timothy A. , Gadgeel Shirish , Nepert Dale , Feng Gang , Reddy Micaela B. , Harney Allison S. , Elsayed Mohamed , Cook Adam W. , Wong Christina E. , Hinklin Ronald J. , Jiang Yutong , Brown Eric N. , Neitzel Nickolas A. , Laird Ellen R. , Wu Wen-I , Singh Anurag , Wei Ping , Ching Keith A. , Gaudino John J. , Lee Patrice A. , Hartley Dylan P. , Rothenberg S. Michael
Published: June 2023

Abstract
Rationally targeted therapies have transformed cancer treatment, but many patients develop resistance through bypass signaling pathway activation. PF-07284892 (ARRY-558) is an allosteric SHP2 inhibitor designed to overcome bypass-signaling-mediated resistance when combined with inhibitors of various oncogenic drivers. Activity in this setting was confirmed in diverse tumor models. Patients with ALK fusion–positive lung cancer, BRAFV600E-mutant colorectal cancer, KRASG12D-mutant ovarian cancer, and ROS1 fusion–positive pancreatic cancer who previously developed targeted therapy resistance were treated with PF-07284892 on the first dose level of a first-in-human clinical trial. After progression on PF-07284892 monotherapy, a novel study design allowed the addition of oncogene-directed targeted therapy that had previously failed. Combination therapy led to rapid tumor and circulating tumor DNA (ctDNA) responses and extended the duration of overall clinical benefit.
Significance:
PF-07284892–targeted therapy combinations overcame bypass-signaling-mediated resistance in a clinical setting in which neither component was active on its own. This provides proof of concept of the utility of SHP2 inhibitors in overcoming resistance to diverse targeted therapies and provides a paradigm for accelerated testing of novel drug combinations early in clinical development.

See related commentary by Hernando-Calvo and Garralda.
Patient-Centric Approaches for Phase I Combination Trials Come on Stage
Authors: Hernando-Calvo Alberto , Garralda Elena
Published: June 2023

A disruptive clinical trial design allowed Drilon and colleagues to demonstrate proof of concept of the potential of PF-07284892 to overcome resistance mechanisms to targeted therapies in the clinic.

See related article by Drilon et al., p. 1789 (7).
Association Between the Route of Administration and Formulation of Estrogen Therapy and Hypertension Risk in Postmenopausal Women: A Prospective Population-Based Study
Authors: Kalenga Cindy Z. , Metcalfe Amy , Robert Magali , Nerenberg Kara A. , MacRae Jennifer M. , Ahmed Sofia B.
Published: June 2023

Background:

Hypertension is the leading global cause of cardiovascular disease and premature mortality in women. The effects of postmenopausal hormone therapy (HT) on blood pressure are uncertain but may be related to route of estrogen administration and formulation of estrogen. We sought to determine the association between route of administration and formulation of estrogen HT and hypertension risk in postmenopausal women.

Methods:

Population-based cohort study with women aged ≥45 years who filled ≥2 consecutive prescriptions for estrogen-only HT, identified from linked provincial health administrative data from Alberta, Canada, between 2008 and 2019. The primary outcome, incident hypertension, was identified using standardized
International Classification of Diseases
,
Ninth and Tenth Revision
. Cox proportional hazard models were used to calculate hazard ratios (HRs) for hypertension in women using oral HT compared with nonoral HT (transdermal, vaginal, or intramuscular).

Results:

In total, 112 240 women used an estrogen-only form of HT. Oral estrogen was associated with a higher risk of hypertension compared with both transdermal (HR, 1.14 [95% CI, 1.08–1.20]) and vaginal (HR, 1.19 [95% CI, 1.13–1.25]) estrogens. Conjugated equine estrogen was associated with an increased risk of hypertension compared with estradiol (HR, 1.08 [95% CI, 1.04–1.14]) but not estrone (HR, 1.00 [95% CI, 0.93–1.10]). Duration of estrogen exposure and cumulative dose of estrogen was positively associated with risk of hypertension.

Conclusions:

Oral estrogen-only HT use was associated with an increased risk of hypertension in women. In women using estrogen-only HT, nonoral estradiol at the lowest dose and for the shortest time-period is associated with the lowest risk of hypertension.
Accuracy of Measurements of the Structural Reserve for Upper Limb Function in Patients With Moderate-to-Severe Stroke
Authors: Yoo Yeun Jie , Jun So Yeon , Park Eun Jin , Kim Youngkook
Published: June 2023

BACKGROUND:

The structural integrity of the corticospinal tract (CST) is an important biomarker of poststroke upper limb recovery. Injured CST undergoes Wallerian degeneration rostrocaudally during the first few months. However, there is no standardized measurement of the structural integrity of the CST. This study aimed to determine the measurement accuracy of the structural integrity of the CST.

METHODS:

This cross-sectional study included 50 consecutive patients with middle cerebral artery stroke who underwent diffusion tensor imaging upon transfer from the acute stroke unit to the inpatient rehabilitation facility (2018–2022). We evaluated hemiplegic upper limb function using Shoulder Abduction and Finger Extension (SAFE) scores. Fractional anisotropy values representing the structural integrity of the CST were evaluated using 4 region of interest-based and 2 tract-based measurements, including the posterior limb of internal capsule, cerebral peduncle, pons, pontomedullary junction, entire CST, and CST in the brainstem. Multivariate linear regression models and the area under the curve (AUC) were used to determine measurement accuracy for hemiplegic upper limb function.

RESULTS:

The structural integrity of the CST at the pontomedullary junction showed the highest explanatory power, followed by the entire CST, in the multivariate linear regression models (adjusted R
2
=
0.459 and 0.425, respectively). The structural integrity of the CST at the pontomedullary junction also showed the highest AUC, followed by the entire CST, in discriminating patients with a SAFE score of <8 or 5 from those with SAFE ≥8 or 5 (SAFE <8: AUC, 0.90 [95% CI, 0.80–1.00]; AUC, 0.83 [0.66–0.99]; SAFE <5: AUC, 0.87 [0.77–0.96]; AUC, 0.83, [0.72–0.95], respectively).

CONCLUSIONS:

The structural integrity of the CST measured at the pontomedullary junction or entire CST demonstrated the highest accuracy for hemiplegic upper limb function in the subacute phase of stroke.
Where Are Children in Missiology? English- Language Publications over the Past Decades
Authors: Scott David H.
Published: June 2023

Twenty-five years ago, it was claimed that only two articles existed in missiological journals that directly considered children and mission together. This article updates and systematizes that research, analyzing the results in English-language publications decade-by-decade in conversation with other trends to better understand and engage with children and young people in the church, in the world, and in the academy. It observes that the number and quality of missiological research and writing related to children and mission in academic journals has greatly expanded over the past decades, even if there is room for further growth.
Spirit-Possession in Fiji: The Pastoral Challenges of Discerning and Healing
Authors: Hoare Francis
Published: June 2023

Spirit possession elicits two common responses – rites to exorcise Satan or medical intervention. Drawing on pastoral experiences in the two major cultures of Fiji, this paper examines different types of spirit possession from the perspectives of social anthropology, psychology, and theology, which all play important roles in dealing with cases of spirit possession. Understanding of and communication within the local cosmology is important. Pastoral discernment is emphasized, especially in cases of ancestor possession, which are common in the indigenous Fijian culture. The character of the pastoral worker and relationship with the patient are also of great importance in the healing process. So too is the healing power of religious ritual and symbol, as will be shown in cases of possession within both cultures. To achieve as accurate a diagnosis as possible, a mixture of spirituality, psychology, and socio-cultural analysis may be necessary for healing.
The Northern League (1991–2020)
Authors: Bouillaud Christophe
Published: June 2023

This article aims to clarify the attitude of the Italian Northern League (Lega Nord) toward the Catholic Church and Catholic faith, since its creation in 1991. The article examines the evolution of the party from the merger of the northern regionalist parties under the leadership of Umberto Bossi (1991–2012) until its current form and its reengineering by its new leader, Matteo Salvini, as a national(ist) League (Lega) aiming to win votes and mandates all over Italy and to become the dominant party of the Italian right. Be it under Bossi or Salvini, the Lega Nord/Lega has always opposed both the humanist teaching of the Catholic Church and mainstream Catholic social organizations, while pretending to defend the “Catholic identity” of the “North,” before turning to the entire country. Under Salvini’s leadership, the Lega joined forces with some rightist Catholic groups prone to complain about Pope Francis’s deemed treason of the Catholic identity, and so reinforced its conservative orientation. As I will show in this article, in the medium term, the enduring success of the Lega Nord/Lega illustrates the decline of mainstream Catholicism in Italy.
Brentano on Act, Content and Intentionality
Authors: Textor Mark
Published: June 2023

This article offers a reconstruction of Brentano’s notion of act content that identifies the content of a mental act with a combination of marks (Merkmale) or a single such mark. The author will first clarify the role act content plays in Brentano’s philosophy of psychology and then go on to locate the proposed notion of content in the historical context of Brentano’s work as well as in his writings at the time of Psychologie. The author will defend this notion against potential objections and explore its explanatory potential.
Judgement and Intentionality in Early Brentano
Authors: van der Schaar Maria
Published: June 2023

There are two notions of intentionality: the first contains the thesis that our acts of thinking, judging and loving have a content; the second that our mental acts are about something external to the act. Brentano uses the term ‘intentionality’ only in relation to the first notion; for him, intentionality does not function as a bridge between the mind and the external world. Is it possible for a phenomenologist like Brentano to give an account of the second notion of intentionality? It is argued that this is possible, but not without introducing the notion of judgement. A comparison with Mill’s distinction between connotation and denotation, and with Frege’s distinction between sense and reference shows how original Brentano’s theory is.
Von den mannigfachen Ausdrücken der „intentionalen Inexistenz“ bei Franz Brentano
Authors: Marques de Carvalho Joelma
Published: June 2023

In this article I provide an overview of the many different terms that Brentano sometimes uses as synonyms or as explanations for “intentional inexistence”. The many terms associated with intentional inexistence appear in many different contexts, and we can conclude that Brentano uses these terms primarily to describe a property that is accidental and dependent on the subject from which it arises and with which it passes away. Ontologically, both properties and substances exist, but the former requires a substance (the subject) for its existence. A mental act is to be considered as a first-order property, whereas the content (or part of the mental act) can be understood as an accident of that accident.
Das intentionale Objekt als Unding
Authors: Ierna Carlo
Published: June 2023

The so-called “intentional object” occupies a central position in the debates about intentionality in Brentano and the Brentano School. How does it relate to the correlate, the content, or the intended, possibly external, transcendent object? Does it perhaps even coincide with one of these? There was no clear consensus on this neither in Brentano’s time nor today. In order to develop a new perspective on the problem of the intentional object, I would like to introduce a deliberately radical interpretation and related terminological change: what if we were to avoid any talk of “object” in this context altogether? Perhaps this could help avoid the ambiguities and misunderstandings associated with talk of “intentional objects.” In my contribution I would like to sketch such an interpretation and consider whether this attempt could be useful to reframe the debate.
Der Gegenstandsbegriff als terminologische Hürde für Brentanos Konzeption intentionaler Inexistenz
Authors: Brandl Johannes L.
Published: June 2023

Brentano’s use of the expression ‘intentional inexistence’ poses a considerable terminological problem. This is due not only to the expressions ‘intentional’ and ‘inexistence’ contained in it. The biggest hurdle is the liberal use of the expression ‘object’, which is encouraged by Brentano’s notion of intentional inexistent (or immanent) objects. Carlo Ierna tries to meet this problem with a strategy that allows to hold on to the notion of intentional inexistence without accepting immanent objects. The originality of his interpretation lies, as I will show in my commentary, in the fact that it tries to achieve its goal by terminological measures alone. Following the same line, I will argue that Brentano’s self-correction, made in the second edition of his Psychology, can also be interpreted in this context as a terminological move.
Streiten über Geschmack
Authors: Luxenburger Matthias
Published: June 2023

The aim of this article is to refute the aphorism “There is no arguing about taste”. On the one hand, judgements of taste arise from individual feelings, on the other hand, they claim to be universally valid. The question of whether there can be sensible dispute about taste arises from this conflict between subjectivity and universality. The article shows how sensible dispute is possible without denying the subjective character of the judgement. Dispute leads to an explication of the standard that determined the individual judgement of taste. Based on this, three stages of sensible dispute open up: adjustment of the standard, improvement of the standard, and idealisation of the standard. Thus, the article demonstrates not only that it is possible to argue about taste in a sensible way, but also on which levels such a dispute can take place.
The Illusion of Neutralism: The Indigenous Third Force and the Filipino Republic from the Late 1940s to the 1950s
Authors: Osteria Tristan Miguel
Published: June 2023

It often has been an illusion that Filipinos lack indigeneity due to the ties with the United States since 1898. Lost in these mists were the indigenous agendas that lay underneath the official narratives. The article presents a background and then examines the administration of Elpidio Quirino, president of the Philippines from 1948 to 1953, particularly his neutralist Pacific Pact initiative and the failed use of military force against the Huks. It concludes with a discussion of the rise of Ramón Magsaysay. It then examines Magsaysay, Philippine president from 1953 to 1957, beginning as defense secretary, support from the United States, the Magsaysay myth, his counterinsurgency campaign against the Huks, his election as president, international leadership, and legacies after his death. The study will show how the top-down policies of Quirino reliant on military force gave way to the unifying, reformist, inclusive, and inspirational leadership of Magsaysay, which became a kind of third force apart from the oligarchy and the Communists.