bluuebunny/crossref_metadata_2025 huggingface dataset:
Less is More: Removing Redundancy of Graph Convolutional Networks for Recommendation
Authors: Peng Shaowen , Sugiyama Kazunari , Mine Tsunenori
Published: November 2023

While Graph Convolutional Networks (GCNs) have shown great potential in recommender systems and collaborative filtering (CF), they suffer from expensive computational complexity and poor scalability. On top of that, recent works mostly combine GCNs with other advanced algorithms which further sacrifice model efficiency and scalability. In this work, we unveil the redundancy of existing GCN-based methods in three aspects: (1)
Feature redundancy
. By reviewing GCNs from a spectral perspective, we show that most spectral graph features are noisy for recommendation, while stacking graph convolution layers can suppress but cannot completely remove the noisy features, which we mostly summarize from our previous work; (2)
Structure redundancy
. By providing a deep insight into how user/item representations are generated, we show that what makes them distinctive lies in the spectral graph features, while the core idea of GCNs (i.e., neighborhood aggregation) is not the reason making GCNs effective; and (3)
Distribution redundancy
. Following observations from (1), we further show that the number of required spectral features is closely related to the spectral distribution, where important information tends to be concentrated in more (fewer) spectral features on a flatter (sharper) distribution. To make important information be concentrated in as few features as possible, we sharpen the spectral distribution by increasing the node similarity without changing the original data, thereby reducing the computational cost. To remove these three kinds of redundancies, we propose a Simplified Graph Denoising Encoder (SGDE) only exploiting the top-
K
singular vectors without explicitly aggregating neighborhood, which significantly reduces the complexity of GCN-based methods. We further propose a scalable contrastive learning framework to alleviate data sparsity and to boost model robustness and generalization, leading to significant improvement. Extensive experiments on three real-world datasets show that our proposed SGDE not only achieves state-of-the-art but also shows higher scalability and efficiency than our previously proposed GDE as well as traditional and GCN-based CF methods.
Coherence Attacks and Countermeasures in Interposer-based Chiplet Systems
Authors: Chacon Gino A. , Williams Charles , Knechtel Johann , Sinanoglu Ozgur , Gratz Paul V. , Soteriou Vassos
Published: November 2023

Industry is moving towards large-scale hardware systems that bundle processor cores, memories, accelerators, and so on. via 2.5D integration. These components are fabricated separately as chiplets and then integrated using an interposer as an interconnect carrier. This new design style is beneficial in terms of yield and economies of scale, as chiplets may come from various vendors and are relatively easy to integrate into one larger sophisticated system. However, the benefits of this approach come at the cost of new security challenges, especially when integrating chiplets that come from untrusted or not fully trusted, third- party vendors.

In this work, we explore these challenges for modern interposer-based systems of cache-coherent, multi-core chiplets. First, we present basic coherence-oriented hardware Trojan attacks that pose a significant threat to chiplet-based designs and demonstrate how these basic attacks can be orchestrated to pose a significant threat to interposer-based systems. Second, we propose a novel scheme using an active interposer as a generic, secure-by-construction platform that forms a physical root of trust for modern 2.5D systems. The implementation of our scheme is confined to the interposer, resulting in little cost and leaving the chiplets and coherence system untouched. We show that our scheme prevents a range of coherence attacks with low overheads on system performance, ∼4%. Further, we demonstrate that our scheme scales efficiently as system size and memory capacities increase, resulting in reduced performance overheads.
Wearable Devices: Implications for Precision Medicine and the Future of Health Care
Authors: Babu Mohan , Lautman Ziv , Lin Xiangping , Sobota Milan H.B. , Snyder Michael P.
Published: November 2023

Wearable devices are integrated analytical units equipped with sensitive physical, chemical, and biological sensors capable of noninvasive and continuous monitoring of vital physiological parameters. Recent advances in disciplines including electronics, computation, and material science have resulted in affordable and highly sensitive wearable devices that are routinely used for tracking and managing health and well-being. Combined with longitudinal monitoring of physiological parameters, wearables are poised to transform the early detection, diagnosis, and treatment/management of a range of clinical conditions. Smartwatches are the most commonly used wearable devices and have already demonstrated valuable biomedical potential in detecting clinical conditions such as arrhythmias, Lyme disease, inflammation, and, more recently, COVID-19 infection. Despite significant clinical promise shown in research settings, there remain major hurdles in translating the medical uses of wearables to the clinic. There is a clear need for more effective collaboration among stakeholders, including users, data scientists, clinicians, payers, and governments, to improve device security, user privacy, data standardization, regulatory approval, and clinical validity. This review examines the potential of wearables to offer affordable and reliable measures of physiological status that are on par with FDA-approved specialized medical devices. We briefly examine studies where wearables proved critical for the early detection of acute and chronic clinical conditions with a particular focus on cardiovascular disease, viral infections, and mental health. Finally, we discuss current obstacles to the clinical implementation of wearables and provide perspectives on their potential to deliver increasingly personalized proactive health care across a wide variety of conditions.
More Tailored Approaches to Tuberculosis Treatment and Prevention
Authors: Bark Charles M. , Boom W. Henry , Furin Jennifer J.
Published: November 2023

Recent advances in the treatment of tuberculosis (TB) have led to improvements unprecedented in our lifetime. Decades of research in developing new drugs, especially for multidrug-resistant TB, have created not only multiple new antituberculous agents but also a new approach to development and treatment, with a focus on maximizing the benefit to the individual patient. Prevention of TB disease has also been improved and recognized as a critical component of global TB control. While the momentum is positive, it will take continued investment at all levels, especially training of new dedicated TB researchers and advocates around the world, to maintain this progress.
Effect of Accelerated Stress Testing Conditions on Combined Chemical and Mechanical Membrane Durability in Fuel Cells
Authors: Chen Yixuan , Bahrami MohammadAmin , Kumar Nitish , Orfino Francesco P. , Dutta Monica , Lauritzen Michael , Setzler Erin , Agapov Alexander L. , Kjeang Erik
Published: November 2023

Understanding membrane degradation induced by combined chemical and mechanical stresses is critical to designing durable polymer electrolyte membrane fuel cells. Accelerated stress tests (ASTs) are usually designed and carried out to study membrane degradation and identify stresses leading to it. In this work, a customized small-scale fuel cell fixture designed for in situ X-ray computed tomography (XCT) imaging is utilized to study the impact of different AST conditions on combined chemical and mechanical membrane durability. The XCT imaging technique allows the acquisition of a tomographic dataset yielding an integrated 3D image stack, which in turn, is used to analyze and compare global membrane degradation mechanisms. It was identified that cell temperature and relative humidity (RH) strongly influence the chemical membrane degradation rate, whereas the mechanical degradation rate was promoted by RH cycles with high amplitude and short period, which were dynamically diagnosed through a single frequency electrochemical impedance spectroscopy technique developed to track membrane hydration. When applied consecutively, the high chemical and mechanical stress intensities produced a joint chemo-mechanical failure mode with distinct evidence of chemical (thinning) and mechanical (fatigue-fracture) contributions in a relatively short time. The proposed AST is thus recommended for chemo-mechanical membrane durability evaluation in fuel cells.
Map-Pointed Fuzzy Hyperoperations
Authors: Sharbati Mohammad Esmaeil , Rasouli Hamid , Karimi Feizabadi Abolghasem , Tehranian Abolfazl
Published: November 2023

In this paper, we establish a correspondence between fuzzy hypergroupoids and certain types of hypergroupoids that possess map-pointed properties. Specifically, we introduce a new type of fuzzy hyperoperations, known as map-pointed fuzzy hyperoperations, and show that this correspondence yields an adjunction.
Influence of Ultracapacitor and Plug-In Electric Vehicle for Frequency Regulation of Hybrid Power System Utilizing Artificial Gorilla Troops Optimizer Algorithm
Authors: Nayak Smruti Ranjan , Khadanga Rajendra Kumar , Das Deepa , Arya Yogendra , Panda Sidhartha , Sahu Preeti Ranjan
Published: November 2023

The proposed research work considers the effect of ultracapacitor (UC) and plug-in electric vehicle (PEV) inside a distributed energy sources based on three-area hybrid power system. Recently developed artificial gorilla troops optimizer (GTO) algorithm-based fractional order tilt integral derivative (FOTID) controller is suggested for load frequency control (LFC) of a three-area hybrid power system. By setting up a TID controller for the hybrid system’s frequency regulation, the algorithms’ realistic use is attempted via showcasing its immense potential. The results of the GTO-based TID regulator are observed better over GTO-based PID. Next, by considering a modification of system settings and under existence of intermittent behavior of renewable energy sources, it is evident that the influence of UC and PEV is more ethical compared to the conventional regulator-based frequency control. Additionally, it is seen that the suggested GTO-based FOTID controller along with the UC and PEV outperforms GTO-based TID controller in terms of lesser overshoots/settling times and fast responses.
Performance Optimization of Piled Raft Foundations in Layered Soil under Uniform Vertical Loading Using Plaxis 3D
Authors: Teji Biya Degefu , Ashango Argaw Asha
Published: November 2023

Piled raft foundations are composite foundations that combine piles and raft to support civil engineering structure and to reduce the settlement. The data were obtained from Addis Ababa, Ethiopia. In this study, the effects of raft thickness, number of piles, pile length, spacing of piles, and pile diameter on the response of piled-raft foundations were investigated using the finite element-based program Plaxis 3D for layered soils (medium to very stiff high plastic silty clay and medium to very dense silty sand soil) subjected to uniform vertical loading. The results showed that increasing the thickness of the raft from 0.7 m to 1.7 m reduced the differential settlement by 78.21% when there were 16 piles. However, the maximum settlement also increased by 2.81%. Increasing the number of piles from 4 to 16 reduced the maximum settlement by 22.09% for a pile spacing of 4D. Moreover, increasing the pile length from 9 m to 15 m contributed to a 19.49% reduction in the total settlement for a pile spacing of 5D. Therefore, the current study provides a useful framework for analyzing and designing large piled-raft foundations.
Supplementary Table 3 from Associations between MICA and MICB Genetic Variants, Protein Levels, and Colorectal Cancer: Atherosclerosis Risk in Communities (ARIC)
Authors: Wang Shuo , Onyeaghala Guillaume C. , Pankratz Nathan , Nelson Heather H. , Thyagarajan Bharat , Tang Weihong , Norby Faye L. , Ugoji Chinenye , Joshu Corinne E. , Gomez Christian R. , Couper David J. , Coresh Josef , Platz Elizabeth A. , Prizment Anna E.
Published: November 2023

Supplemental Table 3 shows the associations between pre-selected SNPs and CRC risk stratified by sex, race, or diabetes status.
Supplementary Table 2 from Somatic Mosaic Chromosomal Alterations and Death of Cardiovascular Disease Causes among Cancer Survivors
Authors: Sun Maxine , Cyr Marie-Christyne , Sandoval Johanna , Lemieux Perreault Louis-Philippe , Busque Lambert , Tardif Jean-Claude , Dubé Marie-Pierre
Published: November 2023

Supplementary Table 2: ICD-9 and ICD-10 diagnostic and procedure codes for inpatient cardiovascular-related endpoints and for the primary endpoints
Supplementary Table 12 from Somatic Mosaic Chromosomal Alterations and Death of Cardiovascular Disease Causes among Cancer Survivors
Authors: Sun Maxine , Cyr Marie-Christyne , Sandoval Johanna , Lemieux Perreault Louis-Philippe , Busque Lambert , Tardif Jean-Claude , Dubé Marie-Pierre
Published: November 2023

Supplementary Table 12: Cox regression analyses of the effect of mosaic chromosomal alterations on the risk of death of cardiovascular disease causes per cancer type
Supplementary Table 1 from Somatic Mosaic Chromosomal Alterations and Death of Cardiovascular Disease Causes among Cancer Survivors
Authors: Sun Maxine , Cyr Marie-Christyne , Sandoval Johanna , Lemieux Perreault Louis-Philippe , Busque Lambert , Tardif Jean-Claude , Dubé Marie-Pierre
Published: November 2023

Supplementary Table 1: Primary diagnostic codes for selected cancers
Supplemental Table 5 from Nitrated Polycyclic Aromatic Hydrocarbon (Nitro-PAH) Signatures and Somatic Mutations in Diesel Exhaust-Exposed Bladder Tumors
Authors: Gonzalez Nicole , Rao Nina , Dean Michael , Lee Donghyuk , Hurson Amber N. , Baris Dalsu , Schwenn Molly , Johnson Alison , Prokunina-Olsson Ludmila , Friesen Melissa C. , Zhu Bin , Rothman Nathaniel , Silverman Debra T. , Koutros Stella
Published: November 2023

REC and nitro-PAH signatures in New England
Supplementary Figure 1 from Somatic Mosaic Chromosomal Alterations and Death of Cardiovascular Disease Causes among Cancer Survivors
Authors: Sun Maxine , Cyr Marie-Christyne , Sandoval Johanna , Lemieux Perreault Louis-Philippe , Busque Lambert , Tardif Jean-Claude , Dubé Marie-Pierre
Published: November 2023

Supplementary Figure 1: Visual depiction of the proportion of patients with at least 1 mosaic chromosomal alteration
Supplemental Table 5 from Measurement of Ovarian Tumor Immune Profiles by Multiplex Immunohistochemistry: Implications for Epidemiologic Studies
Authors: Hathaway Cassandra A. , Conejo-Garcia Jose R. , Fridley Brooke L. , Rosner Bernard , Saeed-Vafa Daryoush , Moran Segura Carlos , Nguyen Jonathan V. , Hecht Jonathan L. , Sasamoto Naoko , Terry Kathryn L. , Tworoger Shelley S. , Townsend Mary K.
Published: November 2023

Supplemental Table 5 shows beta binomial models, odds ratios and 95% confidence intervals for marker positivity in the tumor, by population characteristics
Supplementary Table S3 from COVID-19 Outcomes by Cancer Status, Site, Treatment, and Vaccination
Authors: Salvatore Maxwell , Hu Miriam M. , Beesley Lauren J. , Mondul Alison M. , Pearce Celeste Leigh , Friese Christopher R. , Fritsche Lars G. , Mukherjee Bhramar
Published: November 2023

Phecodes corresponding to the comorbidity classes included in the comorbidity score and their counts in the analytic tested-positive cohort.
Table S4 from Trend in Cervical Cancer Incidence and Mortality Rates in China, 2006–2030: A Bayesian Age-Period-Cohort Modeling Study
Authors: Yuan Meiwen , Zhao Xuelian , Wang Honghao , Hu Shangying , Zhao Fanghui
Published: November 2023

Table S4 shows average age and standardized average age at death for cervical cancer between 2006 to 2030.
Supplementary Figure S6 from COVID-19 Outcomes by Cancer Status, Site, Treatment, and Vaccination
Authors: Salvatore Maxwell , Hu Miriam M. , Beesley Lauren J. , Mondul Alison M. , Pearce Celeste Leigh , Friese Christopher R. , Fritsche Lars G. , Mukherjee Bhramar
Published: November 2023

COVID-19 hospitalization among cancer (n = 12,995) and non-cancer patients (n = 34,693) who tested positive and had non-missing covariates. The results were from the model logit P(YHospitalization = 1|X, Cancer, Covariate) = β0 + βXX + βCancerCancerStatus + βIntX × CancerStatus + βCovCovariate, where Covariate = Age + Race/Ethnicity + Sex + Disadvantage Index (quartile) + Comorbidity Score. Reference groups were age: 18 to 35, sex: female, BMI: 18.5 to 25, race: white/non-Hispanic, smoking status: never. A unit change in the continuous age variable is 10 years. The comorbidity score ranges from 0 to 6 and is the sum of indicators for presence of six categories of preexisting conditions in the electronic health record.
Supplementary Figure S3 from COVID-19 Outcomes by Cancer Status, Site, Treatment, and Vaccination
Authors: Salvatore Maxwell , Hu Miriam M. , Beesley Lauren J. , Mondul Alison M. , Pearce Celeste Leigh , Friese Christopher R. , Fritsche Lars G. , Mukherjee Bhramar
Published: November 2023

A schematic representing electronic health record scenarios and their resulting (panel A) classification of individuals with cancer for the primary and cancer recency analyses and (panel B) vaccination status for vaccine-related analyses.
Supplementary Table 2 from Low-Carbohydrate Diet Score and the Risk of Colorectal Cancer: Findings from the Singapore Chinese Health Study
Authors: Yu Yi-Chuan , Paragomi Pedram , Jin Aizhen , Wang Renwei , Schoen Robert E. , Koh Woon-Puay , Yuan Jian-Min , Luu Hung N.
Published: November 2023

Supplementary Table S2 is for sensitivity analysis, excluding cases and person-years within the first 2 years of observation
Table S2 from Exploring the Complex Relationship between Gut Microbiota and Risk of Colorectal Neoplasia Using Bidirectional Mendelian Randomization Analysis
Authors: Li Wanxin , Zhou Xuan , Yuan Shuai , Wang Lijuan , Yu Lili , Sun Jing , Chen Jie , Xiao Qian , Wan Zhongxiao , Zheng Ju-Sheng , Zhang Cai-Xia , Larsson Susanna C. , Farrington Susan M. , Law Philip , Houlston Richard S. , Tomlinson Ian , Ding Ke-Feng , Dunlop Malcolm G. , Theodoratou Evropi , Li Xue
Published: November 2023

Table S2 shows the SNPs that associated with nine microbiota taxa (P<1×10-5).
Data from Low-Carbohydrate Diet Score and the Risk of Colorectal Cancer: Findings from the Singapore Chinese Health Study
Authors: Yu Yi-Chuan , Paragomi Pedram , Jin Aizhen , Wang Renwei , Schoen Robert E. , Koh Woon-Puay , Yuan Jian-Min , Luu Hung N.
Published: November 2023

AbstractBackground:
Colorectal cancer is common cancer with a high mortality rate. Low-carbohydrate diet (LCD) score holistically evaluates the LCD pattern from carbohydrate, protein, and fat intake. Epidemiologic data of LCD–colorectal cancer association are sparse.
Methods:
We evaluated the associations between LCD (i.e., total, animal- and plant-based) and colorectal cancer risk in the Singapore Chinese Health Study, a population-based prospective cohort study including 61,321 Chinese in Singapore who were 45 to 74 years old at baseline. Cox proportional hazard regression model was used to determine the HRs and respective 95% confidence intervals (CI) for colorectal cancer associated with LCD after adjusting for potential confounders, including age, sex, BMI, physical activity, family history of colorectal cancer, etc.
Results:
After an average of 19.5 years of follow-up, 2,520 participants developed colorectal cancer (1,608 colon cancer and 912 rectal cancer). Overall, the association between total or plant-based LCD scores with the risk of colorectal, colon, or rectal cancer was null (all Ptrend ≥ 0.28). The animal-based LCD was modestly associated with colon cancer risk (Ptrend = 0.02), but not with rectal cancer. Compared with the lowest quartile, HRs (95% CIs) of colon cancer for quartiles 2, 3, and 4 of animal-based LCD were 1.12 (0.98–1.29), 1.27 (1.10–1.46), and 1.14 (0.99–1.31), respectively.
Conclusions:
A low-level carbohydrate diet with a high level of animal protein and fat was associated with a moderate increase in the risk of colon cancer among Chinese Singaporeans.
Impact:
High consumption of animal protein/fat and low consumption of carbohydrates may increase colon cancer risk.
A PERK-Specific Inhibitor Blocks Metastatic Progression by Limiting Integrated Stress Response–Dependent Survival of Quiescent Cancer Cells
Authors: Calvo Veronica , Zheng Wei , Adam-Artigues Anna , Staschke Kirk A. , Huang Xin , Cheung Julie F. , Nobre Ana Rita , Fujisawa Sho , Liu David , Fumagalli Maria , Surguladze David , Stokes Michael E. , Nowacek Ari , Mulvihill Mark , Farias Eduardo F. , Aguirre-Ghiso Julio A.
Published: November 2023

Purpose:

The integrated stress response (ISR) kinase PERK serves as a survival factor for both proliferative and dormant cancer cells. We aim to validate PERK inhibition as a new strategy to specifically eliminate solitary disseminated cancer cells (DCC) in secondary sites that eventually reawake and originate metastasis.

Experimental Design:

A novel clinical-grade PERK inhibitor (HC4) was tested in mouse syngeneic and PDX models that present quiescent/dormant DCCs or growth-arrested cancer cells in micro-metastatic lesions that upregulate ISR.

Results:

HC4 significantly blocks metastasis, by killing quiescent/slow-cycling ISRhigh, but not proliferative ISRlow DCCs. HC4 blocked expansion of established micro-metastasis that contained ISRhigh slow-cycling cells. Single-cell gene expression profiling and imaging revealed that a significant proportion of solitary DCCs in lungs were indeed dormant and displayed an unresolved ER stress as revealed by high expression of a PERK-regulated signature. In human breast cancer metastasis biopsies, GADD34 expression (PERK-regulated gene) and quiescence were positively correlated. HC4 effectively eradicated dormant bone marrow DCCs, which usually persist after rounds of therapies. Importantly, treatment with CDK4/6 inhibitors (to force a quiescent state) followed by HC4 further reduced metastatic burden. In HNSCC and HER2+ cancers HC4 caused cell death in dormant DCCs. In HER2+ tumors, PERK inhibition caused killing by reducing HER2 activity because of sub-optimal HER2 trafficking and phosphorylation in response to EGF.

Conclusions:

Our data identify PERK as a unique vulnerability in quiescent or slow-cycling ISRhigh DCCs. The use of PERK inhibitors may allow targeting of pre-existing or therapy-induced growth arrested “persister” cells that escape anti-proliferative therapies.
Selective DNA-PK Inhibition Enhances Chemotherapy and Ionizing Radiation Activity in Soft-Tissue Sarcomas
Authors: Laroche-Clary Audrey , Josensi Coralie , Derieppe Marie-Alix , Belhomme Sarah , Vendrely Véronique , Perret Raul , Cadogan Elaine , Italiano Antoine
Published: November 2023

Purpose:

Patients with advanced soft-tissue sarcomas (STS) exhibit a poor prognosis and have few therapeutic options. DNA-dependent protein kinase (DNA-PK) catalytic subunit is a multifunctional serine–threonine protein kinase that plays a crucial role in DNA double-strand damage repair via nonhomologous end joining.

Experimental Design:

To investigate the therapeutic potential of DNA-PK targeting in STS, we first evaluated the prognostic value of DNA-PK expression in two large cohorts of patients with STS. We then used the potent and selective DNA-PK inhibitor AZD7648 compound to investigate the antitumor effect of the pharmacologic inhibition of DNA-PK in vitro via MTT, apoptosis, cell cycle, and proliferation assays. In vivo studies were performed with patient-derived xenograft models to evaluate the effects of AZD7648 in combination with chemotherapy or ionizing radiation on tumor growth. The mechanisms of sensitivity and resistance to DNA-PK inhibition were investigated by using a genome-wide CRISPR-Cas9 positive screen.

Results:

DNA-PK overexpression is significantly associated with poor prognosis in patients with sarcomas. Selective pharmacologic inhibition of DNA-PK strongly synergizes with radiation- and doxorubicin-based regimen in sarcoma models. By using a genome-wide CRISPR-Cas9 positive screen, we identified genes involved in sensitivity to DNA-PK inhibition.

Conclusions:

DNA-PK inhibition deserves clinical investigation to improve response to current therapies in patients with sarcoma.
Supplementary Table 3 from Concurrent Targeting of HDAC and PI3K to Overcome Phenotypic Heterogeneity of Castration-resistant and Neuroendocrine Prostate Cancers
Authors: Zhang Ailin , Lau Nathan A. , Wong Alicia , Brown Lisha G. , Coleman Ilsa M. , De Sarkar Navonil , Li Dapei , DeLucia Diana C. , Labrecque Mark P. , Nguyen Holly M. , Conner Jennifer L. , Dumpit Ruth F. , True Lawrence D. , Lin Daniel W. , Corey Eva , Alumkal Joshi J. , Nelson Peter S. , Morrissey Colm , Lee John K.
Published: November 2023

Supplementary Table 3
Supplementary Figure 15 from Concurrent Targeting of HDAC and PI3K to Overcome Phenotypic Heterogeneity of Castration-resistant and Neuroendocrine Prostate Cancers
Authors: Zhang Ailin , Lau Nathan A. , Wong Alicia , Brown Lisha G. , Coleman Ilsa M. , De Sarkar Navonil , Li Dapei , DeLucia Diana C. , Labrecque Mark P. , Nguyen Holly M. , Conner Jennifer L. , Dumpit Ruth F. , True Lawrence D. , Lin Daniel W. , Corey Eva , Alumkal Joshi J. , Nelson Peter S. , Morrissey Colm , Lee John K.
Published: November 2023

Supplementary Figure 15. RNA-seq volcano plots of C4-2B and NCI-H660 cells treated with vehicle, fimepinostat, ipatasertib, romidepsin, or a combination of ispatasertib + romidepsin.
Supplementary Figure 14 from Concurrent Targeting of HDAC and PI3K to Overcome Phenotypic Heterogeneity of Castration-resistant and Neuroendocrine Prostate Cancers
Authors: Zhang Ailin , Lau Nathan A. , Wong Alicia , Brown Lisha G. , Coleman Ilsa M. , De Sarkar Navonil , Li Dapei , DeLucia Diana C. , Labrecque Mark P. , Nguyen Holly M. , Conner Jennifer L. , Dumpit Ruth F. , True Lawrence D. , Lin Daniel W. , Corey Eva , Alumkal Joshi J. , Nelson Peter S. , Morrissey Colm , Lee John K.
Published: November 2023

Supplementary Figure 14. Genomic assessment of RB1 and PTEN/PI3K/AKT pathway mutations in LuCaP patient-derived xenograft (PDX) models and prostate cancer cell lines.
Supplementary Figure 12 from Concurrent Targeting of HDAC and PI3K to Overcome Phenotypic Heterogeneity of Castration-resistant and Neuroendocrine Prostate Cancers
Authors: Zhang Ailin , Lau Nathan A. , Wong Alicia , Brown Lisha G. , Coleman Ilsa M. , De Sarkar Navonil , Li Dapei , DeLucia Diana C. , Labrecque Mark P. , Nguyen Holly M. , Conner Jennifer L. , Dumpit Ruth F. , True Lawrence D. , Lin Daniel W. , Corey Eva , Alumkal Joshi J. , Nelson Peter S. , Morrissey Colm , Lee John K.
Published: November 2023

Supplementary Figure 12. RNA-Seq and pathway analysis of romidepsin treated prostate adenocarcinoma and NEPC dissociated tumor cells and cell lines in vitro.
FIGURE 6 from Concurrent Targeting of HDAC and PI3K to Overcome Phenotypic Heterogeneity of Castration-resistant and Neuroendocrine Prostate Cancers
Authors: Zhang Ailin , Lau Nathan A. , Wong Alicia , Brown Lisha G. , Coleman Ilsa M. , De Sarkar Navonil , Li Dapei , DeLucia Diana C. , Labrecque Mark P. , Nguyen Holly M. , Conner Jennifer L. , Dumpit Ruth F. , True Lawrence D. , Lin Daniel W. , Corey Eva , Alumkal Joshi J. , Nelson Peter S. , Morrissey Colm , Lee John K.
Published: November 2023

HDAC and PI3K/AKT pathway inhibition in NCI-H660 and C4-2B cells in vitro. Cell viability assays of C4-2B (A) and NCI-H660 (B) cells in response to romidepsin and ipatasertib combination treatment or C4-2B (C) and NCI-H660 (D) cells in response to romidepsin and BYL719 or AZD8186 combination treatment and fimepinostat for 96 hours in vitro. Experiments were repeated a minimum of three times. Results are expressed as percent viable cells and are normalized to vehicle-treated controls. Caspase 3/7 activity after romidepsin, ipatasertib, BYL719, or AZD8186 combination treatment of C4-2B (E) and NCI-H660 (F) cells for 48 hours in vitro. Cell-cycle analysis after romidepsin, ipatasertib, BYL719, or AZD8186 combination treatment of C4-2B (G) and NCI-H660 (H) cells for 48 hours in vitro. P values = *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001.
FIGURE 4 from Concurrent Targeting of HDAC and PI3K to Overcome Phenotypic Heterogeneity of Castration-resistant and Neuroendocrine Prostate Cancers
Authors: Zhang Ailin , Lau Nathan A. , Wong Alicia , Brown Lisha G. , Coleman Ilsa M. , De Sarkar Navonil , Li Dapei , DeLucia Diana C. , Labrecque Mark P. , Nguyen Holly M. , Conner Jennifer L. , Dumpit Ruth F. , True Lawrence D. , Lin Daniel W. , Corey Eva , Alumkal Joshi J. , Nelson Peter S. , Morrissey Colm , Lee John K.
Published: November 2023

Fimepinostat treatment inhibits growth of CRPC cell line xenograft and PDX tumors. CRPC cell line xenograft tumors [(A) 22Rv1] and PDX tumors [(B) LuCaP 35CR] were treated with 75 mg/kg fimepinostat (22Rv1, n = 5; LuCaP 35CR, n = 8) or vehicle control (22Rv1, n = 6; LuCaP 35CR, n = 9) for up to 3.5 weeks. Blue = vehicle versus red = fimepinostat. P values = *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001. Representative photomicrographs and quantification of Ki-67 (C and D) and cleaved caspase-3 (E and F) staining by IHC of 22Rv1 and LuCaP 35CR tumors treated with vehicle or fimepinostat.
Data from Concurrent Targeting of HDAC and PI3K to Overcome Phenotypic Heterogeneity of Castration-resistant and Neuroendocrine Prostate Cancers
Authors: Zhang Ailin , Lau Nathan A. , Wong Alicia , Brown Lisha G. , Coleman Ilsa M. , De Sarkar Navonil , Li Dapei , DeLucia Diana C. , Labrecque Mark P. , Nguyen Holly M. , Conner Jennifer L. , Dumpit Ruth F. , True Lawrence D. , Lin Daniel W. , Corey Eva , Alumkal Joshi J. , Nelson Peter S. , Morrissey Colm , Lee John K.
Published: November 2023

Abstract
Castration-resistant prostate cancer (CRPC) consists of multiple phenotypic subtypes including androgen receptor (AR)-active prostate cancer (ARPC) and neuroendocrine prostate cancer (NEPC). Tumor cells with these phenotypes can coexist between metastases within a patient and within an individual tumor. Treatments that are effective across CRPC subtypes are currently lacking. Histone deacetylation is crucial for the regulation of chromatin structure and maintenance of cancer cell state and activation of the PI3K/AKT/mTOR signaling cascade is a tumor growth–promoting pathway. We therefore investigated combined targeting of histone deacetylase (HDAC) and PI3K using a rationally designed dual inhibitor, fimepinostat, in CRPC subtypes in vitro and in vivo. Dual HDAC1/2 and PI3K/AKT pathway inhibition by fimepinostat led to robust tumor growth inhibition in both ARPC and NEPC models including cell line– and patient-derived xenografts. HDAC1/2 inhibition combined with PI3K/AKT inhibition was more effective than targeting each pathway alone, producing growth inhibitory effects through cell-cycle inhibition and apoptosis. Molecular profiling revealed on-target effects of combined HDAC1/2 and PI3K/AKT inhibition independent of tumor phenotype. Fimepinostat therapy was also associated with the suppression of lineage transcription factors including AR in ARPC and Achaete-scute homolog 1 (ASCL1) in NEPC. Together, these results indicate that fimepinostat represents a novel therapeutic that may be effective against both ARPC and NEPC through CRPC subtype-dependent and -independent mechanisms.
Significance:
CRPC is a heterogeneous disease constituting multiple phenotypic subtypes that often co-occur within tumors or across metastases in patients. Existing targeted therapies for CRPC do not take this into account. Here we show that fimepinostat, a dual HDAC1/2 and PI3K/AKT inhibitor investigated clinically in other cancer types but not prostate cancer, may overcome this heterogeneity by effectively inhibiting both ARPC and NEPC subtypes of CRPC.
Performance of Cardiovascular Risk Prediction Models in Korean Patients With New‐Onset Rheumatoid Arthritis: National Cohort Study
Authors: Kim Jae Hyun , Lee Gaeun , Hwang Jinseub , Kim Ji‐Won , Kwon Jin‐Won , Song Yun‐Kyoung
Published: November 2023

Background

This study aimed to compare the performance of established cardiovascular risk algorithms in Korean patients with new‐onset rheumatoid arthritis.

Methods and Results

This retrospective cohort study identified patients newly diagnosed with rheumatoid arthritis without a history of cardiovascular diseases between 2013 and 2019 using the National Health Insurance Service database. The cohort was followed up until 2020 for the development of the first major adverse cardiovascular event. General cardiovascular risk prediction algorithms, such as the systematic coronary risk evaluation model, the Korean risk prediction model for atherosclerotic cardiovascular diseases, the American College of Cardiology/American Heart Association pooled equations, and the Framingham Risk Score, were used. The discrimination and calibration of cardiovascular risk prediction models were evaluated. Hazard ratios were estimated using Cox proportional hazards regression. A total of 611 patients among 24 889 patients experienced a major adverse cardiovascular event during follow‐up. The median 10‐year atherosclerotic cardiovascular diseases risk score was significantly higher in patients with major adverse cardiovascular events than those without. The C‐statistics of risk algorithms ranged between 0.72 and 0.74. Compared with the low‐risk group, the actual risk of developing major adverse cardiovascular events increased significantly in the intermediate‐ and high‐risk groups for all algorithms. However, the risk predictions calculated from all algorithms overestimated the observed cardiovascular risk in the middle to high deciles, and only the systematic coronary risk evaluation algorithm showed comparable observed and predicted event rates in the low‐intermediate deciles with the highest sensitivity.

Conclusions

The systematic coronary risk evaluation model algorithm and the general risk prediction models discriminated patients with rheumatoid arthritis appropriately. However, overestimation should be considered when applying the cardiovascular risk prediction model in Korean patients.
Validation of an Integrated Genetic‐Epigenetic Test for the Assessment of Coronary Heart Disease
Authors: Philibert Robert , Dogan Timur K. , Knight Stacey , Ahmad Ferhaan , Lau Stanley , Miles George , Knowlton Kirk U. , Dogan Meeshanthini V.
Published: November 2023

Background

Coronary heart disease (CHD) is the leading cause of death in the world. Unfortunately, many of the key diagnostic tools for CHD are insensitive, invasive, and costly; require significant specialized infrastructure investments; and do not provide information to guide postdiagnosis therapy. In prior work using data from the Framingham Heart Study, we provided in silico evidence that integrated genetic–epigenetic tools may provide a new avenue for assessing CHD.

Methods and Results

In this communication, we use an improved machine learning approach and data from 2 additional cohorts, totaling 449 cases and 2067 controls, to develop a better model for ascertaining symptomatic CHD. Using the DNA from the 2 new cohorts, we translate and validate the in silico findings into an artificial intelligence–guided, clinically implementable method that uses input from 6 methylation‐sensitive digital polymerase chain reaction and 10 genotyping assays. Using this method, the overall average area under the curve, sensitivity, and specificity in the 3 test cohorts is 82%, 79%, and 76%, respectively. Analysis of targeted cytosine‐phospho‐guanine loci shows that they map to key risk pathways involved in atherosclerosis that suggest specific therapeutic approaches.

Conclusions

We conclude that this scalable integrated genetic–epigenetic approach is useful for the diagnosis of symptomatic CHD, performs favorably as compared with many existing methods, and may provide personalized insight to CHD therapy. Furthermore, given the dynamic nature of DNA methylation and the ease of methylation‐sensitive digital polymerase chain reaction methodologies, these findings may pave a pathway for precision epigenetic approaches for monitoring CHD treatment response.
Cardiovascular effects on high-resolution 3D multi-shot diffusion MRI of the rhesus macaque brain
Authors: Bihan-Poudec Yann , Tounekti Slimane , Troalen Thomas , Rayson Holly , Froesel Mathilda , Lamberton Franck , Zariry Zakaria , Gacoin Maëva , Richard Nathalie , Hamed Suliann Ben , Hiba Bassem
Published: November 2023

The monkey brain represents a key research model thanks to its strong homologies with the humans, but diffusion-MRI (dMRI) performed at millimeter-level resolution using clinical scanners and pulse-sequences cannot take full advantage of this. Cardiovascular effects on 3D multi-shot Echo-Planar Imaging (3D-msEPI) dMRI were characterized at submillimetric resolution by comparing triggered and non-triggered diffusion-weighted (DW)-images and diffusion tensor imaging (DTI) maps. We also investigated the value of 3D-msEPI with cardiovascular-triggering to achieve dMRI of the anesthetized macaque brain with high resolution previously restricted to ex-vivo brains. Eight DW-images with voxel-size = 0.5 × 0.5 × 1 mm3 and b = 1500 s/mm2 were collected at 3 Tesla from two macaques using triggered and then non-triggered 3D-msEPI. Statistical analysis by mixed models was used to compare signal-to-noise ratio (SNR) and ghost-to-signal ratio (GSR) of DW-images with and without triggering. Brain DTI with isotropic-resolution of 0.4 mm and b = 1000 s/mm2 was also collected in three macaques with triggered 3D-msEPI and reapplied without triggering in one. Cardiovascular pulsations induce inter-shot phase-errors with non-linear spatial dependency on DW-images, resulting in ghost-artifacts and signal loss particularly in the brainstem, thalamus, and cerebellum. Cardiovascular-triggering proved effective in addressing these, recovering SNR in white and gray matter (all p < 0.0001), and reducing GSR from 16.5 ± 10% to 4.7 ± 4.2% on DW-images (p < 0.0001). Triggered 3D-msEPI provided DTI-maps with the unprecedented spatial-resolution of 0.4 mm, enabling several substructures of the macaque brain to be discerned and thus analyzed in vivo. The value of cardiovascular-triggering in maintaining DTI-map sharpness and guaranteeing accurate tractography results in the brainstem, thalamus, and cerebellum was also demonstrated. In conclusion, this work highlights the effects of cardiovascular pulsations on brain 3D-dMRI and the value of triggered 3D-msEPI to provide high-quality diffusion-MRI of the anesthetized macaque brain. For routine studies, 3D-msEPI must be coupled with appropriate techniques to reduce acquisition duration.
BASIL: A toolbox for perfusion quantification using arterial spin labelling
Authors: Chappell Michael A. , Kirk Thomas F. , Craig Martin S. , McConnell Flora A. Kennedy , Zhao Moss Y. , MacIntosh Bradley J. , Okell Thomas W. , Woolrich Mark W.
Published: November 2023

Arterial Spin Labelling (ASL) MRI is now an established non-invasive method to quantify cerebral blood flow and is increasingly being used in a variety of neuroimaging applications. With standard ASL acquisition protocols widely available, there is a growing interest in advanced options that offer added quantitative precision and information about haemodynamics beyond perfusion. In this article, we introduce the BASIL toolbox, a research tool for the analysis of ASL data included within the FMRIB Software Library (FSL), and explain its operation in a variety of typical use cases. BASIL is not offered as a clinical tool, and nor is this work intended to guide the clinical application of ASL. Built around a Bayesian model-based inference algorithm, the toolbox is designed to quantify perfusion and other haemodynamic measures, such as arterial transit times, from a variety of possible ASL input data, particularly exploiting the information available in more advanced multi-delay acquisitions. At its simplest, the BASIL toolbox offers a graphical user interface that provides the analysis options needed by most users; through command line tools, it offers more bespoke options for users needing customised analyses. As part of FSL, the toolbox exploits a range of complementary neuroimaging analysis tools so that ASL data can be easily integrated into neuroimaging studies and used alongside other modalities.
New species and record of Tyrodes Raffray (Coleoptera: Staphylinidae: Pselaphinae) from Japan
Authors: INOUE SHOTA , NOMURA SHÛHEI
Published: November 2023

The tyrine species Tyrodes segrex Kurbatov, 1990, known from Far East Russia, is newly discovered from Japan, and Tyrodes amamianus sp. nov. is described from Amami-ôshima Is., Japan. Also, we suggest that some characteristics may be useful for the diagnosis of the genus and provide an updated diagnosis of Tyrodes segrex.
Revision of Sinomesuropetala daohugensis Boudet, Nel & Huang, 2023 (Odonata: Aeshnoptera: Mesuropetalidae)
Authors: QI PENGLIANG , NEL ANDRÉ , XIAO CHUANTAO , ZHENG DARAN
Published: November 2023

The mesuropetalid dragonfly Sinomesuropetala daohugensis Boudet, Nel & Huang, 2023, is here revised based on a new well-preserved dragonfly from the Haifanggou Formation of Inner Mongolia, northeastern China. The new specimen allows us to complete the forewing characters of this species, showing the close relationship of Sinomesuropetala Boudet, Nel & Huang, 2023 with Mesuropetala Handlirsch, 1906. The mesuropetalid dragonflies are currently recorded from the Late Jurassic and Lower Cretaceous deposits of east Asia, East Central South Europe, and southern America, indicating the wide distribution and the possible long-distance migration ability of some basal aeshnopteran dragonflies during these epochs.
Grand-Scale Atmospheric Imaging Apparatus (GAIA) and Wind Lidar Multiscale Measurements in the Atmospheric Surface Layer
Authors: Iungo Giacomo Valerio , Guala Michele , Hong Jiarong , Bristow Nathaniel , Puccioni Matteo , Hartford Peter , Ehsani Roozbeh , Letizia Stefano , Li Jiaqi , Moss Coleman
Published: November 2023

Understanding the organization and dynamics of turbulence structures in the atmospheric surface layer (ASL) is important for fundamental and applied research in different fields, including weather prediction, snow settling, particle and pollutant transport, and wind energy. The main challenges associated with probing and modeling turbulence in the ASL are (i) the broad range of turbulent scales associated with the different eddies present in high Reynolds number boundary layers ranging from the viscous scale (on the order of millimeters) up to large energy-containing structures (on the order of kilometers); (ii) the nonstationarity of the wind conditions and the variability associated with the daily cycle of the atmospheric stability; and (iii) the interactions among eddies of different sizes populating different layers of the ASL, which contribute to momentum, energy, and scalar turbulent fluxes. Creative and innovative measurement techniques are required to probe near-surface turbulence by generating spatiotemporally resolved data in the proximity of the ground and, at the same time, covering the entire ASL height with large enough streamwise extent to characterize the dynamics of larger eddies evolving aloft. To this aim, the U.S. National Science Foundation sponsored the development of the Grand-scale Atmospheric Imaging Apparatus (GAIA) enabling super-large snow particle image velocimetry (SLPIV) in the near-surface region of the ASL. This inaugural version of GAIA provides a comprehensive measuring system by coupling SLPIV and two scanning Doppler lidars to probe the ASL at an unprecedented resolution. A field campaign performed in 2021–22 and its preliminary results are presented herein elucidating new research opportunities enabled by the GAIA measuring system.
Navigating the twisted path of gaslighting: A manifestation of epistemic injustice for Palestinian women entrepreneurs
Authors: Omran Wojdan , Yousafzai Shumaila
Published: November 2023

What exactly is gaslighting and how does it play out in the gendered context of women’s entrepreneurship? We contribute to Stern’s three-stage model of gaslighting by presenting a contextualised perspective through a ‘twisted path’ of gaslighting that maps out gaslighting interactions and consequences, reflecting how our findings coincide with, depart from and enrich this model; meanwhile identifying primary and subsequent (secondary and tertiary) gaslighting interactions. By examining gaslighting through the lens of epistemic injustice and testimonial injustice, we explain why some women entrepreneurs succumb to gaslighting, while others strategically employ testimonial smothering and infrapolitics as an empowered agential strategy rather than a disenfranchised consequence. Considering the lack of research on gaslighting in entrepreneurship, our geopolitical context emphasises the role of spatial position and identity within multiple systems of injustice, such as occupation and patriarchy, adding novel insights theorised and grounded in lived experiences. In doing so, we disrupt the influence of western feminism by embracing a postcolonial feminist perspective and promoting social justice through centring the voices of 40 internally displaced Palestinian women entrepreneurs. Policy implications underscore the need to raise awareness of gaslighting, facilitate its identification and promote preventive measures to hold gaslighters accountable.
Realisation of Sustainable Development Goals Through Panchayati Raj Institutions
Authors: Kumar Chandra Shekhar , Sharma Manoj
Published: November 2023

Gram panchayats (GPs), being constitutionally mandated and closest to the people, can anchor the responsibility of localising the implementation of the UN Sustainable Development Goals (SDGs) and achieving them by the year 2030. In this article, published reports have been used for analysing state-wise status of SDGs achievements and their correlations with attainments in areas of poverty-reduction and other developmental indicators. Also, progress made by GPs on various metrics related to SDGs has been corroborated with other relevant metrics. For effective functioning and service-delivery capacity of panchayats, it is necessary that they are sufficiently empowered with functions and responsibilities as per aspirations of the provisions of the 73rd Constitutional Amendment, 1993, strengthened with basic infrastructure and technical manpower to harness the full potential of digitisation and also incentivised for augmenting their own sources of revenue.