bluuebunny/crossref_metadata_2025 huggingface dataset:
Large-Eddy Simulation of Separated Flows on Unconventionally Coarse Grids
Authors: Bin Yuanwei , Park George I. , Lv Yu , Yang Xiang I. A.
Published: February 2024

We examine and benchmark the emerging idea of applying the large-eddy simulation (LES) formalism to unconventionally coarse grids where RANS would be considered more appropriate at first glance. We distinguish this idea from very-large-eddy-simulation (VLES) and detached-eddy-simulation (DES), which require switching between RANS and LES formalism. LES on RANS grid is appealing because first, it requires minimal changes to a production code; second, it is more cost-effective than LES; third, it converges to LES; and most importantly, it accurately predicts flows with separation. This work quantifies the benefit of LES on RANS-like grids as compared to RANS on the same grids. Three canonical cases are considered: periodic hill, backward-facing step, and jet in cross flow. We conduct direct numerical simulation (DNS), proper LES on LES grids, LES on RANS-quality grids, and RANS. We show that while the LES solutions on the RANS-quality grids are not grid converged, they are twice as accurate as the RANS on the same grids.
Variability Analysis in Judo Para Athletes With Visual Impairments: Match-Outcome Performance in the Tokyo 2020 Paralympic Games With Evidence From the New Classification System
Authors: Kons Rafael Lima , França Conceição dos Santos Danilo , Carvalho Raiane , Ferreira da Silva Adriano , Lopes-Silva João Paulo , Franchini Emerson , Detanico Daniele
Published: February 2024

Match-related performance analysis in judo Para athletes with visual impairments is important to coaches and staff to identify technical–tactical profiles of their athletes and opponents but also to identify whether there are similar characteristics in each visual class. Thus, this study explores the match-related performance in judo Para athletes and verifies the relationship between performance using the old and new classification systems. The match-derived variables were analyzed using different statistical methods considering a total of 182 matches from the Tokyo 2020 Paralympic Games. The results indicated that performance was affected by sex and degree of impairment. The new classification system seems suitable for grouping Para judo athletes, as it differentiates performance between the two proposed classes (J1 and J2), since athletes from each group compete separately. Furthermore, different variability index measures were correlated with competitive performance, demonstrating a specific performance profile for each sport class in judo.
Genomic editing in
Burkholderia multivorans
by CRISPR/Cas9
Authors: Ferreira Mirela R. , Queiroga Vasco , Moreira Leonilde M.
Published: February 2024

Burkholderia cepacia
complex bacteria have emerged as opportunistic pathogens in patients with cystic fibrosis and immunocompromised individuals, causing life-threatening infections. Because of the relevance of these microorganisms, genetic manipulation is crucial for explaining the genetic mechanisms leading to pathogenesis. Despite the availability of allelic exchange tools to obtain unmarked gene deletions in
Burkholderia
, these require a step of merodiploid formation and another of merodiploid resolution through two independent homologous recombination events, making the procedure long-lasting. The CRISPR/Cas9-based system could ease this constraint, as only one step is needed for allelic exchange. Here, we report the modification of a two-plasmid system (pCasPA and pACRISPR) for genome editing in
Burkholderia multivorans
. Several modifications were implemented, including selection marker replacement, the optimization of
araB
promoter induction for the expression of Cas9 and λ-Red system encoding genes, and the establishment of plasmid curing procedures based on the
sacB
gene or growth at a sub-optimal temperature of 18°C–20°C with serial passages. We have shown the efficiency of this CRISPR/Cas9 method in the precise and unmarked deletion of different genes (
rpfR
,
bceF
,
cepR
, and
bcsB
) from two strains of
B. multivorans
, as well as its usefulness in the targeted insertion of the
gfp
gene encoding the green fluorescence protein into a precise genome location. As pCasPA was successfully introduced in other
Burkholderia cepacia
complex species, this study opens up the possibility of using CRISPR/Cas9-based systems as efficient tools for genome editing in these species, allowing faster and more cost-effective genetic manipulation.

IMPORTANCE

Burkholderia
encompasses different species of bacteria, some of them pathogenic to animals and plants, but others are beneficial by promoting plant growth through symbiosis or as biocontrol agents. Among these species,
Burkholderia multivorans
, a member of the
Burkholderia cepacia
complex, is one of the predominant species infecting the lungs of cystic fibrosis patients, often causing respiratory chronic infections that are very difficult to eradicate. Since the
B. multivorans
species is understudied, we have developed a genetic tool based on the CRISPR/Cas9 system to delete genes efficiently from the genomes of these strains. We could also insert foreign genes that can be precisely placed in a chosen genomic region. This method, faster than other conventional strategies based on allelic exchange, will have a major contribution to understanding the virulence mechanisms in
B. multivorans
, but it can likely be extended to other
Burkholderia
species.
mSphere of Influence: The discovery of a missing link in bacterial cell envelope biogenesis
Authors: Harrison Gregory A.
Published: February 2024

Gregory Harrison is a bacteriologist researching essential pathways in bacteria as potential therapeutic targets. In this mSphere of Influence article, he reflects on a series of studies that employ complementary genetic approaches to define the crucial role of AsmA-family proteins in transporting phospholipids between the inner and outer membranes of Gram-negative bacteria. The authors of these three studies identify this family of lipid transporters through the means of bacterial genetics, answering a long-standing question in bacterial physiology, and serving as a reminder that a well-designed genetic strategy can go a long way in uncovering new biology.
Anti-
Aspergillus
activities of olorofim at sub-MIC levels during early-stage growth
Authors: Kühbacher Alexander , Birch Mike , Oliver Jason D. , Gsaller Fabio
Published: February 2024

Olorofim, the first member of the novel class of antifungal drugs, the orotomides, shows promising anti-
Aspergillus
activity and is currently in phase III clinical development. Using high-throughput microscopy, we monitored olorofim’s antifungal potential at sub-minimum inhibitory concentration (MIC) levels with a focus on early-stage growth. Unlike voriconazole, olorofim showed significant growth inhibitory activities against three main pathogenic
Aspergillus
species,
Aspergillus fumigatus
,
Aspergillus flavus
, and
Aspergillus niger
, at concentrations >100,000-fold below its MIC.

IMPORTANCE

Among antifungal compounds in clinical development for systemic disease, the orotomide olorofim is one of only two that target a completely new mechanism of action. Olorofim is highly potent against pathogenic
Aspergillus
species including cryptic species that frequently show increased resistance to current agents. In this study, our primary focus was on evaluating in detail the inhibitory activity of voriconazole and olorofim against different pathogenic
Aspergillus
species employing high-throughput microscopy. Compared to standardized, less-sensitive visual assessment-based methods, microscopy-assisted growth monitoring allowed us to detect sub-MIC drug concentration ranges with significant inhibitory activity at early-stage growth. This revealed that olorofim exerts growth inhibition at concentrations that are several magnitudes below those of voriconazole.
Design differences and variation in results between randomised trials and non-randomised emulations: meta-analysis of RCT-DUPLICATE data
Authors: Heyard Rachel , Held Leonhard , Schneeweiss Sebastian , Wang Shirley V
Published: February 2024

Objective

To explore how design emulation and population differences relate to variation in results between randomised controlled trials (RCT) and non-randomised real world evidence (RWE) studies, based on the RCT-DUPLICATE initiative (Randomised, Controlled Trials Duplicated Using Prospective Longitudinal Insurance Claims: Applying Techniques of Epidemiology).

Design

Meta-analysis of RCT-DUPLICATE data.

Data sources

Trials included in RCT-DUPLICATE, a demonstration project that emulated 32 randomised controlled trials using three real world data sources: Optum Clinformatics Data Mart, 2004-19; IBM MarketScan, 2003-17; and subsets of Medicare parts A, B, and D, 2009-17.

Eligibility criteria for selecting studies

Trials where the primary analysis resulted in a hazard ratio; 29 RCT-RWE study pairs from RCT-DUPLICATE.

Results

Differences and variation in effect sizes between the results from randomised controlled trials and real world evidence studies were investigated. Most of the heterogeneity in effect estimates between the RCT-RWE study pairs in this sample could be explained by three emulation differences in the meta-regression model: treatment started in hospital (which does not appear in health insurance claims data), discontinuation of some baseline treatments at randomisation (which would have been an unusual care decision in clinical practice), and delayed onset of drug effects (which would be under-reported in real world clinical practice because of the relatively short persistence of the treatment). Adding the three emulation differences to the meta-regression reduced heterogeneity from 1.9 to almost 1 (absence of heterogeneity).

Conclusions

This analysis suggests that a substantial proportion of the observed variation between results from randomised controlled trials and real world evidence studies can be attributed to differences in design emulation.
Hypoxia-inducible factor in cancer: from pathway regulation to therapeutic opportunity
Authors: Ortmann Brian M
Published: February 2024

Cancer remains one of the most formidable challenges in modern medicine, due to its complex and dynamic nature, which demands innovative therapeutic approaches. One major challenge to cancer treatment is the tumour microenvironment and in particular tumour hypoxia (low oxygen levels), which contributes to tumour progression and immune evasion. At the cellular level, this is primarily governed by hypoxia-inducible factor (HIF). HIF is a transcription factor that orchestrates cellular responses to low oxygen levels, driving angiogenesis, metabolic adaptation and immune regulation. HIF’s dysregulation is frequently observed in various cancer types and correlates with increased aggressiveness, metastasis, resistance to therapy and poor patient prognosis. Consequently, understanding the cellular mechanisms underlying HIF activation and its downstream effects has become crucial to developing targeted cancer therapies for improving cancer patient outcomes and represents a key step towards precision medicine.

Recent advancements in drug development have led to the emergence of HIF inhibitors, which aim to disrupt HIF-driven processes in cancer providing therapeutic benefit. Here, we provide a review of the molecular mechanisms through which HIF promotes tumour growth and resistance, emphasising the potential clinical benefits of HIF-targeted therapies. This review will discuss the challenges and opportunities associated with translating HIF inhibition into clinical practice, including ongoing clinical trials and future directions in the development of HIF-based cancer treatments.
Metastatic gastric cancer target lesion complete response with Claudin18.2-CAR T cells
Authors: Botta Gregory P , Chao Joseph , Ma Hong , Hahn Michael , Sierra Gloria , Jia Jie , Hendrix Amanda Y , Nolte Fong Joy V , Ween Audrey , Vu Peter , Miller Aaron , Choi Michael , Heyman Benjamin , Daniels Gregory A , Kaufman Dan , Jamieson Catriona , Li Zonghai , Cohen Ezra
Published: February 2024

Treatment of hematologic malignancies with patient-derived anti-CD19 chimeric antigen receptor (CAR) T-cells has demonstrated long-term remissions for patients with otherwise treatment-refractory advanced leukemia and lymphoma. Conversely, CAR T-cell treatment of solid tumors, including advanced gastric cancer (GC), has proven more challenging due to on-target off-tumor toxicities, poor tumor T-cell infiltration, inefficient CAR T-cell expansion, immunosuppressive tumor microenvironments, and demanding preconditioning regimens. We report the exceptional results of autologous Claudin18.2-targeted CAR T cells (CT041) in a patient with metastatic GC, who had progressed on four lines of combined systemic chemotherapy and immunotherapy. After two CT041 infusions, the patient had target lesion complete response and sustained an 8-month overall partial response with only minimal ascites. Moreover, tumor-informed circulating tumor DNA (ctDNA) reductions coincided with rapid CAR T-cell expansion and radiologic response. No severe toxicities occurred, and the patient’s quality of life significantly improved. This experience supports targeting Claudin18.2-positive GC with CAR T-cell therapy and helps to validate ctDNA as a biomarker in CAR T-cell therapy.

Clinical Insight:Claudin18.2-targeted CAR T cells can safely provide complete objective and ctDNA response in salvage metastatic GC.
Optimizing quality of life: integrating palliative care for patients with hand-foot syndrome in oncology practice
Authors: Vanumu Divya Sai , Kodisharapu Praveen Kumar , Suvvari Praneeth , Rayani Basanth Kumar , Pathi Nikhil , Tewani Rohan , Rajappa Senthil J
Published: February 2024

Hand-foot syndrome (HFS) emerges as one of the common dermatological side effects associated with anticancer medications such as 5-fluorouracil (5-FU), capecitabine and docetaxel. This condition can be notably debilitating, exerting a predominant impact on the clinical, functional and psychosocial domains of health. With prevalence rates of HFS, ranging from 43% to 71%, there exists an unmet need among palliative care physicians to comprehend this syndrome in addressing physical, psychological dimensions and its integrated management within healthcare. This understanding enables them to adopt diverse approaches aimed at preserving the quality of life for patients, by enhancing the overall healthcare experience. Our primary objective is to underscore the imperative for the high-quality integration of palliative care with respect to HFS in contemporary oncology practices. We aim to achieve this by providing evidence-based insights to enhance patient outcomes.

The intent of this study: (1) The article delves into the range of symptoms linked to HFS, and stresses the necessity of a holistic strategy and the difference that a palliative physician can contribute during cancer treatment—in picking up certain intricate aspects of patient care and addressing them. (2) The article also highlights the comprehensive approach through the incorporation of quality-of-life assessments, with the goal of enhancing patient outcomes, overall care experience within an integrated healthcare framework.
Time behavior of hubble parameter by torsion
Authors: Morawetz Klaus
Published: February 2024

Consequences of the consistent exact solution of Einstein–Cartan equation on the time dependence of Hubble parameter are discussed. The torsion leads to a space and time-dependent expansion parameter which results into nontrivial windows of Hubble parameter between diverging behavior. Only one window shows a period of decreasing followed by increasing time dependence. Provided a known cosmological constant and the present values of Hubble and deceleration parameter this changing time can be given in the past as well as the ending time of the windows or universe. The comparison with the present experimental data allows to determine all parameters of the model. Large-scale spatial periodic structures appear. From the metric with torsion outside matter, it is seen that torsion can feign dark matter.
Enhancing Rigor in Computational Methods for Biological Data Analysis
Authors: Ge Xinzhou
Published: February 2024

When you use the most popular computational methods for biological data analysis, have you checked whether their models are reasonable in your settings?
Tarazu: An Adaptive End-to-end I/O Load-balancing Framework for Large-scale Parallel File Systems
Authors: Paul Arnab K. , Neuwirth Sarah , Wadhwa Bharti , Wang Feiyi , Oral Sarp , Butt Ali R.
Published: February 2024

The imbalanced I/O load on large parallel file systems affects the parallel I/O performance of high-performance computing (HPC) applications. One of the main reasons for I/O imbalances is the lack of a global view of system-wide resource consumption. While approaches to address the problem already exist, the diversity of HPC workloads combined with different file striping patterns prevents widespread adoption of these approaches. In addition, load-balancing techniques should be transparent to client applications. To address these issues, we propose
Tarazu
, an end-to-end control plane where clients transparently and adaptively write to a set of selected I/O servers to achieve balanced data placement. Our control plane leverages real-time load statistics for global data placement on distributed storage servers, while our design model employs trace-based optimization techniques to minimize latency for I/O load requests between clients and servers and to handle multiple striping patterns in files. We evaluate our proposed system on an experimental cluster for two common use cases: the synthetic I/O benchmark IOR and the scientific application I/O kernel HACC-I/O. We also use a discrete-time simulator with real HPC application traces from emerging workloads running on the Summit supercomputer to validate the effectiveness and scalability of
Tarazu
in large-scale storage environments. The results show improvements in load balancing and read performance of up to 33% and 43%, respectively, compared to the state-of-the-art.
Flexible Updating of Internet of Things Computing Functions through Optimizing Dynamic Partial Reconfiguration
Authors: Kornaros George , Leivadaros Svoronos , Kolimbianakis Filippos
Published: February 2024

With applications to become increasingly compute- and data-intensive, requiring more processing power, many Internet of Things (IoT) platforms in robots, drones, and autonomous vehicles that implement neural network inference, cryptographic functions or signal processing (e.g., multimedia, communication), employ field programmable gate arrays (FPGAs). At the same time, dynamic partial reconfiguration (DPR) in modern FPGAs enable changing the function of a part of the FPGA by dynamically loading new bitstreams to the logic regions without affecting the function of other parts of the FPGA. This is especially useful to update functions of IoT devices while in operation for bug fixing or functionality adjustments and, more importantly, when these IoT devices integrate low-cost FPGAs that can hardly realize many hard accelerators. To deal with one of the major limitations of using partial reconfiguration in IoT devices, this work introduces techniques to flexibly use DPR, namely, FLEXDPR, by sharing reconfigurable partitions among different accelerator functions and by supporting virtual relocation of these functions. Experimental results on the Xilinx Zynq-7000 platform reveal energy and latency efficiency improvements of about 20%, on average. Overall, the suggested approach can reduce partial reconfiguration overhead while easing the scheduler’s decisions for the deployment of hardware functions throughout time and space in a performance-conscious manner.
DeLink: An Adversarial Framework for Defending against Cross-site User Identity Linkage
Authors: Zhang Peng , Zhou Qi , Lu Tun , Gu Hansu , Gu Ning
Published: February 2024

Cross-site user identity linkage (UIL) aims to link the identities of the same person across different social media platforms. Social media practitioners and service providers can construct composite user portraits based on cross-site UIL, which helps understand user behavior holistically and conduct accurate recommendations and personalization. However, many social media users expect each profile to stay within the platform where it was created and thus do not want the identities of different platforms to be linked. For this problem, we first investigate the approaches people would like to use to defend against cross-site UIL and the corresponding challenges. Based on the findings, we build an adversarial framework, DeLink, based on the thoughts of adversarial text generation to help people improve their social media screen names to defend against cross-site UIL. DeLink can support both Chinese and English languages and has good generalizability to the varying numbers of social media accounts and different cross-site user identity linkage models. Extensive evaluations validate DeLink’s better performance, including a higher success rate, higher efficiency, less impact on human perception, and capability to defend against different cross-site UIL models.
A Machine Learning and Optimization Framework for Efficient Alert Management in a Cybersecurity Operations Center
Authors: Ghadermazi Jalal , Shah Ankit , Jajodia Sushil
Published: February 2024

Cybersecurity operations centers (CSOCs) protect organizations by monitoring network traffic and detecting suspicious activities in the form of alerts. The security response team within CSOCs is responsible for investigating and mitigating alerts. However, an imbalance between alert volume and available analysts creates a backlog, putting the network at risk of exploitation. Recent research has focused on improving the alert-management process by triaging alerts, optimizing analyst scheduling, and reducing analyst workload through systematic discarding of alerts. However, these works overlook the delays caused in alert investigations by several factors, including: (i) false or benign alerts contributing to the backlog; (ii) analysts experiencing cognitive burden from repeatedly reviewing unrelated alerts; and (iii) analysts being assigned to alerts that do not match well with their expertise. We propose a novel framework that considers these factors and utilizes machine learning and mathematical optimization methods to dynamically improve throughput during work shifts. The framework achieves efficiency by automating the identification and removal of a portion of benign alerts, forming clusters of similar alerts, and assigning analysts to alerts with matching attributes. Experiments conducted using real-world CSOC data demonstrate a 60.16% reduction in the alert backlog for an 8-h work shift compared to currently employed approach.
Everolimus exerts anticancer effects through inhibiting the interaction of matrix metalloproteinase-7 with syndecan-2 in colon cancer cells
Authors: Lee Seohyeon , Jang Bohee , Hwang Jisun , Lee Yejin , Cho Subin , Yang Hyeonju , Yun Ji-Hye , Shin Dong Hae , Lee Weontae , Oh Eok-Soo
Published: February 2024

The utility of cancer therapeutics targeting the proteolytic activities of MMPs is limited because MMPs are widely distributed throughout the body and involved in many different aspects of cell functions. This work specifically targets the activation of MMP-7 through its interaction with syndecan-2. Notably, everolimus, a known mTOR inhibitor, blocked this interaction, demonstrating a novel role for everolimus in inhibiting mTOR signaling and impairing the interaction of MMP-7 with syndecan-2 in colon cancer.
Caffeine-induced protein kinase A activation restores cognitive deficits induced by sleep deprivation by regulating O-GlcNAc cycling in adult zebrafish
Authors: Tran Thuy-Duong Thi , Park Jiwon , Kim Dong Yeol , Han Inn-Oc
Published: February 2024

Our observation highlights the intricate interplay between cAMP/PKA signaling and O-GlcNAc cycling, unveiling a novel mechanism that potentially governs the regulation of learning and memory functions. The dynamic interplay between these two pathways provides a novel and nuanced perspective on the molecular foundation of learning and memory regulation. These insights open avenues for the development of targeted interventions to treat conditions that impact cognitive function, including SD.
Rodent models of AKI and AKI-CKD transition: an update in 2024
Authors: Fu Ying , Xiang Yu , Wei Qingqing , Ilatovskaya Daria , Dong Zheng
Published: February 2024

Despite known drawbacks, rodent models are essential tools in the research of renal development, physiology, and pathogenesis. In the past decade, rodent models have been developed and used to mimic different etiologies of acute kidney injury (AKI), AKI to chronic kidney disease (CKD) transition or progression, and AKI with comorbidities. These models have been applied for both mechanistic research and preclinical drug development. However, current rodent models have their limitations, especially since they often do not fully recapitulate the pathophysiology of AKI in human patients, and thus need further refinement. Here, we discuss the present status of these rodent models, including the pathophysiologic compatibility, clinical translational significance, key factors affecting model consistency, and their main limitations. Future efforts should focus on establishing robust models that simulate the major clinical and molecular phenotypes of human AKI and its progression.
Estrogen-mediated individual differences in female rat voluntary running behavior
Authors: Mathis Victoria , Wegman-Points Lauren , Pope Brock , Lee Chia-Ming Jimmy , Mohamed Merna , Rhodes Justin S. , Clark Peter J. , Clayton Sarah , Yuan Li-Lian
Published: February 2024

This study investigates estrogen’s role in voluntary wheel running (VWR) behavior in female rats. Female rats exhibit greater running than males, with estrogen signaling regulating this activity. The estrous cycle influences running, whereas ovariectomy reduces it, and estrogen replacement restores it, maintaining individual differences under all conditions. Both running speed and duration contribute to VWR variations. These findings emphasize individual estrogen regulation in female exercise and provide an estrogen replacement animal model for investigating neurobiological underpinnings that drive voluntary exercise behavior.
Passive heat therapy: a promising preventive measure for people at risk of adverse health outcomes during heat extremes
Authors: Rodrigues Patrick , Orssatto Lucas B. R. , Gagnon Daniel , Dahhak Amine , Hecksteden Anne , Stewart Ian B. , Minett Geoffrey M.
Published: February 2024

Passive heat therapy improves cardiovascular function and health in middle-aged and older adults living with or without chronic diseases. In addition, preliminary studies indicate that passive heat interventions can induce heat acclimation, improving thermoregulatory responses. Thus, passive heat therapy could serve as a preventive measure for people at risk of adverse health outcomes during extreme heat events, improving resilience to ongoing climate change.
Clinical and Laboratory Predictors of Long-Term Outcomes after Catheter Ablation for a Ventricular Electrical Storm
Authors: Sławiński Grzegorz , Hawryszko Maja , Dyda-Kristowska Julia , Królak Tomasz , Kempa Maciej , Świetlik Dariusz , Kozłowski Dariusz , Daniłowicz-Szymanowicz Ludmiła , Lewicka Ewa
Published: February 2024

Background. Ventricular electrical storm (VES) is characterized by the occurrence of multiple episodes of sustained ventricular arrhythmias (VA) over a short period of time. Radiofrequency ablation (RFA) has been reported as an effective treatment in patients with ventricular tachycardia (VT). Objective. The aim of the present study was to indicate the short-term and long-term predictors of recurrent VA after RFA was performed due to VES. Methods. A retrospective, single-centre study included patients, who had undergone RFA due to VT between 2012 and 2021. In terms of the short-term (at the end of RFA) effectiveness of RFA, the following scenarios were distinguished: complete success: inability to induce any VT; partial success: absence of clinical VT; failure: inducible clinical VT. In terms of the long-term (12 months) effectiveness of RFA, the following scenarios were distinguished: effective ablation: no recurrence of any VT; partially successful ablation: VT recurrence; ineffective ablation: VES recurrence. Results. The study included 62 patients. Complete short-term RFA success was obtained in 77.4% of patients. The estimated cumulative VT-free survival and VES-free survival were, respectively, 28% and 33% at the 12-month follow-up. Ischemic cardiomyopathy and complete short-term RFA success were predictors of long-term RFA efficacy. Neutrophil to lymphocyte ratio (NLR) and GFR <60 mL/min/1.73 m2 were associated with VES recurrence. NLR ≥2.95 predicted VT and/or VES recurrence with a sensitivity of 66.7% and specificity of 72.2%. Conclusion. Ischemic cardiomyopathy and short-term complete success of RFA were predictors of no VES recurrence during the 12-month follow-up, while NLR and GFR <60 ml/min/1.73 m2 were associated with VES relapse.
Policy Evaluation of the Reform of Ambulatory Patient Groups Based on Access, Quality, and Cost of the Iron Triangle Value Chain in China
Authors: Li Lele , Tian Mengyi , Gu Debin
Published: February 2024

Objective. As part of the efforts to build a practical, effective, and diversified medical insurance payment method, it is crucial for China to deepen the reform of ambulatory patient groups (APGs). This study was aimed to explore the mechanism and effect of this policy from three dimensions, including medical expenses, medical insurance funds, and medical services. Methods. In 2020, China’s pilot reform of APG was initiated in Jinhua City, Zhejiang Province. Descriptive statistics, correlation analysis, and OLS regression analysis were utilized to evaluate the effect of the APG reform in Jinhua. Results. The implementation of the reform can contribute significantly to establishing a comprehensive medical service governance mechanism of classified settlement and coordinated promotion. It also plays a critical role in safeguarding people’s lives and health by promoting the high‐level development of medical insurance systems and public hospitals, optimizing the quality of medical services, and improving the efficiency of medical insurance funds. Conclusion. Through the lens of policy evaluation, our findings can provide useful experience for the implementation of the outpatient medical insurance payment method in developing countries.
Community Pharmacists’ Knowledge and Perception towards Telepharmacy Services and Willingness to Practice It in Light of COVID-19
Authors: Siddiqua Ayesha , Makki Soha , Siddiqui Sazada , A. Abdelkarim Randa , Jubran Tahani , Nwar Wejdan , Alqahtani Ahlam , Alshehri Maryam , Saeed Maram , Khaled Arwa
Published: February 2024

Background. During the COVID-19 pandemic, there was increased adoption of telepharmacy, which has proven benefits. This study was conducted to assess the knowledge and perception of the community pharmacists of Aseer region, Saudi Arabia, towards telepharmacy services and evaluate their willingness to adopt telepharmacy in clinical practice during the COVID-19 pandemic. Materials and Methods. A cross-sectional study was conducted using an online self-administered structured anonymous questionnaire on the community pharmacists of Aseer region, Saudi Arabia. It covers demographics, computer access and literacy, knowledge and perception, and willingness to practice telepharmacy. Results were expressed as frequencies, percentages, and mean. The comparison between the classes of the demographic variables and the scores was done via Kruskal–Wallis and Mann–Whitney tests. Result. About half of the pharmacists in our study showed average knowledge about telepharmacy, the practical application of telepharmacy technology, and telepharmacy guidelines with a percentage of 53%, 52%, and 47%, respectively). Majority of the participants showed high perception towards telepharmacy in Saudi Arabia, while 93% of the pharmacists in Saudi Arabia agreed that the implementation of telepharmacy technology is appropriate due to the current COVID-19 pandemic. Only a significant relation was found between gender and computer access, literacy, and perceptions towards telepharmacy with p values of 0.033 and 0.026, respectively. Conclusion. The majority of the community pharmacists exhibited a positive perception and are willing to practice the concept of telepharmacy despite having a below average knowledge of telepharmacy. A future study involving the entire kingdom of Saudi Arabia could help identify the gaps in the knowledge, perception, and willingness to practice telepharmacy on a broader scale and thus promote telepharmacy adoption in the entire kingdom.
Uncovering the Multitarget Therapeutic Mechanism of Tong-Xie-Yao-Fang on Irritable Bowel Syndrome
Authors: Ma Xiangxue , Huang Jinke , Wu Haomeng , Li Xia , Wang Fengyun , Tang Xudong
Published: February 2024

Background. This study investigated the pharmacological mechanisms of Tong-Xie-Yao-Fang (TXYF) against irritable bowel syndrome (IBS). Methods. The chemical profile of TXYF was identified through UHPLC-QTOF-MS. Next, the obtained chemical profile served as the basis for network pharmacological analysis. Finally, the predictive performance of network pharmacology was validated by conducting molecular docking and animal experiment. Results. Seven key compounds of TXYF, namely, quercetin, ellagic acid, nobiletin, formononetin, isorhamnetin, vestitol, and licochalcone, were confirmed as the key components acting on IBS. TXYF treatment on IBS was mainly realized through the regulation of some key pathways of immune system, such as inflammatory bowel disease, cytokine-cytokine receptor interaction, HIF-1, and T cell receptor signaling pathway. NOS2, ACHE, ESR1, PTGS2, and RELA were the target genes of TXYF to improve IBS. Stable bonds between the key components and the core target genes were further verified by the results of molecular docking. In vivo experiments confirmed the effects of TXYF on IBS. Further Western blot analysis showed that NOS2, ACHE, and ERα were significantly upregulated in the model group in comparison with controls (P<0.001) but then significantly downregulated after treatment with TXYF for 14 days (P<0.001). Conclusion. This study applied an integrated method based on network pharmacology and experimental validation to examine the underlying “multicomponent, multitarget, and multipathway” mode of action of TXYF in treating IBS. The current findings provided indicative paradigms and new insights into exploring the multitarget therapeutic mechanism of Chinese herbal compound.
Supplementary Table from A Multiethnic Germline–Somatic Association Database Deciphers Multilayered and Interconnected Genetic Mutations in Cancer
Authors: Xin Junyi , Mo Zongchao , Chai Ruichao , Hua Wei , Wang Jiguang
Published: February 2024

Supplementary Tables 1-2
Supplementary Data from SUMOylation-Driven mRNA Circularization Enhances Translation and Promotes Lymphatic Metastasis of Bladder Cancer
Authors: Zhao Yue , Chen Jiancheng , Zheng Hanhao , Luo Yuming , An Mingjie , Lin Yan , Pang Mingrui , Li Yuanlong , Kong Yao , He Wang , Lin Tianxin , Chen Changhao
Published: February 2024

Figure S7
Supplementary Table from Neuronal Activity Promotes Glioma Progression by Inducing Proneural-to-Mesenchymal Transition in Glioma Stem Cells
Authors: Guo Xiaofan , Qiu Wei , Wang Chaochao , Qi Yanhua , Li Boyan , Wang Shaobo , Zhao Rongrong , Cheng Bo , Han Xiao , Du Hao , Gao Zijie , Pan Ziwen , Zhao Shulin , Li Gang , Xue Hao
Published: February 2024

Supplementary Table
Supplementary Data from Neuronal Activity Promotes Glioma Progression by Inducing Proneural-to-Mesenchymal Transition in Glioma Stem Cells
Authors: Guo Xiaofan , Qiu Wei , Wang Chaochao , Qi Yanhua , Li Boyan , Wang Shaobo , Zhao Rongrong , Cheng Bo , Han Xiao , Du Hao , Gao Zijie , Pan Ziwen , Zhao Shulin , Li Gang , Xue Hao
Published: February 2024

Figure S2. Original western blots 2
Supplementary Data from Neuronal Activity Promotes Glioma Progression by Inducing Proneural-to-Mesenchymal Transition in Glioma Stem Cells
Authors: Guo Xiaofan , Qiu Wei , Wang Chaochao , Qi Yanhua , Li Boyan , Wang Shaobo , Zhao Rongrong , Cheng Bo , Han Xiao , Du Hao , Gao Zijie , Pan Ziwen , Zhao Shulin , Li Gang , Xue Hao
Published: February 2024

Figure S4. Neuronal activity promotes exosomes release
Supplementary Data from Neuronal Activity Promotes Glioma Progression by Inducing Proneural-to-Mesenchymal Transition in Glioma Stem Cells
Authors: Guo Xiaofan , Qiu Wei , Wang Chaochao , Qi Yanhua , Li Boyan , Wang Shaobo , Zhao Rongrong , Cheng Bo , Han Xiao , Du Hao , Gao Zijie , Pan Ziwen , Zhao Shulin , Li Gang , Xue Hao
Published: February 2024

Figure S16. miR-184-3p promotes the PMT in GSC by targeting RBM15
Table S1 from Clinical and Immunologic Features of Germline Pathogenic Variant–Positive Patients with Melanoma
Authors: Shen Alan , Arbesman Michelle , Lodha Roshan , Rayman Patricia , Bungo Brandon , Ni Ying , Chan Timothy , Gastman Brian , Ko Jennifer , Diaz-Montero C. Marcela , Arbesman Joshua , Funchain Pauline
Published: February 2024

Eligibility criteria amongst patient cohort.
Supplemental Table S2 from Aneuploidy Landscape in Precursors of Ovarian Cancer
Authors: Wang Yeh , Douville Christopher , Chien Yen-Wei , Wang Brant G. , Chen Chi-Long , Pinto Andre , Smith Saron Ann , Drapkin Ronny , Chui M. Herman , Numan Tricia , Vang Russell , Papadopoulos Nickolas , Wang Tian-Li , Shih Ie-Ming
Published: February 2024

The information of antibodies used in the study.
Supplemental Table S1 from Aneuploidy Landscape in Precursors of Ovarian Cancer
Authors: Wang Yeh , Douville Christopher , Chien Yen-Wei , Wang Brant G. , Chen Chi-Long , Pinto Andre , Smith Saron Ann , Drapkin Ronny , Chui M. Herman , Numan Tricia , Vang Russell , Papadopoulos Nickolas , Wang Tian-Li , Shih Ie-Ming
Published: February 2024

The numbers of specimen subtypes included in the study.
Supplemental Figure S2 from Aneuploidy Landscape in Precursors of Ovarian Cancer
Authors: Wang Yeh , Douville Christopher , Chien Yen-Wei , Wang Brant G. , Chen Chi-Long , Pinto Andre , Smith Saron Ann , Drapkin Ronny , Chui M. Herman , Numan Tricia , Vang Russell , Papadopoulos Nickolas , Wang Tian-Li , Shih Ie-Ming
Published: February 2024

Degree of aneuploidy between incidental active STIC and HGSC.
Supplementary Table S9 from Phase I Study of Elraglusib (9-ING-41), a Glycogen Synthase Kinase-3β Inhibitor, as Monotherapy or Combined with Chemotherapy in Patients with Advanced Malignancies
Authors: Carneiro Benedito A. , Cavalcante Ludimila , Mahalingam Devalingam , Saeed Anwaar , Safran Howard , Ma Wen Wee , Coveler Andrew L. , Powell Steven , Bastos Bruno , Davis Elizabeth , Sahai Vaibhav , Mikrut William , Longstreth James , Smith Sheri , Weisskittel Taylor , Li Hu , Borden Brittany A. , Harvey R. Donald , Sahebjam Solmaz , Cervantes Andrés , Koukol Austin , Mazar Andrew P. , Steeghs Neeltje , Kurzrock Razelle , Giles Francis J. , Munster Pamela
Published: February 2024

Tumor Types by Elraglusib Dose Level in Part 2.
Arm A count matrices 3 from PD-1 Blockade Induces Reactivation of Nonproductive T-Cell Responses Characterized by NF-κB Signaling in Patients with Pancreatic Cancer
Authors: Ali Lestat R. , Lenehan Patrick J. , Cardot-Ruffino Victoire , Dias Costa Andressa , Katz Matthew H.G. , Bauer Todd W. , Nowak Jonathan A. , Wolpin Brian M. , Abrams Thomas A. , Patel Anuj , Clancy Thomas E. , Wang Jiping , Mancias Joseph D. , Reilley Matthew J. , Stucky Chee-Chee H. , Bekaii-Saab Tanios S. , Elias Rawad , Merchant Nipun , Slingluff Craig L. , Rahma Osama E. , Dougan Stephanie K.
Published: February 2024

Arm A count matrices
Supplementary Figure 2 from Neoadjuvant Selicrelumab, an Agonist CD40 Antibody, Induces Changes in the Tumor Microenvironment in Patients with Resectable Pancreatic Cancer
Authors: Byrne Katelyn T. , Betts Courtney B. , Mick Rosemarie , Sivagnanam Shamilene , Bajor David L. , Laheru Daniel A. , Chiorean E. Gabriela , O'Hara Mark H. , Liudahl Shannon M. , Newcomb Craig , Alanio Cécile , Ferreira Ana P. , Park Byung S. , Ohtani Takuya , Huffman Austin P. , Väyrynen Sara A. , Dias Costa Andressa , Kaiser Judith C. , Lacroix Andreanne M. , Redlinger Colleen , Stern Martin , Nowak Jonathan A. , Wherry E. John , Cheever Martin A. , Wolpin Brian M. , Furth Emma E. , Jaffee Elizabeth M. , Coussens Lisa M. , Vonderheide Robert H.
Published: February 2024

Figure S2 shows the antibody panel and protocol, the gating strategy, and the immune cell populations identified using the mIHC platform.
Data from Modulating Gut Microbiota Prevents Anastomotic Leak to Reduce Local Implantation and Dissemination of Colorectal Cancer Cells after Surgery
Authors: Hajjar Roy , Oliero Manon , Fragoso Gabriela , Ajayi Ayodeji Samuel , Alaoui Ahmed Amine , Vennin Rendos Hervé , Calvé Annie , Cuisiniere Thibault , Gerkins Claire , Thérien Sophie , Taleb Nassima , Dagbert François , Sebajang Herawaty , Loungnarath Rasmy , Schwenter Frank , Ratelle Richard , Wassef Ramses , De Broux Eric , Richard Carole , Santos Manuela M.
Published: February 2024

AbstractPurpose:
Anastomotic leak (AL) is a major complication in colorectal cancer surgery and consists of the leakage of intestinal content through a poorly healed colonic wound. Colorectal cancer recurrence after surgery is a major determinant of survival. We hypothesize that AL may allow cancer cells to escape the gut and lead to cancer recurrence and that improving anastomotic healing may prevent local implantation and metastatic dissemination of cancer cells.
Experimental Design:
We investigated the association between AL and postoperative outcomes in patients with colorectal cancer. Using mouse models of poor anastomotic healing, we assessed the processes of local implantation and dissemination of cancer cells. The effect of dietary supplementation with inulin and 5-aminosalicylate (5-ASA), which activate PPAR-γ in the gut, on local anastomotic tumors was assessed in mice undergoing colonic surgery. Inulin and 5-ASA were also assessed in a mouse model of liver metastasis.
Results:
Patients experiencing AL displayed lower overall and oncologic survival than non-AL patients. Poor anastomotic healing in mice led to larger anastomotic and peritoneal tumors. The microbiota of patients with AL displays a lower capacity to activate the antineoplastic PPAR-γ in the gut. Modulation of gut microbiota using dietary inulin and 5-ASA reinforced the gut barrier and prevented anastomotic tumors and metastatic spread in mice.
Conclusions:
Our findings reinforce the hypothesis that preventing AL is paramount to improving oncologic outcomes after colorectal cancer surgery. Furthermore, they pave the way toward dietary targeting of PPAR-γ as a novel way to enhance healing and diminish cancer recurrence.
Combining Genomic Biomarkers to Guide Immunotherapy in Non–Small Cell Lung Cancer
Authors: van de Haar Joris , Mankor Joanne M. , Hummelink Karlijn , Monkhorst Kim , Smit Egbert F. , Wessels Lodewyk F.A. , Cuppen Edwin , Aerts Joachim G.J.V. , Voest Emile E.
Published: February 2024

Purpose:

The clinical value of STK11, KEAP1, and EGFR alterations for guiding immune checkpoint blockade (ICB) therapy in non–small cell lung cancer (NSCLC) remains controversial, as some patients with these proposed resistance biomarkers show durable ICB responses. More specific combinatorial biomarker approaches are urgently needed for this disease.

Experimental Design:

To develop a combinatorial biomarker strategy with increased specificity for ICB unresponsiveness in NSCLC, we performed a comprehensive analysis of 254 patients with NSCLC treated with programmed death-ligand 1 (PD-L1) blockade monotherapy, including a discovery cohort of 75 patients subjected to whole-genome sequencing (WGS), and an independent validation cohort of 169 patients subjected to tumor-normal large panel sequencing. The specificity of STK11/KEAP1/EGFR alterations for ICB unresponsiveness was assessed in the contexts of a low (<10 muts/Mb) or high (≥10 muts/Mb) tumor mutational burden (TMB).

Results:

In low TMB cases, STK11/KEAP1/EGFR alterations were highly specific biomarkers for ICB resistance, with 0/15 (0.0%) and 1/34 (2.9%) biomarker-positive patients showing treatment benefit in the discovery and validation cohorts, respectively. This contrasted with high TMB cases, where 11/13 (85%) and 15/34 (44%) patients with at least one STK11/KEAP1/EGFR alteration showed durable treatment benefit in the discovery and validation cohorts, respectively. These findings were supported by analyses of progression-free survival and overall survival.

Conclusions:

The unexpected ICB responses in patients carrying resistance biomarkers in STK11, KEAP1, and EGFR were almost exclusively observed in patients with a high TMB. Considering these alterations in context of the TMB offered a highly specific combinatorial biomarker strategy for limiting overtreatment in NSCLC.
Supplementary figure 5 from Design and Evaluation of Phosphonamidate-Linked Exatecan Constructs for Highly Loaded, Stable, and Efficacious Antibody–Drug Conjugates
Authors: Schmitt Saskia , Machui Paul , Mai Isabelle , Herterich Sarah , Wunder Swetlana , Cyprys Philipp , Gerlach Marcus , Ochtrop Philipp , Hackenberger Christian P.R. , Schumacher Dominik , Helma Jonas , Vogl Annette M. , Kasper Marc-André
Published: February 2024

Enhertu and trastuzumab-LP5 induce DNA damage. DNA damage induced by exatecan, DXd, trastuzumab-LP5 DAR 8 and Enhertu. HER2-positive SKBR-3 cells were treated for indicated time points with 5 µg/ml respective ADCs. Cells were stained with live/dead stain, for DNA damage markers phosphorylated H2A.X (Ser139), cleaved PARP and active caspase 3 and analyzed by flow cytometry. Graphs show means of n = 2 ± SEM.
Figure S6 from Effects of Combined Therapeutic Targeting of AXL and ATR on Pleural Mesothelioma Cells
Authors: Hirai Soichi , Yamada Tadaaki , Katayama Yuki , Ishida Masaki , Kawachi Hayato , Matsui Yohei , Nakamura Ryota , Morimoto Kenji , Horinaka Mano , Sakai Toshiyuki , Sekido Yoshitaka , Tokuda Shinsaku , Takayama Koichi
Published: February 2024

Figure S6
Figure S2 from Effects of Combined Therapeutic Targeting of AXL and ATR on Pleural Mesothelioma Cells
Authors: Hirai Soichi , Yamada Tadaaki , Katayama Yuki , Ishida Masaki , Kawachi Hayato , Matsui Yohei , Nakamura Ryota , Morimoto Kenji , Horinaka Mano , Sakai Toshiyuki , Sekido Yoshitaka , Tokuda Shinsaku , Takayama Koichi
Published: February 2024

Figure S2
Table S1 from SKP2 Knockout in Rb1/p53–Deficient Mouse Models of Osteosarcoma Induces Immune Infiltration and Drives a Transcriptional Program with a Favorable Prognosis
Authors: Ferrena Alexander , Wang Jichuan , Zhang Ranxin , Karadal-Ferrena Burcu , Al-Hardan Waleed , Singh Swapnil , Borjihan Hasibagan , Schwartz Edward L. , Zhao Hongling , Oktay Maja H. , Yang Rui , Geller David S. , Hoang Bang H. , Zheng Deyou
Published: February 2024

RNA-seq sample information