bluuebunny/crossref_metadata_2025 huggingface dataset:
10013- MPC-3 CHARACTERISTICS AND OUTCOMES OF HISTONE H3 K27M-MUTANT DIFFUSE MIDLINE AND NON-MIDLINE GLIOMAS IN THE KANSAI NETWORK COHORT
Authors: Fukai Junya
Published: November 2024

INTRODUCTION

Histone H3 K27M-mutant diffuse gliomas are observed at the midline and, rarely, non-midline locations (abbreviated as DMG and NDMG in this study, respectively). It may be unclear how NDMG should be classified in the 2021 WHO classification. This study investigates clinical and molecular characteristics as well as treatment outcomes of patients with NDMG in comparison with those of DMG.

METHODS

We collected histone H3 K27M-mutant diffuse glioma cases and enrolled in the Kansai Molecular Diagnosis Network for CNS Tumors. Clinical and molecular characteristics and treatment outcomes were analyzed retrospectively and compared between NDMG and DMG cases.

RESULTS

Anatomical tumor locations were classified into five groups: cerebral hemisphere (16), thalamus (47), brainstem (24), spinal cord (12) and other midline locations (10); therefore, a total of 16 patients with NDMG and 93 patients with DMG were included in this study. Clinical and molecular characteristics of the study cohort (NDMG vs. DMG) included: median age 45 vs. 25 years, female sex (37 vs. 41%), lower-grade histology (6 vs. 56%), preoperative Karnofsky performance status (KPS) scores >80 (50 vs. 49%), resection (50 vs. 36%), adjuvant radiation plus chemotherapy (81 vs. 83%), HIST1H3B p.K27M mutation (0 vs. 4%), TERT promoter mutation (0 vs. 3%), MGMT promoter methylation (25 vs. 9%), BRAF p.V600E mutation (6 vs. 1%), FGFR1 mutation (6 vs. 14%) and EGFR mutation (0 vs. 3%). Median overall survival time was 20.0 vs. 16.6 months. In DNA methylation analysis, NDMG clustered within or close to the reference group of DMG.

CONCLUSIONS

Diffuse gliomas harboring histone H3 K27M mutation can be observed at cerebral hemisphere in the older adults. NDMG shares many similarities with DMG, suggesting that they correspond to a rare anatomical presentation of DMG.
10195- MPC-19 CURRENT STATUS OF MULTICENTER STUDIES USING GLIOMA TAILORED CUSTOM DNA/RNA PANELS
Authors: Higa Nayuta , Akahane Toshiaki , Yonezawa Hajime , Yokoyama Seiya , Makino Ryutaro , Uchida Hiroyuki , Kirishima Mari , Yoshimoto Koji , Tanimoto Akihide , Hanaya Ryosuke
Published: November 2024

INTRODUCTION

In 2018, we developed a glioma specific next-generation sequencing NGS panel and analyzed over 500 cases. In April 2023, we have expanded our work to include a custom DNA/RNA panel capable of detecting fusion genes. A multicenter collaborative study utilizing this advanced panel has been in progress since October 2023. This report outlines the diagnostic and screening significance of our panel and provides an update on the ongoing multicenter study.

METHODS

The custom gene panel included a 51 gene DNA and 37 gene RNA panel. DNA and RNA were extracted from formalin fixed paraffin embedded specimens used for histopathological diagnosis. Mutations, copy number and fusion genes were detected using the Illumina NextSeq1000. A multicenter collaborative study is currently underway with 21 institutions, analyzing cases at 43,000 yen each. This system has analyzed 210 consecutive brain tumors cases.

RESULTS

Currently, 12 of the 21 facilities have contracted us for analysis. The average analysis time was 35 days. Of the 210 cases, 35 (16.7%) harbored fusion genes. Nineteen cases (9.0%) had therapeutic target genes, including NTRK1/2, FGFR1/3, MET, and BRAF fusion genes. Eighteen of 112 GBM cases (16.1%) harbored fusion genes. Among receptors tyrosine kinases, EGFR gene alterations were observed in 42% of GBMs, often with EGFR amplification in cases with EGFR fusion or variants. PDGFRA gene alterations were present in 18%. Additionally, 9.8% of the GBMs had FGFR gene alterations, with FGFR1 mutation confined to the kinase domain and FGFR3 exclusively showing fusion genes. No FGFR2 alterations were detected. DNA analysis revealed that 11 cases were molecular GBMs, TERTp mutations were found in nine cases.

CONCLUSION

Our system’s analysis aligns with the WHO 2021 brain tumor classification, demonstrating its value as a screening tool in genomic medicine.
10086- MET-8 A CASE OF METASTASIS OF LUNG CANCER TO INTRACRANIAL MENINGIOMA
Authors: Kohno Shohei , Shinji Yukei , Shinko Aiko , Takahashi Kazuya
Published: November 2024

INTRODUCTION

Meningiomas are the most common benign tumors, and are supplied with nutrients from various blood vessels, and have a very rich cerebral blood flow, making them a potential target for systemic cancer metastasis. We report a case of small cell lung cancer metastasis to a meningioma.

CASE

A 74-year-old man. He had been treated for small cell lung cancer and was under observation. He had gradually lost appetite one month ago and was hospitalized at his previous hospital. A head CT scan revealed a suspected brain tumor, and he was referred to our hospital for treatment. At the initial visit, he only had mild consciousness disorder. Head CT scan showed a tumorous lesion of about 5 cm in the right frontal region, adjacent to the dura mater, with surrounding cerebral edema. Brain MRI showed areas of uniform contrast and areas of poor contrast due to bleeding in the same area. Although the consciousness disorder improved with the administration of steroids, the tumor did not shrink and there was also surrounding edema, so an excision was performed. Intraoperative findings showed a tumor originating from the dura mater, with the anterior portion showing a tumorous lesion of a different nature, and the border with the surrounding brain was unclear. Pathology showed components of meningioma and lung cancer, and it was determined that the lung cancer had metastasized to the meningioma. After surgery, the patient received 30 Gy of whole brain irradiation and was discharged home.

CONCLUSION

Although meningiomas are benign tumors, they have an extremely abundant blood flow, and the survival time for systemic cancer has been increasing, so it is important to keep in mind that there is a possibility of metastasis to meningioma, as in this case.
10193- BT-8 4 CASES OF SECONDARY CANCER AFTER TREATMENT FOR PEDIATRIC MEDULLOBLASTOMA
Authors: Ohe Naoyuki , Tamura Takeaki , Kumagai Toshinobu , Shoda Kenji , Nakayama Noriyuki , Izumo Tsuyoshi
Published: November 2024

INTRODUCTION

The number of long-term survivors of medulloblastoma has increased due to advances in treatment, the occurrence of secondary neoplasms has become a new problem. We report four secondary neoplasms after medulloblastoma treatment.

PATIENTS

Of the 26 cases of pediatric cerebellar medulloblastomas that have undergone initial treatment in our department, four have developed secondary neoplasms. The ages of the patients who developed secondary cancers ranged from 17 to 48 years (mean 30 years), with two men and two women, and the ages ranged from 6 to 33 years (mean 21 years) after initial treatment. Two infratentorial glioblastomas, one DIPG, and one multiple meningiomas occurred. The radiation doses at the tumor site were 50.4 and 55.2 Gy for the cases of glioblastoma, 49.6 Gy for the case of DIGP, and 20.5 Gy for the case of multiple meningiomas.

RESULTS

The two patients with cerebellar glioblastoma underwent treatment, but they had dissemination from the time of onset and died 10 and 12 months after onset. The patient with multiple meningiomas underwent tumor resection and has maintained an independent social life. The patient with DIPG is currently undergoing detailed examination.

DISCUSSION

Secondary neoplasms occurred in 4 of 26 cases (15%) in our overall study, but the incidence rate increased to 2 cases (50%) in 4 long-term survivors who survived for more than 30 years after treatment for pediatric medulloblastomas. The incidence of secondary neoplasms increases over time if the latency period exceeds 10 years, and radiation exposure at a young age in particular is considered to be a risk factor for secondary cancer. It is also said that the incidence of secondary cancers increases in proportion to the radiation dose, but it is necessary to comprehensively evaluate the occurrence of secondary neoplasms, including not only the radiation dose but also chemotherapy, genetic predisposition.
Out-of-Africa migration and clonal expansion of a recombinant Epstein-Barr virus drives frequent nasopharyngeal carcinoma in southern China
Authors: Zhang Xinyi , Chen Yanhong , Liang Jingtong , Yang Yue , Chen Hui , Chen Zehui , Li Minhao , Chen Shuanghui , Chen Tingting , He Haopeng , Liu Yunsong , Liu Zhiyuan , Han Lu , Wu Dafei , Zou Zhengting , Qu Yanhua , Li Mingkun , Stoneking Mark , Fu Qiaomei , Xu Shuhua , Zeng Yi-Xin , Ma Liang , Liu Jianjun , Xu Miao , Zhai Weiwei
Published: November 2024

While Epstein-Barr virus (EBV) infection is ubiquitous globally, a high-risk EBV subtype associated with the extremely high incidence of nasopharyngeal carcinoma (NPC) was found in southern China, but the evolution history of EBV in humans and the origin of this high-risk subtype remains enigmatic. By obtaining one of the largest datasets of EBV genomes across the world, we found that EBV had an evolutionary history matching the out-of-Africa migration of humans. Within the high-risk subtype from southern China, we identified a rapidly expanding clonal strain originated from a recombination event between EBV strains from northern and southern Chinese around 4000 years ago, followed by strong Darwinian evolution with a fitness advantage of 4%. The clonal strain has almost doubled the risk for NPC compared to the high-risk subtype and explained around 66% of the NPCs, representing the highest risk factor for NPC identified so far. Taken together, we unraveled a strong co-evolution history between EBV and humans where human migration and admixture triggered subsequent recombination and expansion of a highly advantageous EBV strain, leading to a cancer epidemic in southern China.
Novel Dolutegravir and Lenacapavir Resistance Patterns in Human Immunodeficiency Virus Type 2 Infection: A Case Report
Authors: van Kampen Jeroen J A , van Nood Els , Mahmud Rizwan , Krullaars Zoë , Voskamp Tess , Voskamp Mike , Nijssen Tess , Voermans Jolanda J C , Charpentier Charlotte , Le Hingrat Quentin , van de Vijver David A M C , Gruters Rob A , Mesplède Thibault
Published: November 2024

Background

The treatment management of human immunodeficiency virus (HIV)-2 infection presents greater challenges compared to HIV-1 infection, primarily because of inherent resistance against non-nucleoside reverse transcriptase inhibitors. Integrase strand transfer inhibitors, particularly dolutegravir, have improved treatment outcomes for people with HIV-2. Lenacapavir, a novel and potent antiretroviral capsid inhibitor, offers additional therapeutic options. However, limited knowledge exists regarding HIV-2 resistance against dolutegravir and lenacapavir.

Methods

We report the case of a treatment-experienced individual who did not achieve virological suppression with regimens containing dolutegravir and lenacapavir. Clinical monitoring, genotypic and phenotypic resistance assays, and in silico structural modeling were performed.

Results

Lenacapavir was added to a failing regimen of boosted darunavir, twice daily dolutegravir, and 2 nucleoside reverse transcriptase inhibitors. Initially, this addition led to a decline in the viral load and increase in CD4+ T-cell count, despite the identification of a previously unreported combination of integrase resistance mutations. However, virological suppression was not achieved and viral load, although reduced, resumed increasing. This rebound was associated with the development of an N73D capsid substitution in HIV-2, which conferred resistance against lenacapavir. Based on cell-based assays predicting hypersusceptibility to bictegravir, the regimen was adjusted to oral lenacapavir plus bictegravir/emtricitabine/tenofovir alafenamide, resulting in a resumption in viral load decline.

Conclusions

Although lenacapavir demonstrated therapeutic potential, our case underscores the critical need to combine it with other fully active antiretroviral agents to prevent the rapid emergence of resistance and achieve long-term virological control in treatment-experienced individuals with HIV-2.
Fairness in policing: how does internal procedural justice translate to external procedural justice?
Authors: Yesberg Julia A , Sargeant Elise , Fenn Liam , Murphy Kristina , Madon Natasha
Published: November 2024

A growing body of research has shown the experience of fair treatment within police organizations (internal procedural justice) leads to a greater willingness among police officers to treat members of the public fairly (external procedural justice). Despite recent scholarship in this area, the associations between internal and external procedural justice, and the intervening mechanisms at play, are still not well understood. Using survey data from new police officers in England and Wales, we test the direct association between internal and external procedural justice, and indirect connections through self-efficacy, job satisfaction, and well-being. Self-efficacy, but not job satisfaction or well-being, was found to partially mediate the relationship between internal and external procedural justice. In other words, perceived internal procedural justice promoted external procedural justice through (in part) cultivating greater confidence in officers’ abilities to perform their job effectively.
Comparison analysis between standard polysomnographic data and in-ear-electroencephalography signals: a preliminary study
Authors: Palo Gianpaolo , Fiorillo Luigi , Monachino Giuliana , Bechny Michal , Wälti Michel , Meier Elias , Pentimalli Biscaretti di Ruffia Francesca , Melnykowycz Mark , Tzovara Athina , Agostini Valentina , Faraci Francesca Dalia
Published: November 2024

Study Objectives

Polysomnography (PSG) currently serves as the benchmark for evaluating sleep disorders. Its discomfort makes long-term monitoring unfeasible, leading to bias in sleep quality assessment. Hence, less invasive, cost-effective, and portable alternatives need to be explored. One promising contender is the in-ear-electroencephalography (EEG) sensor. This study aims to establish a methodology to assess the similarity between the single-channel in-ear-EEG and standard PSG derivations.

Methods

The study involves 4-hour signals recorded from 10 healthy subjects aged 18–60 years. Recordings are analyzed following two complementary approaches: (1) a hypnogram-based analysis aimed at assessing the agreement between PSG and in-ear-EEG-derived hypnograms; and (2) a feature- and analysis-based on time- and frequency-domain feature extraction, unsupervised feature selection, and definition of Feature-based Similarity Index via Jensen–Shannon Divergence (JSD-FSI).

Results

We find large variability between PSG and in-ear-EEG hypnograms scored by the same sleep expert according to Cohen’s kappa metric, with significantly greater agreements for PSG scorers than for in-ear-EEG scorers (p < .001) based on Fleiss’ kappa metric. On average, we demonstrate a high similarity between PSG and in-ear-EEG signals in terms of JSD-FSI—0.79 ± 0.06—awake, 0.77 ± 0.07—nonrapid eye movement, and 0.67 ± 0.10—rapid eye movement—and in line with the similarity values computed independently on standard PSG channel combinations.

Conclusions

In-ear-EEG is a valuable solution for home-based sleep monitoring; however, further studies with a larger and more heterogeneous dataset are needed.
Antimicrobial resistance detection methods in water environments: a scoping review
Authors: Alfahl Zina , Chueiri Alexandra , Carolan Shaunagh , Darcy Gabriel , Hussain Nadia , Cahill Niamh , O’Connor Louise
Published: November 2024

Antimicrobial resistance (AMR) in water environments poses a significant threat to public health, ecosystem stability, and the effectiveness of antimicrobial treatments. This review aims to provide a comprehensive overview of the methods used to detect AMR in various water environments. A literature search was conducted following the PRISMA guidelines. Original articles published in English relating to AMR in water environments were included. Reviews, protocols, and abstracts were excluded. A total of 115 publications were selected for full-text evaluation. Overall, river water samples were the most commonly assessed samples across all of the reviewed studies (49/115 studies, 42%). The top 3 countries investigating AMR genes in water samples were the USA (19 studies, 17%), China (11 studies, 10%), and Brazil (10 studies, 9%). The review revealed that polymerase chain reaction and metagenomic methods are increasingly preferred for their high sensitivity, specificity, and comprehensive detection capabilities, appearing in 65/115 (57%) and 31/115 (27%) studies, respectively. Despite higher costs and technical complexity, these methods provide valuable insights into the resistome of water environments. Culture-dependent methods, while most cost effective and straightforward, are limited by their time-consuming nature and inability to detect non-viable resistant organisms, reducing their effectiveness in comprehensive AMR surveillance. The review addresses the challenges and limitations of current detection methods and proposes directions for future research to develop more robust, cost-effective, and user-friendly detection methods. The review highlights the urgent need for integrated approaches to monitor and mitigate AMR in water environments, ensuring better public health and environmental protection.
Diacylglycerol kinase δ is required for skeletal muscle development and regeneration
Authors: Sakai Hiromichi , Murakami Chiaki , Takechi Mayumi , Urano Takeshi , Sakane Fumio
Published: November 2024

Diacylglycerol kinase δ (DGKδ) phosphorylates diacylglycerol to produce phosphatidic acid. Previously, we demonstrated that down‐regulation of DGKδ suppresses the myogenic differentiation of C2C12 myoblasts. However, the myogenic roles of DGKδ in vivo remain unclear. In the present study, we generated DGKδ‐conditional knockout mice under the control of the myogenic factor 5 (Myf5) gene promoter, which regulates myogenesis and brown adipogenesis. The knockout mice showed a significant body weight reduction and apparent mass decrease in skeletal muscle, including the tibialis anterior (TA) muscle. Moreover, the thickness of a portion of the myofibers was reduced in DGKδ‐deficient TA muscles. However, DGKδ deficiency did not substantially affect brown adipogenesis, suggesting that Myf5‐driven DGKδ deficiency mainly affects muscle development. Notably, skeletal muscle injury induced by a cardiotoxin highly up‐regulated DGKδ protein expression, and the DGKδ deficiency significantly reduced the thickness of myofibers, the expression levels of myogenic differentiation markers such as embryonic myosin heavy chain and myogenin, and the number of newly formed myofibers containing multiple central nuclei during muscle regeneration. DGKδ was strongly expressed in myogenin‐positive satellite cells around the injured myofibers and centronucleated myofibers. These results indicate that DGKδ has important roles in muscle regeneration in activated satellite cells. Moreover, the conditional knockout mice fed with a high‐fat diet showed increased fat mass and glucose intolerance. Taken together, these results demonstrate that DGKδ plays crucial roles in skeletal muscle development, regeneration, and function.
The advent of immune checkpoint inhibition for the treatment of patients with primary advanced or recurrent dMMR/MSI high endometrial cancer in 2025
Authors: Silk Tarik , Hacker Kari E. , Growdon Whitfield , Pothuri Bhavana
Published: November 2024

Purpose of review

The Cancer Genome Atlas identified four distinct molecular subtypes of endometrial cancer (EC): POLE mutated, mismatch repair deficient (dMMR), copy number low, and copy number high. The goal of this review is to summarize the profound clinical implications of molecular subtyping, particularly in guiding treatment decisions for dMMR and microsatellite instability high (MSI-H) EC.

Recent findings

Clinical trials have demonstrated the remarkable efficacy of immunotherapy in dMMR/MSI-H EC tumors. Trials including GARNET, KEYNOTE-158, NRG GY-018, and RUBY have shown significant improvements in clinical outcomes for patients with advanced and recurrent disease, leading to FDA approvals for immunotherapy in both frontline and recurrent EC treatment settings.

Building on these successes, recent studies, including DUO-E, are exploring combination therapies to enhance the efficacy of immunotherapy in EC. Simultaneously, trials including NRG GY-020, are investigating the potential benefits of immunotherapy in early-stage disease.

Immunotherapy therapy has revolutionized the treatment of endometrial cancer in both upfront and recurrent settings, with molecular subtyping identifying patients most likely to benefit, especially those with dMMR/MSI-H tumors.
Quantitative assessment of the associations between ABCA1 gene polymorphism and glaucoma risk, evidence from a meta-analysis
Authors: Wang Fabin , Gou Xin , Wu Fan , Qiao Hong , Zhao Dengli
Published: November 2024

Background:

The association between polymorphisms in the ATP-binding cassette transporter A1 (ABCA1) gene and the risk of developing glaucoma has yielded conflicting results across various studies. This meta-analysis aims to comprehensively assess whether genetic variations in ABCA1 significantly contribute to the susceptibility to glaucoma.

Methods:

An extensive search was conducted across major databases, including PubMed, EMBASE, and the China National Knowledge Infrastructure (CNKI), covering all publications from the inception of each database through December 2023. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to quantify the strength of the association between ABCA1 polymorphisms and glaucoma risk.

Results:

A significant association was observed between ABCA1 gene polymorphisms and glaucoma risk in the overall analysis, as demonstrated by allele contrast (P < .001), homozygote comparison (P < .001), heterozygote comparison (P < .001), recessive genetic model (P = .017), and dominant genetic model (P < .001). Notably, these associations were particularly pronounced in the Asian population, with all models showing statistical significance (P < .05). However, no significant association was detected in Caucasian or mixed populations, suggesting a potential ethnic specificity in the genetic susceptibility to glaucoma conferred by ABCA1 polymorphisms.

Conclusions:

Our findings indicate that ABCA1 polymorphisms may play a role in increasing the risk of glaucoma, specifically within Asian populations. This contrast highlights the importance of considering ethnic background in genetic association studies.
Two case reports of breast cancer combined with synchronous primary intrahepatic cholangiocarcinoma/mixed liver cancer
Authors: Tan Miduo , Luo Liu , Wang Taoli , Zhang Zhiyong , Wei Yuqin , Long Chenyan
Published: November 2024

Rationale:

This case report discusses multiple primary malignant tumors, which refer to the occurrence of 2 or more different histological types of malignant tumors simultaneously or successively in the same individual.

Patient concerns:

We present 2 female patients who were admitted to the hospital due to a “left breast mass” and were found to have multiple solid masses in the liver upon imaging.

Diagnoses:

Postoperative pathology revealed that one patient had breast invasive ductal carcinoma was complicated with primary intrahepatic cholangiocarcinoma and mixed hepatocellular carcinoma with intrahepatic cholangiocarcinoma.

Interventions:

Both patients underwent extensive resection of the lesion.

Outcomes:

Regular postoperative checkups and follow-ups have been conducted, and both patient’s current conditions are stable.

Lessons:

The treatment approach adopted in this case report may serve as a favorable reference for the management of similar cases. However, further extensive biological studies are still needed to investigate the biological mechanisms of multiple primary malignant tumors and to discover specific therapeutic approaches to achieve more clinical benefits for patients.
Effects of genetic variants of organic cation transporters on metformin response in newly diagnosed patients with type 2 diabetes
Authors: AlKreathy Huda M. , Alzahrani Abdulhhakim A. , Esmat Ahmed , Damanhouri Zoheir A.
Published: November 2024

Type 2 diabetes mellitus (T2DM) is a chronic disease that affects millions of people worldwide. Metformin is the optimal initial therapy for patients with T2DM. Genetic factors play a vital role in metformin response, including variations in drug efficacy and potential side effects. To determine the effects of genetic variants of multidrug and toxin extrusion protein 2 (MATE2), ataxia telangiectasia mutated (ATM), and serine/threonine kinase 11 (STK11) genes on metformin response in a cohort of Saudi patients. This prospective observational study included 76 T2DM newly diagnosed Saudi patients treated with metformin monotherapy and 80 control individuals. Demographic data, lipid profiles, creatinine levels, and hemoglobin A1c (HbA1c) levels were collected before and after treatment. All participants were genotyped for 5 single-nucleotide polymorphisms (SNPs), including rs4621031, rs34399035, rs2301759, rs1800058, and rs11212617, using TaqMan R genotyping assays. This study included 156 subjects. The subjects’ mean ± SD age was 50.4 ± 10.14 years. The difference in HbA1c levels in T2DM after treatment ranged from −1.20% to 8.8%, with a mean value of 0.927 ± 1.73%. In general, 73.7% of the patients with T2DM showed an adequate response to metformin (HbA1c < 7%). STK11 (rs2301759) significantly affects the response to metformin in T2DM patients. In the rs2301759 single-nucleotide polymorphisms, the prevalence of an adequate response to metformin was significantly higher among patients with C/C and T/C genotypes than among non-responders (P = .021). However, no statistically significant associations were observed for the other tested SNPs. Our study provides evidence of an association between STK11 (rs2301759) and response to metformin in Saudi patients with T2DM. The need for targeted studies on specific gene-drug associations is emphasized, and further studies with a larger population should be conducted.
Optimal duration of medical therapy for patients with acute myocardial infarction
Authors: Boo Ki Yung , Joo Seung-Jae , Lee Jae-Geun , Choi Joon-Hyouk , Kim Song-Yi , Ko Geum , Yun Hae Eun , Jeong Myung Ho ,   on behalf of the KAMIR-NIH investigators
Published: November 2024

Optimal medical therapy, including Beta-blockers (BB), inhibitors of the renin-angiotensin system (RAS), and statins, is recommended for patients with acute myocardial infarction (AMI) in the absence of contraindications. However, the optimal duration of these medications has not been clearly established in clinical studies. This observational study aimed to investigate the period during which these medications are associated with improved clinical outcomes. Among patients enrolled in the Korea Acute Myocardial Infarction Registry-National Institute of Health (KAMIR-NIH), in-hospital survivors were selected. In a Cox-proportional hazard analysis of 12,200 patients, BB (hazard ratio [HR] = 0.73; 95% confidence interval [CI] = 0.57–0.95; P = .019), RAS inhibitors (HR 0.70; 95% CI = 0.55–0.89; P = .004), and statins at discharge (HR = 0.65; 95% CI = 0.48–0.87; P = .004) were all associated with lower 1-year cardiac mortality. At 1-year, 10,613 patients without all-cause death, myocardial infarction, revascularization, or re-hospitalization due to heart failure were selected for further analysis. RAS inhibitors (HR = 0.53; 95% CI = 0.37–0.76; P = .001) and statins (HR = 0.30; 95% CI = 0.14–0.61; P = .001) prescribed at 1-year were associated with lower 2-year cardiac mortality, whereas BB were not (HR = 0.79; 95% CI = 0.51–1.23; P = .23). However, none of these medications prescribed at 2-years were associated with reduced 3-year cardiac mortality among the 9232 patients who remained event-free until then. RAS inhibitors and statins were associated with reduced cardiac mortality for up to 2-years, and BB for up to 1-year after the initial attack. The effectiveness of these medications beyond these periods remains questionable.
Metabolomics as a promising technology for investigating external therapy of traditional Chinese medicine: A review
Authors: Yang Xinyue , He Min , Tang Qingqing , Cao Jiazhen , Wei Zhe , Li Tie , Sun Mengmeng
Published: November 2024

To demonstrate the potential for connecting metabolomics with traditional Chinese medicine (TCM) external therapies such as acupuncture and moxibustion, we conducted a literature review on metabolomics as a measurement tool for determining the efficacy of various TCM external therapies. Human research and animal models published in the last 10 years were summarized. The investigation can be classified as follows: Using metabolomics to study metabolic profile changes produced by stimulation of a specific acupoint ST36 indicates the perturbation of metabolites produced by stimulation of acupoints by external TCM treatments can be characterized by metabolomics; and Using metabolomics to reveal the molecular mechanism of various TCM external therapy methods to treat specific diseases such as digestive system disease, cardiovascular disease, neurological disorder, bone disease, and muscle fatigue. We conclude that metabolomics has considerable potential for comprehending TCM external treatment interventions, particularly from a systems perspective. Linking TCM external therapy research with metabolomics can further bridge detailed biological mechanisms with the systematic effect of TCM external therapy, hence providing new paths for gaining a deeper knowledge of the importance of TCM in the treatment and maintenance of health.
A comprehensive review of biomarker research in diabetic nephropathy from a global bibliometric and visualization perspective
Authors: Li Qin , Xie Yafei , Zuo Meiying , Li Fang
Published: November 2024

Background:

Diabetic nephropathy (DN) is a common complication of diabetes, which is prone to develop into end-stage renal disease, and early diagnosis and treatment is the key to effective management of DN. Biomarkers have important clinical significance in the diagnosis and treatment of DN and have attracted extensive attention from researchers in recent years. The aim of this study was to visualize the field of biomarker research in DN through bibliometric analysis, to summarize the current status and predict future trends of this field, with a view to providing valuable insights for scholars and policy makers.

Methods:

Literature search and data collection from Web of Science Core Collection. Calculations and visualizations were performed using Microsoft Excel, VOSviewer, Bibliometrix R-package, and CiteSpace.

Results:

We identified 1274 publications about biomarker research in DN from 1995 to November 01, 2023, with a steady increase in annual publications. China, Steno Diabetes Center in Denmark, andFrontiers in Endocrinologywere the most productive country, institution, and journal, respectively; Mischak, Harald was both the most productive and highly cited author, andKidney Internationalwas the most cited journal. The high frequency keywords were “albuminuria,” “chronic kidney disease” and “expression.” In addition, “macrophage,” “fibrosis” and “omics” are potentially promising topics.

Conclusion:

Our study comprehensively and visually summarized the important findings of global biomarker research in DN and revealed the structure, hotspots, and evolutionary trends in this field. It would inspire subsequent studies from a macroscopic perspective and provide a basis for rational allocation of resources and identification of collaborations among researchers.
Association between serum folate and sleep duration in American adults: A cross-sectional analysis of the National Health and Nutrition Examination Survey 2005 to 2010
Authors: Dong Yandong , Luo Mei
Published: November 2024

Folate is a vitamin that is exclusively derived from diet sources. Low folate levels are typically associated with cardiovascular disease, cognitive impairment, and cancer risk. However, few studies have examined the direct relationship between serum folate levels and sleep duration. Accordingly, we aimed to examine the relationship between serum folate levels and sleep duration. Using data from the National Health and Nutrition Examination Survey (NHANES), we examined the association between serum folate levels and sleep duration. We used laboratory data to obtain independent serum folate, and covariate data, including total cholesterol, high-density lipoprotein, blood glucose, and glycated hemoglobin; dependent variable sleep duration and covariate data including race, family income, marital status, education, and country of birth from questionnaire data; and other covariate data such as systolic blood pressure, diastolic blood pressure, waist circumference, and body mass index data from the measured data. Data was primarily analyzed using multiple regression analysis, stratified analysis with interactions, restricted cubic splines (RCS), and threshold effect analysis. A total of 14,072 participants over 19 years of age were enrolled, comprising 6923 (49.2%) males and 7149 (50.8%) females, with a median age of 48 years. The association between serum folate levels and sleep duration exhibited an inverted L-shaped curve (P = .033) in RCS. In the threshold analysis, for participants with serum folate of <32.208 nmol/L (β = 0.608, 95% CI: (0.275, 0.942), P < .001), the sleep duration was significantly increased by 0.608 minutes, with every 1 nmol/L in serum folate increased. At serum folate of ≥32.208 nmol/L, no significant association between serum folate and sleep duration was detected [β = 5.686, 95% CI: (−1.508, 12.88), P = .118]. Our findings revealed an inverted L-shaped relationship and saturation effects between serum folate levels and sleep duration in adults in the United States.
Functional variability of Nef in antagonizing SERINC5 during acute to chronic HIV-1 infection
Authors: Li Weiting , Li Guoqing , Liu Yuyang , Meng Lina , Zhang Tianxin , Wang Libian , Li Haochen , Yu Bin , Wu Jiaxin , Wang Chu , Yu Xianghui
Published: November 2024

Objective:

The ability of HIV-1 Nef to counteract the host restriction factor SERINC5 and enhance virion infectivity has been well established. However, the impact of long-term within-host Nef evolution on this antagonistic capability remains unclear.

Design:

Analysis of longitudinal activity of Nef in antagonizing SERINC5.

Methods:

We investigated the downregulation activity of Nef against SERINC5 at different stages of infection by analyzing the cognate transmitted/founder, set point, and/or chronic Nef isolates from a cohort of 19 people with either subtype B or C HIV-1.

Results:

The Nef isolates from different stages exhibited varying abilities to antagonize SERINC5. Long-term evolution resulted in mutations accumulated in Nef and a decline of Nef-mediated SERINC5 downregulation function in subtype B, but not in subtype C viruses, leading to a rapid reduction in viral load from peak viremia. Furthermore, we identified four polymorphisms of both subtype B and C Nef that are associated with variations in the SERINC5 antagonistic function and viral infectivity. HIV-1NL4–3 variants encoding Nef E63G, A83G, R105K, or D108E mutants exhibited reduced replication capacity through a SERINC5-dependent mechanism. However, among different subjects, only a small part of naturally occurring mutations at these sites were selected by host T-cell responses, suggesting a limited impact of host T-cell responses on influencing Nef's ability to antagonize SERINC5.

Conclusion:

These results highlight the potential contribution of functional variation in Nef to differences in HIV-1 pathogenesis and provide significant implications for understanding the evolutionary interaction between Nef and SERINC5 in vivo.
Cognitive functions supporting learning over time in naming treatment for aphasia
Authors: Goldberg Emily B. , Hula William D. , Cavanaugh Robert , Swiderski Alexander M. , Autenreith Alyssa , Dickey Michael Walsh
Published: November 2024

Purpose

Aphasia rehabilitation is a learning process that unfolds over time. Previous work has examined aphasia treatment response using pre- to post-treatment comparison, largely ignoring the unfolding learning response that occurs session-to-session. We aimed to: (1) characterize the shape of learning while individuals with aphasia received intensive anomia intervention, and (2) identify the cognitive predictors of this learning response.

Method

Individuals (n=39) with chronic post-stroke aphasia received intensive semantic feature analysis (SFA). Naming accuracy for trained and semantically-related, untrained words was probed daily. We used Bayesian generalized linear mixed effects models to estimate the shape of learning during SFA treatment, and to measure the influence of key cognitive functions on treatment response.

Results

Most treatment gains appeared early during treatment, after the first four hours of intervention. Verbal recognition and visuospatial memory were associated with the magnitude of those early treatment gains, favoring strong cognitive performers. Treatment generalization to untrained targets was present but modest, with some evidence suggesting that visuospatial recall performance may be associated with treatment generalization.

Conclusions

Monitoring SFA treatment response early could help inform clinicians whether patients will respond optimally to intervention. Verbal recognition and visuospatial recall support learning during treatment, helping elucidate cognitive underpinnings of learning during aphasia rehabilitation.
Synergistic Multi-Pronged Interactions Mediate the Effective Inhibition of Alpha-Synuclein Aggregation by the Chaperone HtrA1
Authors: Chinchilla Priscilla , Wang Baifan , Lubin Joseph H. , Yang Xue , Roth Jonathan , Khare Sagar D. , Baum Jean
Published: November 2024

The misfolding, aggregation, and the seeded spread of alpha synuclein (α-Syn) aggregates are linked to the pathogenesis of various neurodegenerative diseases, including Parkinson’s disease (PD). Understanding the mechanisms by which chaperone proteins prevent the production and seeding of α-Syn aggregates is crucial for developing effective therapeutic leads for tackling neurodegenerative diseases. We show that a catalytically inactive variant of the chaperone HtrA1 (HtrA1*) effectively inhibits both α-Syn monomer aggregation and templated fibril seeding, and demonstrate that this inhibition is mediated by synergistic interactions between its PDZ and Protease domains and α-Syn. Using biomolecular NMR, AFM and Rosetta-based computational analyses, we propose that the PDZ domain interacts with the C-terminal end of the monomer and the intrinsically disordered C-terminal domain of the α-Syn fibril. Furthermore, in agreement with sequence specificity calculations, the Protease domain cleaves in the aggregation-prone NAC domain at site T92/A93 in the monomer. Thus, through multi-pronged interactions and multi-site recognition of α-Syn, HtrA1* can effectively intervene at different stages along the α-Syn aggregation pathway, making it a robust inhibitor of α-Syn aggregation and templated seeding. Our studies illustrate, at high resolution, the crucial role of HtrA1 interactions with both the intrinsically disordered α-Syn monomers and with the dynamic flanking regions around the fibril core for inhibition of aggregation. This inhibition mechanism of the HtrA1 chaperone may provide a natural mechanistic blueprint for highly effective therapeutic agents against protein aggregation.

Significance Statement

PD and other synucleinopathies are marked by misfolding and aggregation of α-Syn, forming higher-order species that propagate aggregation in a prion-like manner. Understanding how chaperone proteins inhibit α-Syn aggregation and spread is essential for therapeutic development against neurodegeneration. Through an integrative approach of solution-based NMR, AFM, aggregation kinetics, and computational analysis, we reveal how a catalytically inactive variant of the chaperone HtrA1 effectively disrupts aggregation pathways. We find that the inactive Protease and PDZ domains of HtrA1 synergistically bind to key intrinsically disordered sites on both α-Syn monomers and fibrils, thereby effectively inhibiting both aggregation and templated seeding. Our work provides a natural and unique blueprint for designing inhibitors to prevent the formation and seeding of aggregates in neurodegenerative diseases.
Effects of Uni- and Bi-directional Interaction During Dyadic Ankle and Wrist Tracking
Authors: Short Matthew R. , Ludvig Daniel , Di Tommaso Francesco , Vianello Lorenzo , Perreault Eric J. , Küçüktabak Emek Barış , Hargrove Levi , Lynch Kevin , Burdet Etienne , Pons Jose L.
Published: November 2024

Haptic human-robot-human interaction allows users to feel and respond to one another’s forces while interfacing with separate robotic devices, providing customizable infrastructure for studying physical interaction during motor tasks (i.e., physical rehabilitation). For both upper- and lower-limb tasks, previous work has shown that virtual interactions with a partner can improve motor performance and enhance individual learning. However, whether the mechanism of these improvements generalizes across different human systems is an open question. In this work, we investigate the effects of haptic interaction between healthy individuals during a trajectory tracking task involving single-joint movements at the wrist and ankle. We compare tracking performance and muscle activation during haptic conditions where pairs of participants were uni- and bidirectionally connected, in order to investigate the contribution of real-time responses from a partner during the interaction. Findings indicate similar improvements in tracking performance during the bidirectional interaction for both the wrist and ankle, despite significant differences in how individuals modulated co-contraction. For each joint, bidirectional and unidirectional interaction resulted in similar improvements for the worse partner in the dyad. For the better partner, bidirectional interaction outperformed unidirectional interaction, likely due to changes in movement planning that were not observed in the unidirectional condition. While these results suggest that unidirectional interaction is sufficient for error correction of less skilled individuals during simple motor tasks, they also highlight the mutual benefits of bidirectional interaction which are consistent across the upper and lower limbs.
An annotated biobank of triple negative breast cancer patient-derived xenografts featuring treatment-naïve and longitudinal samples throughout neoadjuvant chemotherapy
Authors: Rinkenbaugh Amanda L. , Qi Yuan , Cai Shirong , Shao Jiansu , Hancock Faiza , Jeter-Jones Sabrina , Zhang Xiaomei , Powell Emily , Huo Lei , Lau Rosanna , Fu Chunxiao , Gould Rebekah , den Hollander Petra , Ravenberg Elizabeth E. , White Jason B. , Rauch Gaiane M. , Arun Banu , Yam Clinton , Thompson Alastair M. , Echeverria Gloria V. , Moulder Stacy L. , Symmans W. Fraser , Chang Jeffrey T. , Piwnica-Worms Helen
Published: November 2024

Triple negative breast cancer (TNBC) that fails to respond to neoadjuvant chemotherapy (NACT) can be lethal. Developing effective strategies to eradicate chemoresistant disease requires experimental models that recapitulate the heterogeneity characteristic of TNBC. To that end, we established a biobank of 92 orthotopic patient-derived xenograft (PDX) models of TNBC from the tumors of 75 patients enrolled in the ARTEMIS clinical trial (NCT02276443) at MD Anderson Cancer Center, including 12 longitudinal sets generated from serial patient biopsies collected throughout NACT and from metastatic disease. Models were established from both chemosensitive and chemoresistant tumors, and nearly 30% of PDX models were capable of lung metastasis. Comprehensive molecular profiling demonstrated conservation of genomes and transcriptomes between patient and corresponding PDX tumors, with representation of all major transcriptional subtypes. Transcriptional changes observed in the longitudinal PDX models highlight dysregulation in pathways associated with DNA integrity, extracellular matrix interactions, the ubiquitin-proteasome system, epigenetics, and inflammatory signaling. These alterations reveal a complex network of adaptations associated with chemoresistance. This PDX biobank provides a valuable resource for tackling the most pressing issues facing the clinical management of TNBC, namely chemoresistance and metastasis.
Cell competition confers anchorage plasticity of disseminated tumor cells
Authors: Huh Hyunbin D. , Sub Yujin , Kim Jee Hung , Lee Hannah , Oh Jongwook , Lee Dong Ki , Byun Jong Hwa , Pyun Woo Yang , Pak Sehyung , Choi Junjeong , Jeong Joon , Gee Heon Yung , Park Hyun Woo
Published: November 2024

Cell competition within the primary tumor drives tumor growth by promoting the uncontrolled proliferation of winner cells and eliminating loser cells by sensing cell fitness. However, the mechanism how cell competition confers loser cells with the metastatic potential of circulating tumor cells (CTCs) remains elusive. Unexpectedly, we found cell competition-induced less fit but viable cells transformed into CTCs via adherent-to-suspension transition (AST) mechanisms in dissemination assay. The induction of AST factors, hematopoietic transcription factors hijacked by solid tumor cells, rendered CTCs competent to lose anchorage dependency and disseminate into the bloodstream, while subsequent suppression of these factors in CTCs was critical to regain adhesion and colonize metastatic lesions. Disrupting the oscillatory dynamics of AST factors blocked the adherent-suspension plasticity (ASP) of breast cancer CTCs and suppressed lung metastasis. Furthermore, multiregional single-cell transcriptomic analyses of matched primary tumors, CTCs, and metastatic lesions fromde novometastatic breast cancer patients identified the critical role of ASP in metastasis.

Significance

We demonstrate that cell competition-mediated displacement of CTCs manifests dynamic oscillation of AST factors that confer anchorage plasticity of solid tumor cells critical for the dissemination and colonization of CTCs. These findings highlight the potential of targeting AST factors to develop effective anti-metastatic therapies.
BMI Interacts with the Genome to Regulate Gene Expression Globally, with Emphasis in the Brain and Gut
Authors: Signer Rebecca , Seah Carina , Young Hannah , Retallick-Townsley Kayla , de Pins Agathe , Cote Alanna , Lee Seoyeon , Jia Meng , Johnson Jessica S. , Johnston Keira , Xu Jiayi , Brennand Kristen , Huckins Laura M
Published: November 2024

Genome-wide association studies identify common genomic variants associated with disease across a population. Individual environmental effects are often not included, despite evidence that environment mediates genomic regulation of higher order biology. Body mass index (BMI) is associated with complex disorders across clinical specialties, yet has not been modeled as a genomic environment. Here, we tested for expression quantitative trait (eQTL) loci that contextually regulate gene expression across the BMI spectrum using an interaction approach. We parsed the impact of cell type, enhancer interactions, and created novel BMI-dynamic gene expression predictor models. We found that BMI main effects associated with endocrine gene expression, while interactive variant-by-BMI effects impacted gene expression in the brain and gut. Cortical BMI-dynamic loci were experimentally dysregulated by inflammatory cytokines in an in vitro system. Using BMI-dynamic models, we identify novel genes in nitric oxide signaling pathways in the nucleus accumbens significantly associated with depression and smoking. While neither genetics nor BMI are sufficient as standalone measures to capture the complexity of downstream cellular consequences, including environment powers disease gene discovery.