bluuebunny/crossref_metadata_2025 huggingface dataset:
Trends in complexity of single-agent and combination therapies for solid tumor cancers approved by the US Food and Drug Administration
Authors: Chen Emerson Y , Rai Manoj , Tadikonda Yash , Roy Preeyam , Nollner Dakota W , Chitkara Akshit , Hamilton Julia , Thawani Rajat
Published: November 2024

Background

Many FDA-approved cancer therapies, whether as a multiagent combination or as a single agent, have demonstrated only modest clinical benefit. To investigate the drug development landscape, this analysis focuses on whether newly approved drugs are added to existing standards as combination therapy or replace a former drug as monotherapy.

Methods

A retrospective analysis of package inserts and corresponding trials for the treatment of nonhematology solid tumor malignancies from January 2011 to December 2023 was conducted to categorize an approval as monotherapy or combination therapy. Drug characteristics, treatment indications, study design, approval history, and efficacy results were compared between the 2 cohorts.

Results

Among the 292 approval entries and 110 drugs, 193 (66.1%) were monotherapies and 99 (33.9%) were combinations. Combinations, when compared with monotherapies, were more frequently approved as regular than accelerated approval (85 [85.9%] vs 132 [68.4%], P <.01), in the first-line setting (66 [66.7%] vs 69 [35.8%], P <.01), and with overall survival as the criteria (49 [49.5%] vs 40 [20.7%], P <.01). Monotherapies were more likely to be novel drugs compared with combinations (80 [41.5%] vs 14 [14.1%] P <.01). Monotherapies were more likely to be small molecule targeted agents, while combinations were more likely to be immunotherapies (P <.02). There was no difference comparing the time-to-event endpoints and validated clinical benefit scale, but the median response rate of combinations (46%) was higher than monotherapies (34%, P <.01).

Discussion

Given that clinical benefit appears limited in combination therapy compared with monotherapy, drug development could focus on simplifying cancer therapies toward patient-centered paradigms.
Causal relationship between benign prostatic hyperplasia and prostate cancer: a bidirectional Mendelian randomization analysis
Authors: Zhang Yi , Ou Guangyang , Li Rongkang , Peng Lei , Shi Jianguo
Published: November 2024

Objective

Our aim is to explore the relation between benign prostatic hyperplasia (BPH) and prostate cancer (PCa) from a genetic level utilizing Mendelian randomization (MR).

Methods

The IEU genome-wide association studies database was surveyed for single nucleotide polymorphisms (SNPs) associated with BPH, PCa, and PCa (validation cohort). Single nucleotide polymorphisms were subjected to stringent quality control based on rigorous screening criteria. BPH and PCa risk were evaluated using the inverse-variance weighted method (IVW), MR-Egger, simple mode, weighted median, and weighted mode. Horizontal pleiotropy of single nucleotide polymorphisms was assessed using the MR-Egger intercept test, while heterogeneity was evaluated using Cochran’s Q test. Reverse causality was assessed by evaluating PCa as the exposure and BPH as the outcome. A validation database was used to verify the exposure and outcome.

Results

The risk of PCa increased significantly with genetically predicted BPH (IVW: OR [95% CI] = 1.3849 × 107 [2330, 8.2294 × 1010], P = 2.0814 × 10−4). In reverse MR analysis, PCa also increased the risk of BPH (IVW: OR [95% CI] = 1.0011 [1.0003, 1.0019], P = 0.0031). The findings were consistent with the MR analysis results of the PCa validation cohort. Sensitivity analyses indicated the presence of heterogeneity but no horizontal pleiotropy.

Conclusion

The study presents proof of a significant bidirectional causal relationship between genetically predicted BPH and an increased risk of PCa.

Key message Three research questions and three bullet points  What is already known on this topic?  Observational studies suggest a controversial relationship between BPH and PCa. MR allows investigation of causality using genetic variants as instrumental variables (IVs). What does this study add?  The study presents proof of a significant bidirectional causal relationship between genetically predicted BPH and an increased risk of PCa. How this study might affect research, practice, or policy?  Recognizing the bidirectional relationship between BPH and PCa, men diagnosed with BPH may benefit from more stringent PCa screening protocols.
Warm Surprises from Cold Duets: N-Body Simulations with Two-Component Dark Matter
Authors: Kim Jeong Han , Kong Kyoungchul , Lim Se Hwan , Park Jong-Chul
Published: November 2024

We explore extensive N-body simulations with two-component cold dark matter candidates. We delve into the temperature evolution, power spectrum, density perturbation, and maximum circular velocity functions. We find that the substantial mass difference between the two candidates and the annihilation of the heavier components to the lighter ones effectively endow the latter with warm dark matter-like behavior, taking advantage of all distinct features that warm dark matter candidates offer, without observational bounds on the warm dark matter mass. Moreover, we demonstrate that the two-component dark matter model aligns well with observational data, providing valuable insights into where and how to search for the elusive dark matter candidates in terrestrial experiments.
The association of objective daytime sleepiness with impaired glucose metabolism in patients with obstructive sleep apnea: a multi-omics study
Authors: Chen Le , Chen Baixin , Dai Yanyuan , Sun Qimeng , Wu Jun , Zheng Dandan , Vgontzas Alexandros N , Tang Xiangdong , Li Yun
Published: November 2024

Study Objectives

To examine the joint effect of obstructive sleep apnea (OSA) and objective excessive daytime sleepiness (EDS) on glucose metabolism and the underlying mechanisms.

Methods

We included 127 patients with OSA. The multiple sleep latency test (MSLT) and Epworth sleepiness scale (ESS) were used to assess objective and subjective EDS, respectively. Disordered glucose metabolism was defined as either a physician diagnosis or having fasting blood glucose levels ≥5.6 mmol/L. Values of fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) higher than the median values of our sample were defined as high fasting insulin and insulin resistance. Serum metabolomics and fecal microbiota were used to explore underlying mechanisms.

Results

Lower MSLT values were associated with higher levels of fasting blood glucose, fasting insulin, and HOMA-IR. Furthermore, objective EDS was associated with increased odds of disordered glucose metabolism, elevated fasting insulin, and insulin resistance. Dysregulation of serum valine degradation and dysbiosis of fecal Bacteroides thetaiotaomicron were associated with impaired glucose metabolism in OSA with objective EDS. No association between subjective EDS and impaired glucose metabolism was observed.

Conclusions

OSA with objective, but not subjective, EDS is associated with an increased risk of disordered glucose metabolism and insulin resistance. Dysregulation of valine degradation and dysbiosis of B. thetaiotaomicron appear to link objective EDS and disordered glucose metabolism in OSA.
Sleep and retrieval practice both strengthen and distort story recollection
Authors: Denis Dan , DiPietro Carissa , Spreng R Nathan , Schacter Daniel L , Stickgold Robert , Payne Jessica D
Published: November 2024

Over time, memories lose episodic detail and become distorted, a process with serious ramifications for eyewitness identification. What are the processes contributing to such transformations over time? We investigated the roles of post-learning sleep and retrieval practice in memory accuracy and distortion, using a naturalistic story recollection task. Undergraduate students listened to a recording of the “War of the Ghosts,” a Native American folktale, and were assigned to either a sleep or wake delay group, and either a retrieval practice or listen-only study condition. We found higher accuracy after sleep compared to wake in the listen-only condition, but not in the retrieval practice condition. This effect was driven by participants in the wake, retrieval practice condition showing superior memory compared to the wake, listen-only condition. A similar pattern was found for memory distortion, with both sleep and retrieval practice being associated with more inferences of nonpresented, but story-related information, compared to the wake, listen-only condition. These findings suggest both sleep and retrieval practice contribute to narrative memory stabilization and distortion.
Boosting Your Enemies to Garner the Sympathy of Friends: Pro-Fracking Industry Communications and the Geography of Contention
Authors: Walker Edward T , Vasi Ion Bogdan
Published: November 2024

Scholarship has recognized that contention shapes impression management efforts by business actors but has largely ignored how geographic factors affect industry-level responses and how industry groups may seek advantage based on the protests they face. This is consequential: against intuition, industry groups may respond more robustly to relatively more distant challenges than to ones proximate to their infrastructure, hoping to use this to their benefit. They do this because modestly further-away challenges can be framed as coming from “outsiders” making not-in-your-backyard claims, against claimed support in proximate communities. Using structural topic models, we examine daily communications by two major industry groups supporting hydraulic fracturing (“fracking”) between 2009 and 2019: one more transgressive, one more conventional. We examine how their communications shifted after both proximate and non-proximate antifracking contention (protests and bans). We find that they respond only to relatively more distant contention: the transgressive group boosts distant opponents seeking to delegitimize them, while the conventional group highlights economic benefits. Further, reflecting political partisanship, both associations respond only to distant contention emerging from politically liberal areas, ignoring similar contention in conservative areas. We discuss implications for theories of social movements, organizations, and environmental sociology.
The impact of hemoglobin concentration on farrowing duration in sows
Authors: McClellan Katlyn A , Sheffield Sydney L , Levesque Crystal L
Published: November 2024

Concerns have been raised about the prevalence of anemia in sows, yet our understanding of its consequences, particularly its impact on the farrowing process, remains limited. This study investigated the relationship between hemoglobin concentration (HbC) and farrowing duration in sows. A total of 101 sows (n = 16 parity 0, 15 parity 1, 24 parity 2, and 46 parity 3 sows) were monitored for blood HbC (Hemocue Hb 201 device) from the ear vein before farrowing (day 112 of gestation) and between 40 to 48 h after farrowing (day 2). Sows were categorized as anemic (HbC < 10 g/dL), or nonanemic (HbC ≥ 10 g/dL) based on their day 112 HbC (i.e., prefarrowing status). Surveillance cameras recorded the farrowing process for each sow, complemented by human observation. Farrowing duration was defined as the time elapsed between the first piglet born and the last piglet born. All piglets were individually weighed within 18 h of birth, and stillborn piglets were identified using a lung flotation test conducted within 1 h of birth. The correlation between sow HbC, farrowing duration, and stillborn piglets was assessed using the PROC CORR procedure in SAS. Additionally, the effect of HbC category on labor duration was tested using the PROC MIXED procedure, with total piglets born included as a covariate. Anemic sows had a prolonged farrowing (7.2 h ± 0.92 min, P < 0.001) compared to nonanemic sows (3.5 h ± 0.88 min), and negative correlation was observed between prefarrow HbC and farrowing duration (r = −0.62, P < 0.001). There was a weak correlation between farrowing duration and stillborn piglets (r = 0.32, P = 0.01). No correlation was observed between farrowing duration and total born (r = 0.22, P = 0.11). There was no difference in total born (16.41 ± 0.7 vs 16.3 ± 0.7) between anemic (< 10 g/dL) and nonanemic (≥10 g/dL) sows, respectively. Factors such as barn temperature on the day of parturition and feed intake the day prior did not influence the observed differences in labor duration between anemic and nonanemic sows. In conclusion, maintaining HbC above 10 g/dL appears beneficial for sows, as lower concentrations of HbC are associated with prolonged labor and increased removal rates. Blood HbC could serve as a valuable biomarker for identifying at-risk sows, thereby aiding in improving herd management and productivity.
Stress survival and longevity of Caenorhabditis elegans lacking NCS-1
Authors: Magno Luiz Alexandre Viana , Pinto Sofia Helena Dias Borges , Pacheco Ailla , Rosa Daniela Valadão Freitas , Gubert Priscila , Romano-Silva Marco Aurélio
Published: November 2024

Although dysfunctional Ca2+ signaling can trigger biochemical reactions that lead to cell death, the role of calcium-binding proteins (CBPs) in this process is still a topic of debate. Neuronal calcium sensor 1 (NCS-1) is a CBP that is highly conserved and has been shown to increase cell survival against various types of injuries. As such, we hypothesized that NCS-1 could also be a stress-responsive protein with potential effects on survival and longevity. To explore this possibility, we conducted experiments to examine how Caenorhabditis elegans ncs-1 mutant nematodes fared under three different stress conditions: hyperosmotic, thermal, and chemical oxidant challenges. Our results showed that while the lack of NCS-1 had no effect on survival responses to hyperosmotic and thermal stresses, ncs-1 worms demonstrated remarkable resistance to the oxidant paraquat in a dose-dependent manner. Based on these findings, we conclude that C. elegans may employ adaptive mechanisms in the absence of NCS-1 to survive specific oxidative stress stimuli.
The safety of indocyanine green in patients with advanced chronic kidney disease or kidney transplantation – a scoping review
Authors: Kruiswijk Mo W. , Nguyen Dinh Ha Lan , Tange Floris P. , Koning Stefan , van den Hoven Pim , Peul Roderick C. , Rotmans Joris I. , Huurman Volkert A.L. , Alwayn Ian P.J. , Hamming Jaap F. , Vahrmeijer Alexander L. , van der Vorst Joost R.
Published: November 2024

Near-infrared fluorescence imaging with indocyanine green (ICG) is increasingly being used in the field of image-guided surgery. Although ICG is considered non-nephrotoxic in current literature, caution is advised for the use of ICG in patients with advanced chronic kidney disease (CKD), including kidney transplant recipients. Therefore, a scoping review was performed to assess the safety of ICG in patients with advanced CKD or a renal allograft. This scoping review was guided by the PRISMA-ScR (Preferred Reporting Items for Systematic reviews and Meta-analyses extension for Scoping Reviews). Web of Science, PubMed, and Embase were searched for articles and abstracts in which ICG was administered in patients with CKD or a renal allograft. The extracted data included the incidence of adverse events, kidney function after injection of ICG, preservation of transplant function, and type of other possible complications. The initial search resulted in 635 records of which nineteen studies were found eligible for the review. ICG was used for multiple purposes but never specifically as an objective to investigate possible nephrotoxicity. No adverse events were reported in the transplant group (n=250) or the CKD group (n= 74). Despite ICG-injection, preservation of transplant function after transplantation surgery was 94% in 198 patients, and no increase in possible ICG-related other complications was reported. This scoping review found no evidence that ICG increases the risk of adverse events in patients with CKD, including kidney transplant recipients. Therefore, the administration of ICG should not be withheld from these patients.
Malignant transformation of recurrent benign phyllodes tumor: a case report and comprehensive review of literature
Authors: Khatiwada Abhikanta , Bastakoti Aashish , KC Sharada , Sharma Usha , Rao Shivali
Published: November 2024

Introduction:

Phyllodes tumors (PTs) of the breast are rare fibroepithelial neoplasms, accounting for less than 1% of all breast tumors. The WHO classifies PTs into benign, borderline, or malignant categories based on histological features. While benign PTs generally have a favorable prognosis, they carry a risk of transformation into malignant variants, particularly in cases of recurrence.

Case presentation:

A 33-year-old female presented with a recurrent benign PT, previously treated with lumpectomy on two occasions. Recent imaging suggested possible malignant transformation, and histopathological examination confirmed a malignant PT.

Discussion:

This case highlights the crucial role of imaging in the early detection of malignant transformation in PTs. Surgical management strategies are discussed, with an emphasis on the potential for recurrent benign tumors to progress to malignancy.

Conclusion:

Regular imaging and close follow-up are essential for early detection of malignant transformation in recurrent PTs, guiding timely and appropriate surgical intervention.
Accuracy and Performance Characteristics of Administrative Codes for the Diagnosis of Autoinflammatory Syndromes
Authors: Lee Saeyun , Kim Sujin , Segerstrom Suzanne , Ferguson Polly J. , Lenert Aleksander
Published: November 2024

Objective

The aim of this study was to evaluate and validate the accuracy and performance characteristics of administrative codes in diagnosing autoinflammatory syndromes (AISs).

Methods

We identified potential AIS patients from the electronic medical records at the University of Iowa Hospital and Clinics and the Stead Family Children's Hospital using a screening filter based on the 10th edition of the International Classification of Diseases (ICD-10) codes and interleukin-1 antagonists. Diagnostic criteria for adult-onset Still disease, systemic juvenile idiopathic arthritis, Behçet disease (BD), familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS), and SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome and chronic nonbacterial osteomyelitis (SAPHO-CNO) were reviewed for each patient. Patients who did not meet the diagnostic criteria were categorized as non-AIS. In this cross-sectional study, we calculated the sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operating characteristic curve for the ICD codes in diagnosing AIS.

Results

Out of the 502 patients with potential AIS, 338 patients (67%) had a true AIS diagnosis. Sensitivity ranged from 80% (SAPHO-CNO) to 100% (BD and FMF), and positive predictive value ranged from 15% (FMF) to 80% (SAPHO-CNO). Specificity ranged from 81% (FMF) to 99% (CAPS and SAPHO-CNO), whereas negative predictive value ranged from 98% (adult-onset Still disease) to 100% (systemic juvenile idiopathic arthritis, BD, FMF, and CAPS). All ICD codes or code combinations for the diagnosis of specific AIS subtypes showed high accuracy with areas under the receiver operating characteristic curve ≥0.89.

Conclusions

This study validated the accuracy of administrative codes for diagnosing AIS, supporting their use in constructing AIS cohorts for clinical outcomes research.
Bitter taste genetics and oral health in Canadian Longitudinal Study on Aging
Authors: Shafizadeh Marziyeh , Bhatia Vikram , Ahmed Samah , Drögemöller Britt , Stavropoulou Chrysi , John Philip St. , Bhullar Rajinder P. , Chelikani Prashen , Hitchon Carol A.
Published: November 2024

This study aimed to investigate the association of single nucleotide polymorphisms (SNPs) in 25 Bitter Taste Receptor genes (TAS2Rs) and 12TAS2Rpseudogenes with self-reported oral health outcomes in the Canadian Longitudinal Study on Aging (CLSA) cohort. Following quality control, 124 SNPs with a minor allele frequency > 0.01 and 21,991 individuals of European ancestry were included in the analysis. Fifteen SNPs inTAS2R8, 9, 13, 14, 20, and50were significantly associated with self-reported sore jaw muscles, a symptom commonly linked to temporomandibular disorders (TMDs).TAS2R20exhibited the highest number of associated SNPs. Structure-function analysis suggests that variants inTAS2R20may contribute to this symptom by altering ligand interactions. These findings highlight the potential forTAS2Rgenetic screening to identify individuals at elevated risk for TMD, supporting the development of personalized treatment strategies and advancing our understanding of TMD genetic risk factors.
An Open Access Resource for Marmoset Neuroscientific Apparatus
Authors: Rollin Isabela Zimmermann , Papoti Daniel , Bishop Mitchell , Szczupak Diego , Corigliano Michael R. , Hitchens T. Kevin , Zhang Bei , Pell Sarah K. A. , Guretse Simeon S. , Dureux Audrey , Murai Takeshi , Sukoff Rizzo Stacey J. , Klassen L. Martyn , Zeman Peter , Gilbert Kyle M. , Menon Ravi S. , Lin Meng-Kuan , Everling Stefan , Silva Afonso C. , Schaeffer David J.
Published: November 2024

The use of the common marmoset (Callithrix jacchus) for neuroscientific inquiry has grown precipitously over the past two decades. Despite windfalls of grant support from funding initiatives in North America, Europe, and Asia to model human brain diseases in the marmoset, marmoset- specific apparatus are of sparse availability from commercial vendors and thus are often developed and reside within individual laboratories. Through our collective research efforts, we have designed and vetted myriad designs for awake or anesthetized magnetic resonance imaging (MRI), positron emission tomography (PET), computed tomography (CT), as well as focused ultrasound (FUS), electrophysiology, optical imaging, surgery, and behavior in marmosets across the age- span. This resource makes these designs openly available, reducing the burden of de novo development across the marmoset field. The computer-aided-design (CAD) files are publicly available through the Marmoset Brain Connectome (MBC) resource (https://www.marmosetbrainconnectome.org/apparatus/) and include dozens of downloadable CAD assemblies, software and online calculators for marmoset neuroscience. In addition, we make available a variety of vetted touchscreen and task-based fMRI code and stimuli. Here, we highlight the online interface and the development and validation of a few yet unpublished resources: Software to automatically extract the head morphology of a marmoset from a CT and produce a 3D printable helmet for awake neuroimaging, and the design and validation of 8-channel and 14- channel receive arrays for imaging deep structures during anatomical and functional MRI.
Molecular Basis of Sperm Methylome Response to Aging and Stress
Authors: Arowolo Olatunbosun , Zhu Jiahui , Nowak Karolina , Pilsner J Richard , Suvorov Alexander
Published: November 2024

Changes in the sperm epigenome induced by age and/or stressors often follow common unexplained patterns affecting genes responsible for embryonic development and neurodevelopment. The stochastic epigenetic variation (SEV) hypothesis proposes that in response to stressors naturally variable methylation regions (VMRs) associated with morphogenic genes increase in methylation variation to diversify phenotypes and improve chances of survival of the genetic lineage. Here, we test predictions from the SEV hypothesis using mouse and rat sperm DNA methylation and other -omics data. We demonstrate that the context of DNA regions determines the response of sperm methylome to various factors rather than the stressors and/or timing of these factors. We propose a model explaining age/stress-dependent shifts in methylation in VMRs by an asymmetric increase in methylation variation of these regions. Because methylation variation in VMRs increases with age, sperm methylome response to stressors may be characterized as an acceleration of epigenetic aging.
Proteostasis Associated Mutations in HSPB5 Destabilize the αB-crystallin Domain
Authors: Khatun Mst. Shanzeda , Ali Md. Chayan , Barua Largess , Munni Yeasmin Akter , Dash Raju , Rahman Md Mafizur
Published: November 2024

HSPB5 (αB-crystallin) is an ATP-independent, stress-inducible chaperone protein that improves protein misfolding and degradation in proteotoxicity-related diseases, including several myopathies, neurodegenerative diseases, and cancers. Although single nucleotide polymorphism (SNP) reduces the overall activity of HSPB5, its dynamic behaviour remains unknown. To get molecular insights into the deleterious, pathogenic, and proteotoxicity-related mutations, this study investigates the potential deleterious SNPs associated with HSPB5. Notably, eleven computational tools identified D109H, R120G, and D140N as the most deleterious SNPs from a total of 313 missense SNPs. Interestingly, these three mutations are present in the core αB-crystallin (αB-c) domain. A molecular dynamics simulation for 500 ns was conducted to reveal these variants’ mechanistic insights. The mutant variants showed higher flexibility and significant conformational changes than the wild, which might be noteworthy to reduce these variants’ chaperoning activity. Also, this conformational change elucidated the loss of function mutations, which could alter these variants’ oligomeric properties. This study will help our understanding of the role and molecular mechanism of HSPB5 mutations in proteotoxicity vulnerable diseases.
International multi-cohort analysis identifies novel framework for quantifying immune dysregulation in critical illness: results of the SUBSPACE consortium
Authors: Moore Andrew R , Zheng Hong , Ganesan Ananthakrishnan , Hasin-Brumshtein Yehudit , Maddali Manoj V , Levitt Joseph E , van der Poll Tom , Scicluna Brendon P , Giamarellos-Bourboulis Evangelos J. , Kotsaki Antigone , Martin-Loeches Ignacio , Garduno Alexis , Rothman Richard E. , Sevransky Jonathan , Wright David W , Atreya Mihir R. , Moldawer Lyle L. , Efron Philip A , Marcela Kralovcova , Karvunidis Thomas , Giannini Heather M. , Meyer Nuala J. , Sweeney Timothy E , Rogers Angela J , Khatri Purvesh
Published: November 2024

Progress in the management of critical care syndromes such as sepsis, Acute Respiratory Distress Syndrome (ARDS), and trauma has slowed over the last two decades, limited by the inherent heterogeneity within syndromic illnesses. Numerous immune endotypes have been proposed in sepsis and critical care, however the overlap of the endotypes is unclear, limiting clinical translation. The SUBSPACE consortium is an international consortium that aims to advance precision medicine through the sharing of transcriptomic data. By evaluating the overlap of existing immune endotypes in sepsis across over 6,000 samples, we developed cell-type specific signatures to quantify dysregulation in these immune compartments. Myeloid and lymphoid dysregulation were associated with disease severity and mortality across all cohorts. This dysregulation was not only observed in sepsis but also in ARDS, trauma, and burn patients, indicating a conserved mechanism across various critical illness syndromes. Moreover, analysis of randomized controlled trial data revealed that myeloid and lymphoid dysregulation is linked to differential mortality in patients treated with anakinra or corticosteroids, underscoring its prognostic and therapeutic significance. In conclusion, this novel immunology-based framework for quantifying cellular compartment dysregulation offers a valuable tool for prognosis and therapeutic decision-making in critical illness.
Follow-up of cancer incidence associated with smoke-related PM2.5exposure due to a coal mine fire
Authors: Nayagam Sunav N , Yu Pei , Gao Caroline X , Smith Catherine L , Ikin Jillian F , Brown David , Kinsman Natasha , Guo Yuming , Abramson Michael J , Walker-Bone Karen , Sim Malcolm R , Lane Tyler J
Published: November 2024

Background

The link between chronic exposure to ambient PM2.5and lung cancer is well established. However, there is limited evidence on the effects of more acute, high-level exposure such as that resulting from the 2014 Hazelwood coal mine fire in regional Australia. We investigated the effects of PM2.5from the mine fire on cancer incidence 8.5 years later.

Methodology

We obtained Victorian Cancer Registry data linked to 2872 Hazelwood Health Study Adult Cohort members, for the period August 2014 to December 2022. Individual fire-related PM2.5exposure was estimated by blending time-location diaries with spatial and temporal air pollution modelling data. To assess the cancer risk associated with fire related PM2.5exposure, we employed competing risk regression models, accounting for people who died from causes other than cancer during follow-up and adjusting for confounders, including cigarette smoking.

Results

In the post-mine fire period, 295 people (14.3/1000 person-years) were diagnosed with 332 new cancers (12.7/1000 person-years). No significant association was found between fire-related PM2.5exposure and the overall incidence of cancer (HR = 1.00, 95%CI: 0.90-1.11). Additionally, no associations were identified with any specific cancer subtypes, including lung cancer. However, a higher risk of overall cancer incidence was observed in Morwell compared with Sale, (HR = 1.27, 95% CI: 0.93–1.73).

Conclusions

While we found no evidence that this coal mine fire increased cancer incidence, it would be premature to rule out potential carcinogenic effects. Cancer has a long latency period, which means it will be necessary to analyse new data as they become available to more conclusively determine the effects of medium-duration, high-level smoke exposure.
Factors that influence the implementation of digital health in rural, regional, and remote Australia: Protocol for an overview of reviews
Authors: Krahe Michelle A , Baker Stephanie , Woods Leanna , Larkins Sarah L
Published: November 2024

Background: Although digital transformation holds significant importance for the delivery of health care services, its application in rural, regional, and remote (RRR) settings presents unique challenges which are less comprehensively understood. This review aims to consolidate the available evidence from existing systematic and scoping reviews related to the implementation of digital health in RRR Australia, to examine the health, innovation and implementation outcomes, factors that influence implementation, and the design constructs specific to these settings. Methods: This overview of systematic and scoping reviews will follow the guidelines of the Cochrane Overview of Reviews. Qualitative, quantitative, and mixed-methods reviews of studies focusing on the implementation of digital health in RRR Australia will be in included. We will search the following databases: Cochrane Library, PubMed, SCOPUS, CINAHL, and Web of Science. We will include studies published in English from the inception of the database until May 01, 2024. Two reviewers will conduct all steps independently and a third reviewer will determine and resolve discrepancies. Included reviews will be appraised using the AMSTAR-2 checklist. A theory-based coding of barriers and enablers using the CFIR 2.0 will be applied and a narrative summary of the findings, along with tables and diagrams aligned with the objective and scope of the review will be presented. Discussion: We expect this overview of reviews to provide current evidence and key insights about the factors that inhibit or promote the implementation of digital health in RRR Australia. Findings will orient the selection and adaptation of implementation process strategies tailored to digital health in RRR Australia. We will publish our results in a peer-reviewed journal.
Cohort profile: the Northwest China Real-world and Population-based Cohort
Authors: Huang Qi , Li Yanjun , Yin Bo , Wang Yaoguo , Yuan Yujuan , Guo Yanying , Gu Kuiying , Yang Yining , Di Qian
Published: November 2024

Key Features

The Northwest China Real-World and Population-based cohort is an ongoing prospective cohort with more than 25 million population, covering almost all residents across approximately 1.66 million square kilometers in northwest China

The cohort integrates data from various sources, including health profiles, examination records, electronic health records, mortality records, statistical yearbooks, and environmental datasets, covering comprehensive health-related factors such as demographics, lifestyle factors, family medical history, living conditions, enrollment in national public health services, physical examinations, blood assay tests, diagnostic assessments, disease outcomes, and cause-specific mortality.

This real-world dataset can evaluate clinical treatment effectiveness and prognosis, assess impact of health policy, and investigate the health effects of multiple risk factors .

From January 2019 to December 2023, the cohort has included 13,634,481 participants, accumulating 47,050,707 person-years of follow-up, with 13,598,407 medical diagnosis records and 881,114 recorded deaths.

Cohort data are available upon request. De-identified and anonymized data are stored on local servers and accessed through a data-sharing platform, enabling users to utilize the data without direct access to the raw information. A description of the proposed research can be sent to Yining Yang & Qian Di.
Higher burden of cerebral small vessel disease is associated with risk of incident stroke in community dwelling individuals
Authors: Pinheiro Adlin , Aparicio Hugo , Lioutas Vasileios , Beiser Alexa , Ekenze Oluchi , DeCarli Charles , Seshadri Sudha , Demissie Serkalem , Romero Jose R.
Published: November 2024

Background

Mild manifestations of individual cerebral small vessel disease (CSVD) markers are common and may not denote increased risk, but high CSVD burden identifies individuals at increased risk of stroke and dementia. Scores incorporating multiple individual CSVD markers may better identify a person’s risk. We related a multi-marker CSVD score to risk of incident stroke and compared it with the Framingham Stroke Risk Profile (FSRP) in community-dwelling individuals.

Methods

Framingham Heart Study participants aged ≥55 years, free of stroke and dementia and with brain magnetic resonance imaging ratings of CSVD markers were included. A multi-marker CSVD score reflecting increasing CSVD burden was used, assigning one point each for presence of cerebral microbleeds, severe perivascular spaces, extensive white matter hyperintensities, covert brain infarcts, and cortical superficial siderosis. Multivariable Cox proportional hazards regression analyses were used to relate CSVD score to incident stroke.

Results

Among 1,154 participants (46% male, mean age 70.9±8.7), 92 (8%) developed stroke over a median follow-up of 8.6 years (Q1-Q3: 5.1-12.5). In models adjusting for age, sex, time interval between clinic exam and MRI, FHS cohort, and FSRP, those with three or more markers had increased risk of stroke (HR: 2.62; 95% CI: 1.17-5.88). In comparison, a 5-percent increase in FSRP was also associated with increased risk (aHR: 1.16; 95% CI: 1.04-1.29). The FSRP and CSVD score had similar model discrimination metrics.

Interpretation

Higher CSVD burden is associated with increased risk of stroke, beyond the effect explained by risk factors in the FSRP. These findings support consideration of CSVD burden to identify risk of stroke in community-dwelling individuals for early implementation of preventive strategies.
Drivers of Depression in Chronic Post-Stroke Aphasia
Authors: Mathur Devna , Paul Sachi , DeMarco Andrew , Turkeltaub Peter
Published: November 2024

Background

Approximately one third of stroke survivors develop post-stroke depression, which reduces quality of life. Previous studies have often focused on early phases of recovery and excluded people with significant aphasia. Here, we examine relationships of depression symptoms to demographic factors, and different types of stroke-related disability and impairment in adults with chronic left-hemisphere stroke and a history of aphasia.

Methods

92 chronic left-hemisphere stroke survivors with a history of aphasia and 70 controls participated in this cross-sectional study. The Beck Depression Inventory-II (BDI-II) measured depression symptoms. The Stroke Impact Scale 3.0 (SIS) assessed stroke-related disability in Cognitive, Physical, and Social Participation domains, as well as self-perceived Recovery. The Western Aphasia Battery Aphasia Quotient and the NIH Stroke Scale total motor score measured language and motor impairment. Spearman correlations examined bivariate relationships between variables. Ordinal regression models examined group differences in BDI-II scores (Model 1), and disability and impairment factors that predicted BDI-II scores (Model 2), accounting for demographic factors and antidepressant medication status.

Results

BDI-II scores were on average 3.4 points higher in stroke survivors than controls. Model 1 confirmed that this difference was significant, and found that age was inversely related to BDI-II scores. Bivariate correlations demonstrated that higher BDI-II scores were related to lower SIS Cognitive, Social Participation, and Recovery scores. Model 2 found that these three measures independently predicted BDI-II scores.

Conclusions

The factors related to depression may differ depending on the nature of the stroke, the types of deficits experienced, and the phase of recovery. In the chronic phase of left hemisphere stroke with aphasia, cognitive and communication disabilities, social participation, and self-perceived recovery are the primary correlates of depression symptoms. These findings highlight the importance of assessing for depression even long after left hemisphere stroke, and suggest potential targets for psychotherapy to improve depression.
Canonical Notch2 Signaling Regulates the Development of Iron-recycling Macrophages and Iron Homeostasis
Authors: Schroth Frauline Nicole , Kapanadze Tamar , Sablotny Stefan , Xu Yuangao , Chung Bo Mee , Deuper Lena , Kispert Andreas , Lochner Matthias , Kempf Tibor , Haller Hermann , Schmidt-Ott Kai M. , Gamrekelashvili Jaba , Limbourg Florian P.
Published: November 2024

Red pulp macrophages (RPM) and bone marrow macrophages (BMM) are iron-recycling cells involved in iron homeostasis and erythropoiesis. Here, we show, using conditional deletion strategies of Notch signaling components, that the development of RPM and BMM is regulated by canonical Notch2 signaling. Loss of functionalNotch2, or its nuclear mediatorRbpj, causes impairment in RPM and BMM and iron overload in the spleen and bone marrow, while prototypic RPM genes required for iron handling are downregulated. This was accompanied by splenic extramedullary hematopoiesis and changes in splenic microarchitecture. Furthermore, early postnatal transfer of bone marrow and fetal liver progenitors rescued the defects in RPM and BMM and iron overload in aNotch2-dependent manner, demonstrating the potential to restore defective tissue resident macrophage niches by Notch-competent progenitors. Thus, canonicalNotch2is required for development and function of iron-recycling macrophages.
A genome-wide ATLAS of liver chromatin architecture reveals that sex dictates diet-induced nucleosome dynamics
Authors: Zhang Zhengyi , Su Vivien , Wiese Carrie B. , Cheng Lijing , Wang Dan , Cui Ya , Kim Jason , Wu Xiaohui , Tran Peter H. , Zhou Zhenqi , Casero David , Li Wei , Hevener Andrea L. , Reue Karen , Sallam Tamer
Published: November 2024

The three-dimensional organization of the genome plays an important role in cellular function. Alterations between open and closed chromatin states contributes to DNA binding, collaborative transcriptional activities and informs post-transcriptional processing. The liver orchestrates systemic metabolic control and has the ability to mount a rapid adaptive response to environmental challenges. We interrogated the chromatin architecture in liver under different dietary cues. Using ATAC-seq, we mapped over 120,000 nucleosome peaks, revealing a remarkably preserved hepatic chromatin landscape across feeding conditions. Stringent analysis of nucleosome rearrangements in response to diet revealed sex as the dominant factor segregating changes in chromatin accessibility. A lipid-rich diet led to a more accessible chromatin confirmation at promoter regions in female mice along with enrichment of promoter binding CCAAT-binding domain proteins. Male liver exhibited stronger binding for nutrient sensing nuclear receptors. Integrative analysis with gene expression corroborated a role for chromatin states in informing functional differences in metabolic traits. We distinguished the impact of gonadal sex and chromosomal sex as determinants of chromatin modulation by diet using the Four Core Genotypes mouse model. Our data provide mechanistic evidence underlying the regulation for the critical sex-dimorphic GWAS gene,Pnpla3. In summary, we provide a comprehensive epigenetic resource in murine liver that uncovers the complexity of chromatin dynamics in response to diet and sex.
Improved automated model building for cryo-EM maps using CryFold
Authors: Su Baoquan , Huang Kun , Peng Zhenling , Amunts Alexey , Yang Jianyi
Published: November 2024

Constructing atomic models from cryogenic electron microscopy (cryo-EM) density maps is essential for interpreting molecular mechanisms. In this study, we present CryFold, an approach forde novomodel building in cryo-EM that leverages recent advancements in AlphaFold21to improve the state-of-the-art method ModelAngelo2. To incorporate the cryo-EM map information, CryFold replaces the global attention mechanism in AlphaFold2 to local attention, further enhanced by a novel 3D rotary position embedding. It produces more complete models, accelerates the modeling, and reduces the resolution requirement. Applying CryFold to new maps results in accurate differentiation between paralog sequences in noisy regions, detection of previously uncharacterized proteins with unknown functions, precise compartmentalisation of the map for isolation of non-protein components, and improved modeling of conformational changes. In a particular case, a 104-protein complex was modeled within only 5.6 hours, and a minor conformational change of a single protein domain was detected at the periphery when models from two different maps were compared. CryFold stands as an accurate method currently available for model building of proteins in cryo-EM structure determination. CryFold is open-source software available athttps://github.com/SBQ-1999/CryFold.
A single cysteine residue in vimentin regulates long non-coding RNAXISTto suppress epithelial-mesenchymal transition and stemness in breast cancer
Authors: Usman Saima , Yeudall W. Andrew , Teh Muy-Teck , Ghloum Fatemah , Tummala Hemanth , Waseem Ahmad
Published: November 2024

Vimentin is a type III intermediate filament (IF) protein, that is induced in a large number of solid tumours. A single cysteine at position 328 in vimentin plays a crucial role in assembly, organisation and stability of IFs. However, its exact function during epithelial mesenchymal transition (EMT) and cancer progression has not been investigated. To investigate this, we have transduced wildtype (WT) and C328S vimentin separately in MCF-7 cells that lack endogenous vimentin. The expression of C328-VIM impacted vimentin-actin interactions and induced EMT-like features that include enhanced cell proliferation, migration, invasion accompanied by reduced cell adhesion when compared to the wildtype cells. Functional transcriptomic studies confirmed the upregulation of EMT and mesenchymal markers, downregulation of epithelial markers as well as acquisition of signatures associated with cancer stemness (CD56, Oct4, PROCR and CD49f) thus transforming MCF-7 cells from oestrogen positive to triple reduced (ESR1, PGR, and HER2) status. We also observed a stark increase in the expression of long non-coding RNA,XISTin MCF-7 cells expressing C328-VIM. Targeting the mutant vimentin orXISTby RNA interference partially reversed the phenotypes in C328-VIM expressing MCF-7 cells. Furthermore, introduction of C328-VIM cells into nude mice promoted tumour growth by increasing cancer stemness in an oestrogen independent manner. Altogether, our studies provide insight into how cysteine 328 in vimentin dictates mechano-transduction signals to remodel actin cytoskeleton and protect against EMT and cancer growth via modulating lncRNAXIST. Therefore, targeting vimentin and/orXISTvia RNA interference should be a promising therapeutic strategy for breast cancer treatment.

Abstract Figure
Universal base editing for hemophilia B
Authors: Baatartsogt Nemekhbayar , Kashiwakura Yuji , Hiramoto Takafumi , Ito Rina , Sato Rikako , Nagao Yasumitsu , Naruoka Hina , Takata Haruka , Hayakawa Morisada , Batjargal Khishigjargal , Togashi Tomoki , Hoshino Atsushi , Shimizu Taro , Sato Yusuke , Ishida Tatsuhiro , Nureki Osamu , Ohmori Tsukasa
Published: November 2024

The repair of pathological gene variants is an ultimate aim for treating genetic diseases; however, it is not practical to develop different therapeutic reagents for each of the many variants that can occur in a gene. Here, we investigated whether base editing to induce a gain-of-function variant in blood coagulation factor IX (FIX) can increase FIX activity as a treatment strategy for hemophilia B. We engineered a G:C to A:T substitution at c.1151 ofF9by cytosine base editing to generate R338Q, known as the ShanghaiF9variant, which markedly potentiates coagulation factor activity. An adeno-associated virus vector harboring the base editor converted more than 60% of the target G:C to A:T and increased FIX activity in HEK293 cells harboring patient-derivedF9variants, as well as in knock-in mice harboring a humanF9cDNA. Furthermore, administration of lipid nanoparticles embedded with the base editor mRNA and gRNA increased FIX activity in mice. These data indicate that cytosine base editing to generate R338Q in FIX can become a universal genome editing strategy for hemophilia B.
Alveolar macrophages initiate the spatially targeted neutrophil recruitment during nanoparticle inhalation
Authors: Liu Qiongliang , Yang Lin , Li Chenxi , Zhou Qiaoxia , Han Lianyong , Schröppel Andreas , Kutschke David , Secklehner Judith , Yldirim Ali Önder , Zeuschner Dagmar , Carlin Leo M. , Sperandio Markus , Schmid Otmar , Stoeger Tobias , Rehberg Markus
Published: November 2024

Exposure to air pollution, including nanoparticles (NPs), is a major health concern associated with various diseases, triggered by subtle inflammatory responses in the lung. To investigate the dynamic immune response in vivo, lung intravital microscopy (L-IVM), was used to analyze the behavior of alveolar macrophages (AMs) and neutrophils, combined with ventilator-assisted inhalation of nebulized NPs in mice. Inhalation of fluorescent quantum dot NPs (cQDs) and soot-like carbon black NPs (CNPs, ambient pollutants), led to rapid spatially focused recruitment of neutrophils near alveolar deposited NPs. Neutrophil recruitment was initiated by NPs uptake by AMs, dependent on AM motility and AM NP surface recognition. Prior airway application of neutralizing antibodies against alveolar ICAM-1 and LFA-1, leading to reduced AM motility, inhibition of C5aR1 and FcγRI receptor mediated NPs uptake by AMs, as well as neutralizing of TNFα and application of a cellular degranulation inhibitor, abolished the early immune response induced by NPs. Overall, our data demonstrates the crucial role of AM activity (migration, phagocytosis, cytokine release) in the rapid and site-specific recruitment of neutrophils during the early phase of particle inhalation, suggesting these processes to be key events in mounting the immune response upon NP inhalation in the lung.

Graphical abstract