bluuebunny/crossref_metadata_2025_split huggingface dataset:
Parity and cumulative incidence rates of breast cancer in the Norwegian Woman and Cancer Study (NOWAC)
Authors: Krum-Hansen Sanda , Wiik Arne Bastian , Olsen Karina Standahl , Lukic Marko , Paulssen Ruth H. , Lund Eiliv 
Published: October 2024

AbstractBackgroundThe reduced risk of breast cancer (BC) following increasing parity has been known for decades. Most prospective studies have presented the relative risk as the percentage decrease for each child during follow-up. Since the risk reduction is up to ten percent for each child, the overall lifelong BC risk reduction could be under communicated. In this study we use cumulative incidence rates (CIR) to calculate and describe the lifelong risk of BC in relation to parity.MethodsNOWAC is a prospective cohort study with 172,000 women recruited between 1991 and 2007 with follow-up through questionnaires and national registers of cancer and death. For the present analyses, we included 165 238 women with follow-up from 01.01.2000 until 31.12. 2018. We calculated CIR of BC by parity, stratified by other established BC risk factors (maternal age at first birth, breastfeeding, body mass index (BMI), smoking and alcohol consumption).ResultsAfter 17.3 years of average follow-up, 8120 women aged 35-84 years developed breast cancer. Age-specific incidence rates increased for each age group up to 60-64 years, decreased for the age group 75-79 years, and increased again among the oldest women aged 80-84. CIR for all participants up to 84 years was 11 700 per 100 000 person years (PY). In analyses stratified by parity, the CIR of BC for nullipara was 12 600 per 100 000 PY, for 1-2 children: 12 100, 3-4 children: 10 200, and 5-6 children: 8 700 per 100 000 PY. The parity-specific CIR of BC had the same pattern of decrease in analyses stratified for other BC risk factors.ConclusionCumulative incidence rates showed a consistent decrease in BC risk for each additional child. The decrease was consistent in strata of other established BC risk factors.
Capturing Trial-by-Trial Variability in Behaviour: People with Parkinson’s Disease Exhibit a Greater Rate of Short-Term Fluctuations in Response Times
Authors: MacDonald Hayley J. , Fasmer Ole Bernt , Jønsi Olav T. , Sørensen Lin 
Published: October 2024

AbstractAverage response time is frequently used to reflect executive function. Less often studied is intra-individual variability in response times (IIVRT) which reflects within-person consistency. Higher IIVRT in Parkinson’s disease (PD) has been associated with poor executive function but almost exclusively studied using standard deviations. Such linear measures cannot capture rapid and spontaneous changes in biological systems such as dopaminergic bursting activity. Therefore, nonlinear measures may provide important complementary insights into dopamine-related neurocognition. Our primary aim was to investigate nonlinear IIVRT measures in PD using graph theory, constituting the first use of this approach on RT data. As hypothesized, PD was associated with a greater rate of trial-by-trial IIVRT compared to healthy older adults. These novel results indicate that a similarity graph algorithm may be a useful tool to capture the more rapidly varying and spontaneous changes in RT behavior that result from the dysfunctional dopamine bursting dynamics present in PD.
Accelerated Biological Aging in Familial Pulmonary Fibrosis
Authors: Serezani Ana P.M. , Mitchell Daphne B. , Cogan Joy D. , Malabanan M. Merced U. , Markin Cheryl R. , Garnett Errine T. , Douglas Katrina , Fadely Tisra H. , Kropski Jonathan A. , Salisbury Margaret L. , Blackwell Timothy S. 
Published: October 2024

AbstractSince Familial Pulmonary Fibrosis (FPF) manifests in older adults and telomere attrition is common in FPF and sporadic Idiopathic Pulmonary Fibrosis (IPF), we postulated that accelerated aging, as determined by epigenetic clock (DNA methylation) measurements, could occur in FPF. We measured DNAge from blood of patients with FPF and a group of first-degree relatives of FPF patients without disease (termed “at-risk” for FPF) with or without genetic rare variants (RVs) in telomerase pathway genes. We observed accelerated epigenetic aging with increased DNAge compared to chronological age in individuals at-risk for FPF and FPF patients compared to healthy controls. We found that increased DNAge manifests independently of the presence of RVs in telomerase pathway genes or telomere length in peripheral blood cells. These findings suggest that increased DNAge could be an independent risk factor for the development of FPF.
Association of Bleeding Risk With Recurrent Cardiovascular Events in Asian Patients with Acute Coronary Syndrome: A Nationwide Population-Based Cohort Study
Authors: Chen Chih-Wei , Lin Yi-Cheng , Lin Donna Shu-Han , Chang Chia-Li , Huang Chun-Yao , Chen Jaw-Wen , Lin Shing-Jong , Shao Yu-Hsuan , Hsu Chien-Yi 
Published: October 2024

AbstractBackgroundAcute coronary syndrome (ACS) carries significant risks of recurrent cardiovascular (CV) events and bleeding complications. In particular, Asian patients have higher rates of bleeding complications due to genetic and physiological factors. Bleeding complications are associated with an increased risk of subsequent thrombotic events, and the impact of such complications on long-term outcomes must therefore be investigated. This study compared long-term outcomes and clinical characteristics between ACS patients who experienced a single ACS event and those who experienced multiple CV events.MethodsUtilizing data from Taiwan’s National Health Insurance Research Database, this retrospective cohort study categorized patients into single-event and multiple-event groups based on the occurrence of major adverse CV events within 2 years after the index ACS event. In this cohort study, 28,535 patients were included. After matching by age, sex, and the interval between the first and second CV events at a 1:2 ratio, 8,720 patients were included in the multiple-event group and 17,368 in the single-event group.ResultsThe multiple-event group had higher rates of comorbidities, including hypertension, prior coronary artery disease, heart failure, stroke, and chronic kidney disease. Over a 5-year period, the multiple-event group exhibited higher all-cause mortality (34.1% vs. 24.6%, p < 0.0001) and CV mortality (11.4% vs. 6.2%, p < 0.0001) than the single-event group. The rates of major bleeding events (7.8% vs. 1.6%, p < 0.0001) and minor bleeding events (34.4% vs. 7.2%, p < 0.0001) were also higher in the multiple-event group than in the single-event group. Compared with the single-event group, which showed a significant reduction in major bleeding events 1 month after the index ACS event, the multiple-event group continued to have a higher rate of major bleeding events within 3 months following the index ACS event. In the multiple-event group, patients who experienced a major bleeding event had an earlier onset of subsequent CV events than patients who did not experience a major bleeding event. Specifically, every 1-day earlier occurrence of major bleeding was associated with a 1.0044-day earlier occurrence of a subsequent CV event.ConclusionACS patients with multiple CV events have higher rates of all-cause mortality, CV mortality, and major bleeding than ACS patients with a single CV event. However, major bleeding may be associated with the risk of subsequent CV events, highlighting the importance of implementing a tailored antiplatelet strategy in Asian populations.
Weight loss with different types of fasting in patients with type two diabetes and hypertension: a randomized clinical trial
Authors: Oshakbayev Kuat , Idrissov Alisher , Nabiyev Altay , Manekenova Kenzhekyz , Bedelbayeva Gulnara , Durmanova Aigul , Kuttymuratov Gani , Bikhanov Nurzhan , Dukenbayeva Bibazhar 
Published: October 2024

ABSTRACTBackgroundThe coexistence of type two diabetes (T2D) and cardiovascular diseases (CVD) in patients with overweight increases the risk of macro-vascular complications. Some studies are controversial of the results of Ramadan fasting (RF) in patients T2D+CVD.ObjectiveTo compare different RF (antique and modern) on anthropometric, glycemic, blood pressure (BP), lipids, heel bone mineral density (HBMD), and ejection fraction (EF) in patients with T2D+CVD.MethodsAn open, 60-day, controlled, single-center, randomized clinical trial included 51 patients (29 women) with T2D+CVD: 26 in Main (antique RF); 25 in Controls (modern RF).Primary endpoints:weight loss, fasting blood glucose and, blood insulin, BP.Secondary endpoints:blood lipids, HBMD, and EF.ResultsPatients in Main lost weight –8.02 kg (P<0.0001), in Controls lost weight –2.67 kg (P<0.025); BMI in Main significantly decreased (P<0.0001), but in Controls did not significantly decrease (P>0.025). During a 30-day follow-up, Main did not regain weight and WC; but Controls regained weight and WC.In Main BP, all glycemic parameters (fasting glucose, immunoassay insulin, HOMA-IR), lipids (cholesterol, triglyceride, HDL), HBMD, and EF in patients with and without heart failure (HF) were significantly normalized at 30-day RF (P<0.0001). In Controls BP and all glycemic parameters significantly improved but they did not achieve normal (P>0.025). In Controls HBMD and EF in patients with HF did not change (P>0.025). At 30-day follow-up, glycemic, BP, lipids, HBMD, and EF parameters did not significantly change in Main; but in Controls they worsened as weight regained.ConclusionBoth the RF methods allowed weight loss, but antique RF led to markedly weight loss and significant positive change in glycemic, BP, lipids, bone mineralization, and EF in patients with T2D+CVD; the antique RF allowed patients to stop taking medications. The duration of the positive results depended on the maintenance of the achieved weight loss on RF.Trial RegistrationClinicalTrials.govNCT06410352(05/08/2024):https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S000EG8K&selectaction=Edit&uid=U0006MBT&ts=139&cx=bhsvd1
Cost-utility Analysis of Different Treatment Modalities in Patients Undergoing Percutaneous Coronary Intervention: Thai PCI Registry
Authors: Pattanaprateep Oraluck , Limpijankit Thosaphol , Anothaisintawee Thunyarat , Siriyotha Sukanya , Sansanayudh Nakarin , Thakkinstian Ammarin 
Published: October 2024

AbstractBackgroundCost-utility analyses of percutaneous coronary interventions (PCIs) provide valuable insights into the economic value of these procedures. This analysis aimed to compare the cost-utility of different treatment modalities used for PCI patients within a Thai PCI registry.MethodsClinical and quality-of-life data from 39 hospitals spread throughout Thailand were used in this analysis. Three treatment modalities for PCI procedures were compared: a) radial vs. femoral access, b) partial vs. complete revascularization for multivessel coronary artery disease, and c) use vs. non-use of device-guided PCIs (intracoronary ultrasound, optical coherence tomography or fractional flow reserve). Cost data were obtained from each patient’s bill for their hospital stay. Utility scores were measured using the Thai EQ-5D-5L at admission, discharge, and one-year post-procedure. The incremental cost-effectiveness ratio (ICER) was then estimated and used for each comparison.ResultsOf 19,701 patients enrolled in 2018-19, approximately one-third (n=7,332) had hospital cost data available for analysis. At discharge, the mean costs associated with radial access and partial revascularization were $986 and $391, respectively, less than the costs for device-guided PCIs, which increased by a mean of $2004. The delta utility gains for these approaches were 2.97, 1.60, and 1.07 at discharge and 1.08, 1.06, and 0.29 at one year, respectively. The estimated ICERs at one year were -$894, -$359, and $7041 per unit of utility gained, respectively.ConclusionRadial access and partial revascularization demonstrated cost-effectiveness, while device-guided PCI incurred high costs for the achieved utility scores. Identifying the factors that influence these outcomes may assist clinicians in tailoring interventions to optimize a patient’s quality of life after PCI.
Computational Microbiome Pharmacology Analysis Elucidates the Anti-Cancer Potential of Vaginal Microbes and Metabolites
Authors: Lawore Damilola C. , Jena Smrutiti , Berard Alicia R , Birse Kenzie , Lamont Alana , Mackelprang Romel D. , Noel-Romas Laura , Perner Michelle , Hou Xuanlin , Irungu Elizabeth , Mugo Nelly , Knodel Samantha , Muwonge Timothy R. , Katabira Elly , Hughes Sean M , Levy Claire , Calienes Fernanda L. , Hladik Florian , Lingappa Jairam R. , Burgener Adam D , Green Leopold N , Brubaker Douglas K. 
Published: October 2024

AbstractThe vaginal microbiome’s role in risk, progression, and treatment of female cancers has been widely explored. Yet, there remains a need to develop methods to understand the interaction of microbiome factors with host cells and to characterize their potential therapeutic functions. To address this challenge, we developed a systems biology framework we term the Pharmacobiome for microbiome pharmacology analysis. The Pharmacobiome framework evaluates similarities between microbes and microbial byproducts and known drugs based on their impact on host transcriptomic cellular signatures. Here, we apply our framework to characterization of the Anti-Gynecologic Cancer Vaginal Pharmacobiome. Using published vaginal microbiome multi-omics data from the Partners PrEP clinical trial, we constructed vaginal epithelial gene signatures associated with each profiled vaginal microbe and metabolite. We compared these microbiome-associated host gene signatures to post-drug perturbation host gene signatures associated with 35 FDA-approved anti-cancer drugs from the Library of Integrated Network-based Cellular Signatures database to identify vaginal microbes and metabolites with high statistical and functional similarity to these drugs. We found thatLactobacilliand their metabolites can regulate host gene expression in ways similar to many anti-cancer drugs. Additionally, we experimentally tested our model prediction that taurine, a metabolite produced byL. crispatus,kills cancerous breast and endometrial cancer cells. Our study shows that the Pharmacobiome is a powerful framework for characterizing the anti-cancer therapeutic potential of vaginal microbiome factors with generalizability to other cancers, microbiomes, and diseases.
The small GTPase Ran defines Nuclear Pore Complex Asymmetry
Authors: Sachweh Jenny , Börmel Mandy , Klumpe Sven , Becker Anja , Taniguchi Reiya , Kubańska Marta Anna , Pintschovius Verena , Kaindl Eva , Plitzko Jürgen M. , Wilfling Florian , Beck Martin , Hampoelz Bernhard 
Published: October 2024

SummaryNuclear pore complexes (NPCs) bridge across the nuclear envelope and mediate nucleocytoplasmic exchange. They consist of hundreds of nucleoporin building blocks and exemplify the structural complexity of macromolecular assemblies. To ensure transport directionality, different nucleoporin complexes are attached to the cytosolic and nuclear face of the NPC. How those asymmetric structures are faithfully assembled onto the symmetric scaffold architecture that exposes the same interaction surfaces to either side, remained enigmatic. Here we combine cryo-electron tomography, subtomogram averaging, and template matching with live cell imaging to address this question in budding yeast andDrosophila melanogaster. We genetically induce ectopic nuclear pores and show that pores outside the nuclear envelope are symmetric. We furthermore demonstrate that the peripheral NPC configuration depends on the nucleotide state of the small GTPase Ran. Our findings indicate that the nuclear transport system is self-regulatory, namely the same molecular mechanism controls both transport and transport channel composition.
Cardiolipin deficiency disrupts CoQ-complex III interface in steatohepatitis
Authors: Brothwell Marisa J. , Cao Guoshen , Maschek J. Alan , Poss Annelise M. , Peterlin Alek D. , Wang Liping , Baker Talia B. , Shahtout Justin L. , Siripoksup Piyarat , Pearce Quentinn J. , Johnson Jordan M. , Finger Fabian M. , Prola Alexandre , Pellizzari Sarah A. , Hale Gillian L. , Manuel Allison M. , Watanabe Shinya , Miranda Edwin R. , Affolter Kajsa E. , Tippetts Trevor S. , Nikolova Linda S. , Choi Ran Hee , Decker Stephen T. , Patil Mallikarjun , Catrow J. Leon , Holland William L. , Nowinski Sara M. , Lark Daniel S. , Fisher-Wellman Kelsey H. , Mimche Patrice N. , Evason Kimberley J. , Cox James E. , Summers Scott A. , Gerhart-Hines Zach , Funai Katsuhiko 
Published: October 2024

AbstractMetabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive disorder marked by lipid accumulation, leading to steatohepatitis (MASH). A key feature of the transition to MASH involves oxidative stress resulting from defects in mitochondrial oxidative phosphorylation (OXPHOS). Here, we show that pathological alterations in the lipid composition of the inner mitochondrial membrane (IMM) directly instigate electron transfer inefficiency to promote oxidative stress. Specifically, mitochondrial cardiolipin (CL) was downregulated with MASLD/MASH in mice and in humans. Hepatocyte-specific CL synthase knockout (CLS-LKO) led to spontaneous and robust MASH with extensive steatotic and fibrotic phenotype. Loss of CL paradoxically increased mitochondrial respiratory capacity but also reduced the formation of I+III2+IV1respiratory supercomplex and interfered with the ability of coenzyme Q (CoQ) to transfer electrons to complex III. In turn, the bottleneck at complex III promoted electron leak primarily at site IIIQ0as well as other upstream sites in the electron transport chain. Thus, reduction in mitochondrial CL promotes oxidative stress and contributes to pathogenesis of MASH.
Functional Impact of Nth-like DNA glycosylase on Mitochondrial Dynamics
Authors: Hubers Lisa , Sjetne Alexander Myr , Luna Luisa , Wågbø Ane Marit , Lefol Yohan , Galindo Francisco Jose Naranjo , Berg-Eriksen Anders Knoph , Visnes Torkild , Nilsen Hilde , Montaldo Nicola P. 
Published: October 2024

ABSTRACTNth-like DNA glycosylase (NTHL1) is a base excision repair enzyme, with a crucial role both in nuclear and mitochondrial genomic maintenance. In this study, we demonstrate a key function of NTHL1 on mitochondrial DNA (mtDNA) maintenance and mitochondrial dynamics. Our results reveal significant accumulation of mitochondrial transcripts and increased mtDNA levels in NTHL1-deficient cells, accompanied by an accumulation of mtDNA lesions. These findings underscore the essential role of NTHL1 in protecting against mitochondrial genomic damage. In addition to increased OXPHOS mRNA and protein levels, Seahorse analyzer measurements further demonstrated enhanced mitochondrial respiratory capacity and elevated oxygen consumption rates. Furthermore, NTHL1 deficiency was associated with increased mitochondrial size and elevated protein levels of the mitochondrial fusion protein Dynamin-like GTPase OPA1, mitochondrial, long form (L-OPA1). Notably, NTHL1 knockout cells showed resistance to 1-methyl-4-phenylpyridinium (MPP+)-induced mitochondrial stress, indicating that the loss of NTHL1 promotes mitochondrial resilience and an adaptive response to oxidative stress. Combined, these findings indicate a complex phenotype where in NTHL1 plays a multifaceted role in mitochondrial maintenance and its loss leads to mild mitochondrial dysfunction that activates mitohormesis. This study thus extends the known functions of NTHL1 beyond nuclear DNA repair, highlighting its critical role in mitochondrial health and regulation of cellular resilience to oxidative stress.
Mgat4b mediated selectiveN-glycosylation regulates melanocyte development and melanoma progression
Authors: Sharma Babita , Aswin Keerthic , Jain Tanya , Nasreen Ayesha , Aggarwal Ayush , Subramaniam Yogaspoorthi , Rengaraju Jeyashri , Agrawal Srashti Jyoti , Bhatt Mayank , Paul Bhaskar , Chandrasekaran Koushika , Yadav Aanchal , Soni Jyoti , Ujjainiya Rajat , Akhter Md Quasid , Gupta Shantanu Sen , Pandey Rajesh , Suresh Shruthy , Sampathkumar Srinivasa-Gopalan , Natarajan Vivek T 
Published: October 2024

AbstractMelanocyte development involves key pathways that are often recapitulated during melanoma initiation, highlighting the importance of understanding the regulators that control these early processes and also contribute to cancer onset. Our study identifiesmgat4b, a glycosyl transferase involved in selectiveN-glycan branching enriched in pigment progenitors, as a key regulator of directional melanocyte migration and establishment of melanocyte stem cell (McSC) pool during early development. Single cell RNA (scRNA) sequencing analysis in zebrafish upon targeted disruption ofmgat4breveals, that migratory melanocyte progenitors marked by galectin expression fail to persist. Lectin affinity proteomic analysis reveals the glycosylation of key melanocyte proteins GPNMB, KIT, and TYRP1 to be under the control of MGAT4B in melanocytic cells. Additionally, mislocalization of Junctional plakoglobin (JUP) explains the observed defects in cell adhesion and migration to be regulated by MGAT4B but not its isozyme MGAT4A. Our meta-analysis further reveals that melanoma patients with both the BRAFV600Emutation and elevated MGAT4B levels have significantly worse survival outcomes compared to those with only the BRAFV600Emutation. By leveraging the MAZERATI platform to model BRAFV600Edriver mutationin vivo, we show thatmgat4bmutant cells fail to aggregate and initiate tumors. RNA profiling of the transformed melanocytes revealed cell-cell junction, adhesion and ECM binding to be probable contributing factors that resulted in the failure of tumor onset. Using a small-molecule inhibitor we demonstrate the inhibitory role of this complexN-glycosylation in the progression of early-stage melanoma. Our study underscores the importance of selectiveN-glycan branching in both melanocyte development and melanoma initiation, suggesting MGAT4B as a promising therapeutic target for melanoma treatment.
Dissecting compounded hepatocyte injury in a model of MASLD progression from human induced pluripotent stem cells
Authors: Weihs Julian , Baldo Fatima , Cardinali Alessandra , Youssef Gehad , Ludwik Katarzyna , Stachelscheid Harald , Haep Nils , Tang Peter , Sauer Igor , Kumar Pavitra , Engelmann Cornelius , Quach Susanna , Bufler Philip , Han Namshik , Rezvani Milad 
Published: October 2024

AbstractMetabolic dysfunction-associated steatotic liver disease (MASLD) is a complex, multifactorial condition influenced by genetic predisposition, inter-organ signaling, and immune cell infiltration. The difficulty of modeling the complex nature of the disease makes it increasingly challenging to identify treatments that intercept its progression. Here, we show the suitability of cumulative injury modeling toward steatohepatitis from hepatocyte-like cells (HLCs) generated from human induced pluripotent stem cells (iPSCs). These include insults such as free fatty acid excess, soluble extra-hepatic signaling, pro-inflammatory immune cell co-culture and genomic modifiers (PNPLA3-I148M variant). We harness this model to elucidate the molecular and functional consequences of hepatocellular injury progression and identify suitable points of therapeutic interception. Both healthy and PNPLA3-I148M iPSC-donor derived HLCs developed high-level generic steatosis response, yet the PNPLA3-I148M line was more susceptible to mitochondrial injury by the adipokine resistin and the myokine myostatin. Co-culture with peripheral blood mononuclear cells (PBMCs) compounded the previous multi-hit injury. Further, transcriptomic data revealed inflammatory HLC reprogramming and loss of genomically encoded mitochondrial metabolism along injury progression. We demonstrate a nuanced spectral metabolic injury model, mirroring clinical MASLD progression, suitable for testing stage and donor-specific disease interceptions.