bluuebunny/crossref_metadata_2025_split huggingface dataset:
Autophagic Compartments Gain Access to the MHC Class II Compartments in Thymic Epithelium
Authors: Kasai Michiyuki , Tanida Isei , Ueno Takashi , Kominami Eiki , Seki Sachiko , Ikeda Tohru , Mizuochi Toshiaki 
Published: November 2009

Abstract
The presentation of self-peptides in the context of MHC molecules by thymic epithelial cells (TECs) is essential for T cell repertoire selection in the thymus. However, the underlying mechanisms of this process have not been fully elucidated. To address whether autophagy, a catabolic process involving the degradation of a cell’s components through the lysosomal machinery, intersects the MHC class II-restricted Ag presentation pathway in TECs, we investigated the colocalization of LC3, a peculiar autophagy marker molecule, with MHC class II compartments in in vitro-established TEC lines by immunofluorescence microscopy and Western blotting analyses. We found that in both cortical and medullary TEC lines, LC3 was colocalized with the H2-DM-positive lysosomal compartments, in which MHC class II plus class II-associated invariant chain peptides complexes are formed. Furthermore, our analysis of thymic cryosections from 1-day-old mice revealed that LC3 colocalizes with the H2-DM-positive compartments in TECs. These results strongly suggest that the cytoplasmic self-Ags gain access to the H2-DM-positive compartments via the autophagic process in the thymus.
Mast Cell Differentiation and Activation Is Closely Linked to Expression of Genes Coding for the Serglycin Proteoglycan Core Protein and a Distinct Set of Chondroitin Sulfate and Heparin Sulfotransferases
Authors: Duelli Annette , Rönnberg Elin , Waern Ida , Ringvall Maria , Kolset Svein O. , Pejler Gunnar 
Published: November 2009

Abstract
Serglycin (SG) proteoglycan consists of a small core protein to which glycosaminoglycans of chondroitin sulfate or heparin type are attached. SG is crucial for maintaining mast cell (MC) granule homeostasis through promoting the storage of various basic granule constituents, where the degree of chondroitin sulfate/heparin sulfation is essential for optimal SG functionality. However, the regulation of the SG core protein expression and of the various chondroitin sulfate/heparin sulfotransferases during MC differentiation and activation are poorly understood. Here we addressed these issues and show that expression of the SG core protein, chondroitin 4-sulfotransferase (C4ST)-1, and GalNAc(4S)-6-O-sulfotransferase (GalNAc4S6ST) are closely linked to MC maturation. In contrast, the expression of chondroitin 6-sulfotransferase correlated negatively with MC maturation. The expression of N-deacetylase/N-sulfotransferase (NDST)-2, a key enzyme in heparin synthesis, also correlated strongly with MC maturation, whereas the expression of the NDST-1 isoform was approximately equal at all stages of maturation. MC activation by either calcium ionophore or IgE ligation caused an up-regulated expression of the SG core protein, C4ST-1, and GalNAc4S6ST, accompanied by increased secretion of chondroitin sulfate as shown by biosynthetic labeling experiments. In contrast, NDST-2 was down-regulated after MC activation, suggesting that MC activation modulates the nature of the glycosaminoglycan chains attached to the SG core protein. Taken together, these data show that MC maturation is associated with the expression of a distinct signature of genes involved in SG proteoglycan synthesis, and that MC activation modulates their expression.
Interplay between Chromatin Remodeling and Epigenetic Changes during Lineage-Specific Commitment to Granzyme B Expression
Authors: Juelich Torsten , Sutcliffe Elissa , Denton Alice , He Yiqing , Doherty Peter C. , Parish Christopher , Turner Steven J. , Tremethick David , Rao Sudha 
Published: November 2009

Abstract
The role of chromatin remodeling and histone posttranslational modifications and how they are integrated to control gene expression during the acquisition of cell-specific functions is poorly understood. We show here that following in vitro activation of CD4+ and CD8+ T lymphocytes, both cell types show rapid histone H3 loss at the granzyme B (gzmB) proximal promoter region. However, despite the gzmB proximal promoter being remodeled in both T cell subsets, only CD8+ T cells express high levels of gzmB and display a distinct pattern of key epigenetic marks, notably differential H3 acetylation and methylation. These data suggest that for high levels of transcription to occur a distinct set of histone modifications needs to be established in addition to histone loss at the proximal promoter of gzmB.
Absence of the Transcriptional Repressor Blimp-1 in Hematopoietic Lineages Reveals Its Role in Dendritic Cell Homeostatic Development and Function
Authors: Chan Yueh-Hsuan , Chiang Ming-Feng , Tsai Yueh-Chiao , Su Shin-Tang , Chen Ming-Hsu , Hou Mau-Sheng , Lin Kuo-I 
Published: November 2009

Abstract
Dendritic cells (DCs) are important for the initiation and regulation of immune responses. In this study, we demonstrate that DC homeostatic development in peripheral lymphoid organs is negatively regulated by the transcriptional repressor, Blimp-1, which is critical for regulation of plasma cell differentiation and T cell homeostasis and function. Deletion of Prdm1, the gene encoding Blimp-1, in mouse hematopoietic lineages resulted in an increase in the steady-state number of conventional DCs (cDCs). Specifically, Prdm1 deletion increased immediate CD8− cDC precursors in peripheral lymphoid organs, causing selective expansion of the CD8− cDC population. Upon stimulus-induced maturation, Blimp-1 was up-regulated in bone marrow-derived DCs via the p38 MAPK and NF-κB pathways. Notably, Blimp-1-deficient DCs matured poorly upon stimulation in vitro and in vivo. Blimp-1 binds to the proinflammatory cytokine/chemokine genes, Il-6 and Ccl2, and negatively regulates their expression. Collectively, our findings reveal two new roles for Blimp-1: negative regulation of a select subset of cDCs during homeostatic development, and enhancement of DC maturation.
A Nonadjuvanted Polypeptide Nanoparticle Vaccine Confers Long-Lasting Protection against Rodent Malaria
Authors: Kaba Stephen A. , Brando Clara , Guo Qin , Mittelholzer Christian , Raman Senthilkumar , Tropel David , Aebi Ueli , Burkhard Peter , Lanar David E. 
Published: November 2009

Abstract
We have designed and produced a prototypic malaria vaccine based on a highly versatile self-assembling polypeptide nanoparticle (SAPN) platform that can repetitively display antigenic epitopes. We used this platform to display a tandem repeat of the B cell immunodominant repeat epitope (DPPPPNPN)2D of the malaria parasite Plasmodium berghei circumsporozoite protein. Administered in saline, without the need for a heterologous adjuvant, the SAPN construct P4c-Mal conferred a long-lived, protective immune response to mice with a broad range of genetically distinct immune backgrounds including the H-2b, H-2d, and H-2k alleles. Immunized mice produced a CD4+ T cell-dependent, high-titer, long-lasting, high-avidity Ab response against the B cell epitope. Mice were protected against an initial challenge of parasites up to 6 mo after the last immunization or for up to 15 mo against a second challenge after an initial challenge of parasites had successfully been cleared. Furthermore, we demonstrate that the SAPN platform not only functions to deliver an ordered repetitive array of B cell peptide epitopes but operates as a classical immunological carrier to provide cognate help to the P4c-Mal-specific B cells.
T Cell Intrinsic Heterodimeric Complexes between HVEM and BTLA Determine Receptivity to the Surrounding Microenvironment
Authors: Cheung Timothy C. , Oborne Lisa M. , Steinberg Marcos W. , Macauley Matthew G. , Fukuyama Satoshi , Sanjo Hideki , D'Souza Claire , Norris Paula S. , Pfeffer Klaus , Murphy Kenneth M. , Kronenberg Mitchell , Spear Patricia G. , Ware Carl F. 
Published: November 2009

Abstract
The inhibitory cosignaling pathway formed between the TNF receptor herpesvirus entry mediator (HVEM, TNFRSF14) and the Ig superfamily members, B and T lymphocyte attenuator (BTLA) and CD160, limits the activation of T cells. However, BTLA and CD160 can also serve as activating ligands for HVEM when presented in trans by adjacent cells, thus forming a bidirectional signaling pathway. BTLA and CD160 can directly activate the HVEM-dependent NF-κB RelA transcriptional complex raising the question of how NF-κB activation is repressed in naive T cells. In this study, we show BTLA interacts with HVEM in cis, forming a heterodimeric complex in naive T cells that inhibits HVEM-dependent NF-κB activation. The cis-interaction between HVEM and BTLA is the predominant form expressed on the surface of naive human and mouse T cells. The BTLA ectodomain acts as a competitive inhibitor blocking BTLA and CD160 from binding in trans to HVEM and initiating NF-κB activation. The TNF-related ligand, LIGHT (homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes, or TNFSF14) binds HVEM in the cis-complex, but NF-κB activation was attenuated, suggesting BTLA prevents oligomerization of HVEM in the cis-complex. Genetic deletion of BTLA or pharmacologic disruption of the HVEM-BTLA cis-complex in T cells promoted HVEM activation in trans. Interestingly, herpes simplex virus envelope glycoprotein D formed a cis-complex with HVEM, yet surprisingly, promoted the activation NF-κB RelA. We suggest that the HVEM-BTLA cis-complex competitively inhibits HVEM activation by ligands expressed in the surrounding microenvironment, thus helping maintain T cells in the naive state.
Endogenous IL-21 Restricts CD8+ T Cell Expansion and Is not Required for Tumor Immunity
Authors: Søndergaard Henrik , Coquet Jonathan M. , Uldrich Adam P. , McLaughlin Nicole , Godfrey Dale I. , Sivakumar Pallavur V. , Skak Kresten , Smyth Mark J. 
Published: November 2009

Abstract
IL-21 has antitumor activity through actions on NK cells and CD8+ T cells, and is currently in clinical development for the treatment of cancer. However, no studies have addressed the role of endogenous IL-21 in tumor immunity. In this study, we have studied both primary and secondary immune responses in IL-21−/− and IL-21R−/− mice against several experimental tumors. We found intact immune surveillance toward methylcholanthrene-induced sarcomas in IL-21−/− and IL-21R−/− mice compared with wild-type mice and B16 melanomas showed equal growth kinetics and development of lung metastases. IL-21R−/− mice showed competent NK cell-mediated rejection of NKG2D ligand (Rae1β) expressing H-2b− RMAS lymphomas and sustained transition to CD8+ T cell-dependent memory against H-2b+ RMA lymphomas. α-Galactosylceramide stimulation showed equal expansion and activation of NKT and NK cells and mounted a powerful antitumor response in the absence of IL-21 signaling, despite reduced expression of granzyme B in NKT, NK, and CD8+ T cells. Surprisingly, host IL-21 significantly restricted the expansion of Ag-specific CD8+ T cells and inhibited primary CD8+ T cell immunity against OVA-expressing EG7 lymphomas, as well as the secondary expansion of memory CD8+ T cells. However, host IL-21 did not alter the growth of less immunogenic MC38 colon carcinomas with dim OVA expression. Overall, our results show that endogenous IL-21/IL-21R is not required for NK, NKT, and CD8+ T cell-mediated tumor immunity, but restricts Ag-specific CD8+ T cell expansion and rejection of immunogenic tumors, indicating novel immunosuppressive actions of this cytokine.
Deep Learning–Based Assessment of Built Environment From Satellite Images and Cardiometabolic Disease Prevalence
Authors: Chen Zhuo , Dazard Jean-Eudes , Khalifa Yassin , Motairek Issam , Kreatsoulas Catherine , Rajagopalan Sanjay , Al-Kindi Sadeer 
Published: May 2024

ImportanceBuilt environment plays an important role in development of cardiovascular disease. Large scale, pragmatic evaluation of built environment has been limited owing to scarce data and inconsistent data quality.ObjectiveTo investigate the association between image-based built environment and the prevalence of cardiometabolic disease in urban cities.Design, Setting, and ParticipantsThis cross-sectional study used features extracted from Google satellite images (GSI) to measure the built environment and link them with prevalence of cardiometabolic disease. Convolutional neural networks, light gradient-boosting machines, and activation maps were used to assess the association with health outcomes and identify feature associations with coronary heart disease (CHD), stroke, and chronic kidney disease (CKD). The study obtained aerial images from GSI covering census tracts in 7 cities (Cleveland, Ohio; Fremont, California; Kansas City, Missouri; Detroit, Michigan; Bellevue, Washington; Brownsville, Texas; and Denver, Colorado). The study used census tract-level data from the US Centers for Disease Control and Prevention’s 500 Cities project. The data were originally collected from the Behavioral Risk Factor Surveillance System that surveyed people 18 years and older across the country. Analyses were conducted from February to December 2022.ExposuresGSI images of built environment and cardiometabolic disease prevalence.Main Outcomes and MeasuresCensus tract-level estimated prevalence of CHD, stroke, and CKD based on image-based built environment features.ResultsThe study obtained 31 786 aerial images from GSI covering 789 census tracts. Built environment features extracted from GSI using machine learning were associated with prevalence of CHD (R2 = 0.60), stroke (R2 = 0.65), and CKD (R2 = 0.64). The model performed better at distinguishing differences between cardiometabolic prevalence between cities than within cities (eg, highest within-city R2 = 0.39 vs between-city R2 = 0.64 for CKD). Addition of GSI features both outperformed and improved the model that only included age, sex, race, income, education, and composite indices for social determinants of health (R2 = 0.83 vs R2 = 0.76 for CHD; P &amp;lt;.001). Activation maps from the features revealed certain health-related built environment such as roads, highways, and railroads and recreational facilities such as amusement parks, arenas, and baseball parks.Conclusions and RelevanceIn this cross-sectional study, a significant portion of cardiometabolic disease prevalence was associated with GSI-based built environment using convolutional neural networks.
Plant-Based Diets and Disease Progression in Men With Prostate Cancer
Authors: Liu Vivian N. , Van Blarigan Erin L. , Zhang Li , Graff Rebecca E. , Loeb Stacy , Langlais Crystal S. , Cowan Janet E. , Carroll Peter R. , Chan June M. , Kenfield Stacey A. 
Published: May 2024

ImportancePlant-based diets are associated with many health and environmental benefits, including primary prevention of fatal prostate cancer, but less is known about postdiagnostic plant-based diet patterns in individuals with prostate cancer.ObjectiveTo examine whether postdiagnostic plant-based dietary patterns are associated with risk of prostate cancer progression and prostate cancer–specific mortality.Design, Setting, and ParticipantsThis longitudinal observational cohort study included men with biopsy-proven nonmetastatic prostate cancer (stage ≤T3a) from the diet and lifestyle substudy within the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) enrolled at 43 urology practices across the US from 1999 to 2018. Participants completed a comprehensive diet and lifestyle questionnaire (including a validated food frequency questionnaire [FFQ]) between 2004 and 2016. Data were analyzed from August 2022 to April 2023.ExposuresOverall plant-based diet index (PDI) and healthful plant-based diet index (hPDI) scores were calculated from the FFQ.Main Outcomes and MeasuresThe primary outcome was prostate cancer progression (recurrence, secondary treatment, bone metastases, or prostate cancer–specific mortality). The secondary outcome was prostate cancer–specific mortality.ResultsAmong 2062 participants (median [IQR] age, 65.0 [59.0-70.0] years), 61 (3%) identified as African American, 3 (&amp;lt;1%) identified as American Indian or Alaska Native, 9 (&amp;lt;1%) identified as Asian or Pacific Islander, 15 (1%) identified as Latino, and 1959 (95%) identified as White. Median (IQR) time from prostate cancer diagnosis to FFQ was 31.3 (15.9-62.0) months after diagnosis. During a median (IQR) follow-up of 6.5 (1.3-12.8) years after the FFQ, 190 progression events and 61 prostate cancer–specific mortality events were observed. Men scoring in the highest vs lowest quintile of PDI had a 47% lower risk of progression (HR, 0.53; 95% CI, 0.37-0.74; P for trend = .003). The hPDI was not associated with risk of progression overall. However, among 680 individuals with Gleason grade 7 or higher at diagnosis, the highest hPDI quintile was associated with a 55% lower risk of progression compared with the lowest hPDI quintile (HR 0.45; 95% CI, 0.25-0.81; P for trend = .01); no association was observed in individuals with Gleason grade less than 7.Conclusions and RelevanceIn this cohort study of 2062 men with prostate cancer, higher intake of plant foods after prostate cancer diagnosis was associated with lower risk of cancer progression. These findings suggest nutritional assessment and counseling may be recommended to patients with prostate cancer to help establish healthy dietary practices and support well-being and overall health.
Trends in Incidence of Hip Fracture and Hip Replacement in Denmark, 1996 to 2018
Authors: Jensen Troels Mygind , Pedersen Jacob Krabbe , Waldorff Frans Boch , Søndergaard Jens , Overgaard Søren , Christensen Kaare 
Published: May 2024

ImportanceThe past several decades have witnessed substantial changes in treatments that are particularly relevant for older patients.ObjectivesTo assess changes in national-level incidence rates of fracture- and musculoskeletal-related (ie, arthritis-related) hip replacement procedures for individuals aged 40 to 104 years over a 23-year period in Denmark.Design, Setting, and ParticipantsThis cohort study used national Danish health registers to include the Danish population aged 40 to 104 years from January 1, 1996, to December 31, 2018. Data were analyzed from May 31, 2022, to February 14, 2024.Main Outcomes and MeasuresAge- and period-specific incidence rates of hip fracture and hip replacement stratified on fracture-related vs arthritis-related indication.ResultsFrom 1996 to 2018, a total of 3 664 979 individuals were followed up for a mean (SD) of 14.6 (7.7) years, resulting in a follow-up time of 53 517 861 person-years and 158 982 (first) hip fractures, of which 42 825 involved fracture-related hip replacement procedures. A further 104 422 individuals underwent arthritis-related hip replacement. During the first 2 decades of the 21st century, hip fracture rates declined by 35% to 40% for individuals aged 70 to 104 years, and the proportion of the population undergoing fracture-related hip replacement increased by 50% to 70%, with modest variation across those aged 75 to 99 years. Rates of arthritis-related hip replacements peaked for individuals aged 75 to 79 years, but with the largest relative rate increase (75%-100%) occurring for those aged 80 to 94 years, primarily from 2001 to 2015, whereafter it remained nearly unchanged. The decline in rates of arthritis-related hip replacement after 75 to 79 years of age was gradual and did not suggest an upper age limit for access to arthritis-related hip replacement.Conclusions and RelevanceThe findings of this cohort study suggest that during the past several decades in Denmark, the incidence of hip fractures declined by 35% to 40% among patients aged 80 to 104 years, while the proportion receiving fracture-related hip replacement remained relatively constant after 75 years of age. During the first decades of the 21st century, arthritis-related hip replacement incidence increased by 50% to 100% among older patients and stabilized hereafter, with no apparent cutoff age for this type of procedure. These patterns indicate a positive overall trend with declining hip fracture incidence over the last decades in Denmark, and the observed hip replacement incidence suggests that age is currently not a major determining factor guiding this type of surgery.
Laparoscopic Spleen-Preserving Hilar Lymphadenectomy for Advanced Proximal Gastric Cancer Without Greater Curvature Invasion
Authors: Lin Jian-xian , Xu Bin-bin , Zheng Hua-Long , Li Ping , Xie Jian-wei , Wang Jia-bin , Lu Jun , Chen Qi-yue , Cao Long-long , Lin Mi , Tu Ru-hong , Huang Ze-ning , Lin Ju-li , Yao Zi-hao , Zheng Chao-Hui , Huang Chang-Ming 
Published: May 2024

ImportanceSplenic hilar lymphadenectomy has been recommended for locally advanced proximal gastric cancer (APGC) involving the greater curvature. However, it is unclear whether laparoscopic spleen-preserving splenic hilar lymphadenectomy (LSPSHL) is associated with a long-term survival benefit for APGC without greater curvature invasion.ObjectiveTo present the 5-year follow-up data from a randomized clinical trial that compared laparoscopic total gastrectomy (D2 group) with D2 plus LSPSHL (D2 + No. 10 group) among patients with resectable APGC.Design, Setting, and ParticipantsThis is a post hoc secondary analysis of a randomized clinical trial that enrolled 536 patients with potentially resectable APGC (cT2-4a, N0 or N+, and M0) without greater curvature invasion from January 5, 2015, to October 10, 2018. All patients were tracked for at least 5 years. The final follow-up was on October 30, 2023.InterventionsPatients were randomly assigned in a 1:1 ratio to the D2 + No. 10 or D2 groups.Main Outcomes and MeasuresThe 5-year disease-free survival (DFS) and overall survival (OS) rates were measured. Recurrence patterns and causes of death were compared.ResultsA total of 526 patients (392 men [74.5%]; mean [SD] age, 60.6 [9.6] years) were included in the modified intent-to-treat analysis, with 263 patients in each group. The 5-year DFS rate was 63.9% (95% CI, 58.1%-69.7%) for the D2 + No. 10 group and 55.1% (95% CI, 49.1%-61.1%) for the D2 group (log-rank P = .04). A statistically significant difference was observed in the 5-year OS between the D2 + No. 10 group and the D2 group (66.2% [95% CI, 60.4%-71.9%] vs 57.4% [95% CI, 51.4%-63.4%]; log-rank P = .03). The No. 10 lymph node exhibited a therapeutic value index (TVI) of 6.5, surpassing that of Nos. 8a (TVI, 3.0), 11 (TVI, 5.8), and 12a (TVI, 0.8). A total of 86 patients in the D2 + No. 10 group (cumulative incidence, 32.7%) and 111 patients in the D2 group (cumulative incidence, 42.2%) experienced recurrence (hazard ratio, 0.72; 95% CI, 0.54-0.95; P = .02). The multivariable competing risk regression model demonstrated that D2 + No. 10 remained an independent protective factor for a lower 5-year cumulative recurrence rate after surgery (hazard ratio, 0.75; 95% CI, 0.56-1.00; P = .05). There was a significant difference in the 5-year cumulative recurrence rate at the No. 10 lymph node area between the 2 groups (D2 + No. 10 group vs D2 group: 0% vs 2.3% [n = 6]; P = .01).ConclusionsThis post hoc secondary analysis of a randomized clinical trial found that laparoscopic total gastrectomy with LSPSHL can improve the prognosis and reduce recurrence for APGC without greater curvature invasion. Future multicenter studies are warranted to validate these findings.Trial RegistrationClinicalTrials.gov Identifier: NCT02333721