tbuckley/cabot-search huggingface dataset:
Time will tell: comparing timescales to gain insight into transcriptional bursting
Authors: Joseph V.W. Meeussen, Tineke L. Lenstra
Journal: Trends in Genetics (2024)

Recent imaging studies have captured the dynamics of regulatory events of transcription inside living cells. These events include transcription factor (TF) DNA binding, chromatin remodeling and modification, enhancer-promoter (E-P) proximity, cluster formation, and preinitiation complex (PIC) assembly. Together, these molecular events culminate in stochastic bursts of RNA synthesis, but their kinetic relationship remains largely unclear. In this review, we compare the timescales of upstream regulatory steps (input) with the kinetics of transcriptional bursting (output) to generate mechanistic models of transcription dynamics in single cells. We highlight open questions and potential technical advances to guide future endeavors toward a quantitative and kinetic understanding of transcription regulation.
Withdrawal of immunosuppressants and low-dose steroids in patients with stable IgG4-RD (WInS IgG4-RD): an investigator-initiated, multicentre, open-label, randomised controlled trial
Authors: Linyi Peng, Yuxue Nie, Jiaxin Zhou, Lijun Wu, Xiaomei Chen, Fang Wang, Jieqiong Li, Yu Peng, Hui Lu, Lidan Zhao, Mengtao Li, Yan Zhao, Xiaofeng Zeng, Yunyun Fei, Wen Zhang
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Objectives</h3> IgG4-related disease (IgG4-RD) is an immune-mediated, fibroinflammatory disease. Induction treatment with glucocorticoid (GC) is usually effective, but its tendency of relapse makes the strategy for maintenance treatment a challenge. The WInS IgG4-RD (withdraw immunosuppressants (IMs) and steroid in stable IgG4-RD) trial tested whether discontinuation of GC and IM was feasible in stable IgG4-RD. <h3>Methods</h3> The WInS IgG4-RD trial was a multicentre, open-label, randomised controlled trial. Patients with IgG4-RD receiving GC+IM as maintenance treatment with clinically quiescent disease for at least 12 months were randomised (1:1:1) into three groups: group 1: withdraw GC+IM; group 2: withdraw GC but maintain IM; group 3: maintain GC+IM. The primary outcome was the relapse rate of disease within 18 months. The secondary outcomes included the changes of IgG4-RD Responder Index (RI), Physician's Global Assessment (PGA), serum IgG4 and IgG, as well as adverse events. <h3>Results</h3> One hundred and forty-six patients were randomised, with 48 patients in group 1, 49 patients in group 2 and group 3, respectively. Within the 18-month follow-up period, disease relapse occurred in 25 out of 48 (52.1%) patients in group 1 vs 7 out of 49 (14.2%) in group 2 and 6 out of 49 (12.2%) in group 3 (p&lt;0.001). The changes in RI and PGA were significantly higher in group 1 than in group 2 (p&lt;0.001) or group 3 (p&lt;0.001). <h3>Conclusions</h3> The maintenance of IMs, with or without low-dose GC, was found to be superior to withdraw GC+IM in preventing relapse for long-time stable IgG4-RD. <h3>Trial registration number</h3> NCT04124861.
Engineering mesoporous bioactive glasses for emerging stimuli-responsive drug delivery and theranostic applications
Authors: Ya Cui, Shebin Hong, Weidong Jiang, Xiaojing Li, Xingyu Zhou, Xiaoya He, Jiaqiang Liu, Kaili Lin, Lixia Mao
Journal: Bioactive Materials (2024)

Mesoporous bioactive glasses (MBGs), which belong to the category of modern porous nanomaterials, have garnered significant attention due to their impressive biological activities, appealing physicochemical properties, and desirable morphological features. They hold immense potential for utilization in diverse fields, including adsorption, separation, catalysis, bioengineering, and medicine. Despite possessing interior porous structures, excellent morphological characteristics, and superior biocompatibility, primitive MBGs face challenges related to weak encapsulation efficiency, drug loading, and mechanical strength when applied in biomedical fields. It is important to note that the advantageous attributes of MBGs can be effectively preserved by incorporating supramolecular assemblies, miscellaneous metal species, and their conjugates into the material surfaces or intrinsic mesoporous networks. The innovative advancements in these modified colloidal inorganic nanocarriers inspire researchers to explore novel applications, such as stimuli-responsive drug delivery, with exceptional in-vivo performances. In view of the above, we outline the fabrication process of calcium-silicon-phosphorus based MBGs, followed by discussions on their significant progress in various engineered strategies involving surface functionalization, nanostructures, and network modification. Furthermore, we emphasize the recent advancements in the textural and physicochemical properties of MBGs, along with their theranostic potentials in multiple cancerous and non-cancerous diseases. Lastly, we recapitulate compelling viewpoints, with specific considerations given from bench to bedside.
Tuft cells and fibroblasts promote thymus regeneration through ILC2-mediated type 2 immune response
Authors: Shir Nevo, Noga Frenkel, Noam Kadouri, Tom Gome, Noa Rosenthal, Tal Givony, Ayelet Avin, Cristina Peligero Cruz, Merav Kedmi, Moshit Lindzen, Shifra Ben Dor, Golda Damari, Ziv Porat, Rebecca Haffner-Krausz, Hadas Keren-Shaul, Yosef Yarden, Ariel Munitz, Dena Leshkowitz, Yael Goldfarb, Jakub Abramson
Journal: Science Immunology (2024)

The thymus is a primary lymphoid organ that is essential for the establishment of adaptive immunity through generation of immunocompetent T cells. In response to various stress signals, the thymus undergoes acute but reversible involution. However, the mechanisms governing its recovery are incompletely understood. Here, we used a dexamethasone-induced acute thymic involution mouse model to investigate how thymic hematopoietic cells (excluding T cells) contribute to thymic regeneration. scRNA-seq analysis revealed marked transcriptional and cellular changes in various thymic populations and highlighted thymus-resident innate lymphoid cells type 2 (ILC2) as a key cell type involved in the response to damage. We identified that ILC2 are activated by the alarmins IL-25 and IL-33 produced in response to tissue damage by thymic tuft cells and fibroblasts, respectively. Moreover, using mouse models deficient in either tuft cells and/or IL-33, we found that these alarmins are required for effective thymus regeneration after dexamethasone-induced damage. We also demonstrate that upon their damage-dependent activation, thymic ILC2 produce several effector molecules linked to tissue regeneration, such as amphiregulin and IL-13, which in turn promote thymic epithelial cell differentiation. Collectively, our study elucidates a previously undescribed role for thymic tuft cells and fibroblasts in thymus regeneration through activation of the type 2 immune response.
V H R Krishnan
Authors: Rajaneesh Vallepur, Rajesh Vallepur, Chandini Vallepur, Shalini Vallepur, Regi Alexander
Journal: BMJ (2024)

It is the ability and not the disability that matters."This was just one of V H R Krishnan's personal philosophies that he held close to his heart as a psychiatrist.A lifelong advocate for equality
Breast-conserving surgery is associated with a lower incidence of suicide among females with breast cancer in the United States: a population-based retrospective cohort study
Authors: Guiping Guo, Junteng Li, Yongqiang Zheng, Ze-Xian Liu, Huan Lin
Journal: International Journal of Surgery (2024)

Background: With comparable overall survival and local recurrence rates with mastectomy, breast-conserving surgery (BCS) has become the cornerstone of therapy for breast cancer; however, the difference in the incidence of suicide between BCS and mastectomy among breast cancer survivors remains unclear. This study evaluated the mortality risk from suicide among breast cancer survivors and compared suicide risk between BCS and mastectomy using a population-based cohort. Materials and methods: Female patients newly diagnosed with first primary breast cancer, recorded in the Surveillance, Epidemiology and End Results database, were included. Standardized mortality ratio (SMR) and cumulative mortality rate from suicide among those who underwent BCS and mastectomy were compared. Results: A total of 1 190 991 patients with newly diagnosed first primary breast cancer were included in the study, of whom 56.5% underwent BCS and 36.1% underwent mastectomy. During the follow-up period, 667 suicides were recorded. Patients who underwent mastectomy exhibited significantly higher suicide mortality than the general population [mortality rate, 8.16 per 100 000 person-years; SMR 1.18 (95% CI 1.05–1.33)], while there was no significant difference in suicide rate between patients who underwent BCS and the general population [SMR 0.92 (95% CI 0.83–1.02)]. Multivariate Cox analysis revealed that BCS, compared with mastectomy, was associated with a significantly decreased risk of suicide among females with breast cancer [hazard ratio 0.80 (95% CI 0.68–0.95); P = 0.009]. Conclusion: BCS was associated with a significantly lower incidence of suicide among females with breast cancer. BCS offers a compelling option for improving the quality of life and self-esteem of patients with cancer and provides a novel perspective on cancer management.
A radiogenomic multimodal and whole-transcriptome sequencing for preoperative prediction of axillary lymph node metastasis and drug therapeutic response in breast cancer: a retrospective, machine learning and international multicohort study
Authors: Jianguo Lai, Zijun Chen, Jie Liu, Chao Zhu, Haoxuan Huang, Ying Yi, Gengxi Cai, Ning Liao
Journal: International Journal of Surgery (2024)

Background: Axillary lymph nodes (ALN) status serves as a crucial prognostic indicator in breast cancer (BC). The aim of this study was to construct a radiogenomic multimodal model, based on machine learning and whole-transcriptome sequencing (WTS), to accurately evaluate the risk of ALN metastasis (ALNM), drug therapeutic response and avoid unnecessary axillary surgery in BC patients. Methods: In this study, conducted a retrospective analysis of 1078 BC patients from The Cancer Genome Atlas (TCGA), The Cancer Imaging Archive (TCIA), and Foshan cohort. These patients were divided into the TCIA cohort ( N =103), TCIA validation cohort ( N =51), Duke cohort ( N =138), Foshan cohort ( N =106), and TCGA cohort ( N =680). Radiological features were extracted from BC radiological images and differentially expressed gene expression was calibrated using technology. A support vector machine model was employed to screen radiological and genetic features, and a multimodal model was established based on radiogenomic and clinical pathological features to predict ALNM. The accuracy of the model predictions was assessed using the area under the curve (AUC) and the clinical benefit was measured using decision curve analysis. Risk stratification analysis of BC patients was performed by gene set enrichment analysis, differential comparison of immune checkpoint gene expression, and drug sensitivity testing. Results: For the prediction of ALNM, rad-score was able to significantly differentiate between ALN- and ALN+ patients in both the Duke and Foshan cohorts ( P &lt;0.05). Similarly, the gene-score was able to significantly differentiate between ALN- and ALN+ patients in the TCGA cohort ( P &lt;0.05). The radiogenomic multimodal nomogram demonstrated satisfactory performance in the TCIA cohort (AUC 0.82, 95% CI: 0.74–0.91) and the TCIA validation cohort (AUC 0.77, 95% CI: 0.63–0.91). In the risk sub-stratification analysis, there were significant differences in gene pathway enrichment between high and low-risk groups ( P &lt;0.05). Additionally, different risk groups may exhibit varying treatment responses ( P &lt;0.05). Conclusion: Overall, the radiogenomic multimodal model employs multimodal data, including radiological images, genetic, and clinicopathological typing. The radiogenomic multimodal nomogram can precisely predict ALNM and drug therapeutic response in BC patients.
A bibliometric analysis of gastric cancer liver metastases: advances in mechanisms of occurrence and treatment options
Authors: Chenyuan Wang, Yuzhe Zhang, Ye Zhang, Baifeng Li
Journal: International Journal of Surgery (2024)

Gastric cancer (GC) is the fifth most commonly diagnosed cancer worldwide, and its poor prognosis is predominantly attributed to distant metastasis. The liver is the primary site of GC metastasis. However, there is no universally approved treatment regimen for liver metastasis in GC. The aim of this article is to review the current research status and trends of liver metastasis of GC worldwide.
Unveiling the impact of tertiary lymphoid structures on immunotherapeutic responses of clear cell renal cell carcinoma
Authors: Wenhao Xu, Jiahe Lu, Xi Tian, Shiqi Ye, Shiyin Wei, Jun Wang, Aihetaimujiang Anwaier, Yuanyuan Qu, Wangrui Liu, Kun Chang, Hailiang Zhang, Dingwei Ye
Journal: MedComm (2024)

Abstract Tertiary lymphoid structures (TLS) are organized aggregates of immune cells that form under pathological conditions. However, the predictive value of TLS in clear cell renal cell carcinoma (ccRCC) for immunotherapies remains unclear. We comprehensively assessed the implications for prognosis and immunological responses of the TLS spatial and maturation heterogeneity in 655 ccRCC patients. A higher proportion of early‐TLS was found in peritumoral TLS, while intratumoral TLS mainly comprised secondary follicle‐like TLS (SFL‐TLS), indicating markedly better survival. Notably, presence of TLS, especially intratumoral TLS and SFL‐TLS, significantly correlated with better survival and objective reflection rate for ccRCC patients receiving anti‐Programmed Cell Death Protein‐1 (PD‐1)/Programmed Cell Death‐Ligand‐1 (PD‐L1) immunotherapies. In peritumoral TLS cluster, primary follicle‐like TLS, the proportion of tumor‐associated macrophages, and Treg infiltration in the peritumoral regions increased prominently, suggesting an immunosuppressive tumor microenvironment. Interestingly, spatial transcriptome annotation and multispectral fluorescence showed that an abundance of mature plasma cells within mature TLS has the capacity to produce IgA and IgG, which demonstrate significantly higher objective response rates and a superior prognosis for ccRCC patients subjected to immunotherapy. In conclusion, this study revealed the implications of TLS spatial and maturation heterogeneity on the immunological status and clinical responses, allowing the improvement of precise immunotherapies of ccRCC.
Correction: Digital health application integrating wearable data and behavioral patterns improves metabolic health
Authors: Ashkan Dehghani Zahedani, Tracey McLaughlin, Arvind Veluvali, Nima Aghaeepour, Amir Hosseinian, Saransh Agarwal, Jingyi Ruan, Shital Tripathi, Mark Woodward, Noosheen Hashemi, Michael Snyder
Journal: npj Digital Medicine (2024)
Focus areas and methodological characteristics of North American-based health disparity research in sports medicine: a scoping review
Authors: Stephanie A Kliethermes, Irfan M Asif, Cheri Blauwet, Leslie Christensen, Nailah Coleman, Mark E Lavallee, James L Moeller, Shawn F Phillips, Ashwin Rao, Katherine H Rizzone, Sarah Sund, Jeffrey L Tanji, Yetsa A Tuakli-Wosornu, Cleo D Stafford
Journal: British Journal of Sports Medicine (2024)

Objective Health disparities are widely prevalent; however, little has been done to examine and address their causes and effects in sports and exercise medicine (SEM). We aimed to summarise the focus areas and methodology used for existing North American health disparity research in SEM and to identify gaps in the evidence base. Design Scoping review. Data sources Systematic literature search of PubMed, Scopus, SPORTDiscus, CINAHL Plus with Full Text, Web of Science Core Collection and Cochrane Central Register of Controlled Trials. Eligibility criteria Full-text, peer-reviewed manuscripts of primary research, conducted in North America; published in the year 2000 or after, in English; and focusing on organised sports were included. Results 103 articles met inclusion criteria. Articles were classified into five focus areas: access to and participation in sports (n=45), access to SEM care (n=28), health-related outcomes in SEM (n=24), provider representation in SEM (n=5) and methodology (n=1). Race/ethnicity (n=39), socioeconomic status (n=28) and sex (n=27) were the most studied potential causes of health disparities, whereas sexual orientation (n=5), location (rural/urban/suburban, n=5), education level (n=5), body composition (n=5), gender identity (n=4) and language (n=2) were the least studied. Most articles (n=74) were cross-sectional, conducted on youth (n=55) and originated in the USA (n=90). Conclusion Health disparity research relevant to SEM in North America is limited. The overall volume and breadth of research required to identify patterns in a heterogeneous sports landscape, which can then be used to inform positive change, need expansion. Intentional research focused on assessing the intersectionality, causes and consequences of health disparities in SEM is necessary.
HIV and immunotherapy: correspondence
Authors: Hinpetch Daungsupawong, Viroj Wiwanitkit
Journal: International Journal of Surgery (2024)

aPrivate Academic Consultant, Phonhong, Lao People's Democratic Republic ORCID: 0009-0002-5881-2709 bDepartment of Research Analytics, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences Saveetha University India There is no new dsta generated Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online ■ ■ *Corresponding author. Address: Private Academic Consultant, Phonhong, Lao People's Democratic Republic. E-mail address: [email protected] (H. Daungsupawong). This is an open access article distributed under the Creative Commons Attribution-ShareAlike License 4.0, which allows others to remix, tweak, and build upon the work, even for commercial purposes, as long as the author is credited and the new creations are licensed under the identical terms. http://creativecommons.org/licenses/by-sa/4.0/
Non-apoptotic FAS signaling controls mTOR activation and extrafollicular maturation in human B cells
Authors: Julian Staniek, Tomas Kalina, Geoffroy Andrieux, Melanie Boerries, Iga Janowska, Manuel Fuentes, Paula Díez, Marina Bakardjieva, Jitka Stancikova, Jan Raabe, Julika Neumann, Sabine Schwenk, Leonardo Arpesella, Jan Stuchly, Vladimir Benes, Rodrigo García Valiente, Jonatan Fernández García, Rita Carsetti, Eva Piano Mortari, Albert Catala, Oscar de la Calle, Georgios Sogkas, Bénédicte Neven, Frédéric Rieux-Laucat, Aude Magerus, Olaf Neth, Peter Olbrich, Reinhard E. Voll, Laia Alsina, Luis M. Allende, Luis I. Gonzalez-Granado, Chiara Böhler, Jens Thiel, Nils Venhoff, Raquel Lorenzetti, Klaus Warnatz, Susanne Unger, Maximilian Seidl, Dirk Mielenz, Pascal Schneider, Stephan Ehl, Anne Rensing-Ehl, Cristian Roberto Smulski, Marta Rizzi
Journal: Science Immunology (2024)

Defective FAS (CD95/Apo-1/TNFRSF6) signaling causes autoimmune lymphoproliferative syndrome (ALPS). Hypergammaglobulinemia is a common feature in ALPS with FAS mutations (ALPS-FAS), but paradoxically, fewer conventional memory cells differentiate from FAS-expressing germinal center (GC) B cells. Resistance to FAS-induced apoptosis does not explain this phenotype. We tested the hypothesis that defective non-apoptotic FAS signaling may contribute to impaired B cell differentiation in ALPS. We analyzed secondary lymphoid organs of patients with ALPS-FAS and found low numbers of memory B cells, fewer GC B cells, and an expanded extrafollicular (EF) B cell response. Enhanced mTOR activity has been shown to favor EF versus GC fate decision, and we found enhanced PI3K/mTOR and BCR signaling in ALPS-FAS splenic B cells. Modeling initial T-dependent B cell activation with CD40L in vitro, we showed that FAS competent cells with transient FAS ligation showed specifically decreased mTOR axis activation without apoptosis. Mechanistically, transient FAS engagement with involvement of caspase-8 induced nuclear exclusion of PTEN, leading to mTOR inhibition. In addition, FASL-dependent PTEN nuclear exclusion and mTOR modulation were defective in patients with ALPS-FAS. In the early phase of activation, FAS stimulation promoted expression of genes related to GC initiation at the expense of processes related to the EF response. Hence, our data suggest that non-apoptotic FAS signaling acts as molecular switch between EF versus GC fate decisions via regulation of the mTOR axis and transcription. The defect of this modulatory circuit may explain the observed hypergammaglobulinemia and low memory B cell numbers in ALPS.
Global, regional, and national burdens of early onset pancreatic cancer in adolescents and adults aged 15–49 years from 1990 to 2019 based on the Global Burden of Disease Study 2019: a cross-sectional study
Authors: Zheng Li, Xiaojie Zhang, Chongyuan Sun, Zefeng Li, He Fei, Dongbing Zhao
Journal: International Journal of Surgery (2024)

Background: Early-onset pancreatic cancer (EOPC) in younger populations (age ≤50 years) is likely to be a more aggressive phenotype characterized by poor differentiation. The emerging analysis of the global burden of EOPC is limited and outdated. Aim: To systematically investigate the burden and trend of EOPC based on global populations. Methods: In this systematic analysis based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, the authors present the number of cases, age-standardized rates (ASRs) per 100 000 population, and risk factors for 204 countries and territories. The average annual percentage changes (AAPCs) for the incidence, mortality, and disability-adjusted life-years (DALYs) of EOPC were calculated using joinpoint regression analysis. Results: According to the GBD 2019 estimates, there were 36 852 new cases of EOPC and 32 004 related deaths. East Asia had the highest number of cases, with 11 401 incidences and 10 149 deaths. The ASRs were 0.94 per 100 000 individuals for incidence and 0.81 per 100 000 for mortality. From 1990 to 2019, the age-standardized incidence increased by 46.9%, mortality increased by 44.6%, and DALYs increased by 41.9% globally. In trend analysis, the global incidence (AAPC, 1.26), mortality (AAPC, 1.24), and DALYs (AAPC, 1.25) of EOPC showed an increasing pattern. The ASRs of incidence, mortality, and DALYs of EOPC in Africa, America, and Asia exhibited a continuous upward trend, while the trend in Europe was fluctuating. Asian males exhibited the fastest growth in incidence (AAPC, 2.15) and mortality (AAPC, 2.13), whereas males in the Americas experienced the slowest increase in new cases (AAPC, 0.72) and deaths (AAPC, 0.67). A certain proportion of EOPC DALYs were attributable to known risk factors: tobacco smoking (13.3%), high BMI, 5.6%, and high fasting plasma glucose 3.2%. Integrating the socio-demographic index (SDI), ASRs of incidence and mortality initially increased with rising SDI, reaching a peak in central Europe (1.5 per 100 000 &lt;ASRs &lt;2.0 per 100 000), and decreased with further increase in SDI in 2019. Conclusions: The findings offer valuable insights into the global distribution and magnitude of the EOPC burden. The burden is increasing at a rapid pace worldwide, particularly in Asia, and is notably high in central and eastern Europe. This highlights the need for additional preventive control efforts targeting high-risk populations.
Advances in BRAF-targeted therapies for non-small cell lung cancer: the promise of encorafenib and binimetinib
Authors: Areeba Fareed, Nabiha Amir, Humna Ajaz, Afra Sohail, Rayyan Vaid, Solay Farhat
Journal: International Journal of Surgery (2024)

Fareed, Areeba; Amir, Nabiha; Ajaz, Humna; Sohail, Afra; Vaid, Rayyan; Farhat, Solay MD Author Information