tbuckley/cabot-search huggingface dataset:
The Significance Of Thiopurine Genetic Diversity In The Treatment Of Pediatric Acute Lymphoblastic Leukemia.
Authors: Arwa Abdulrahman Degnah, Haneen Hassan Sembawa, Ayat Abdullah, Rehab Alhejaili, Afnan Hamadah Alharbi, Yazeed Mansour Shawradiyyah, Turki Albarqi, Wafaa Adam Mohammed Fakhraldeen, Maram Abdullah, Saja Ebraheem Mawlawi, Afnan Abdulrahman Degnah, Hams Ali Almalki, Eatizaz Alotaibi, Amnah Saleh Basendwa, Nahid Kamal Eldin Babiker Abashar, Namarig Kamal Eldin Babiker Abashar, Rana Basabrin
Journal: American Journal of Hematology (2025)

Background: Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and 6-mercaptopurine (6-MP) is one of the significant drugs to cure ALL. However, 6-MP toxicity is individualized and influenced by genetic and environmental factors. Further study of genetic variants in Thiopurine Methyltransferase (TPMT) combined with environmental influence constitutes needed research about treatmentrelated toxicity. Purpose: The study examines how genetic variants of TPMT affect 6-MP doses required for ALL patients. Methodology: In this study, the control group consisted of 100 healthy children, while the patient group comprised 100 children with newly diagnosed ALL in the maintenance phase of their treatment. Thiopurine Methyltransferase (TPMT) gene to identify genetic variants. The level of drug toxicity was determined by Complete Blood Count (CBC), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), and serum creatinine before and 6 months after switching to 6-MP therapy. Results: The results show a significant decrease in hemoglobin (HB) and platelet count in patients before treatment and significant improvement after treatment. After treatment, AST and ALT levels were significantly increased, and the White Blood Cells (WBC) count decreased significantly. There were 13% heterozygous patients determined by TPMT genotyping. Conclusion: TPMT genotype before the treatment will help to determine high-risk patients, and accordingly, the dose of 6-MP could be diminished to reduce the risk of toxicity caused by 6-MP.
Improving mobility data for infectious disease research
Authors: Natalya Kostandova, Ronan Corgel, Shweta Bansal, Sophie Bérubé, Eimear Cleary, Chelsea Hansen, Matt D. T. Hitchings, Bernardo García-Carreras, Lauren Gardner, Moritz U. G. Kraemer, Shengjie Lai, Yao Li, Amanda C. Perofsky, Giulia Pullano, Jonathan M. Read, Gabriel Ribeiro dos Santos, Henrik Salje, Saki Takahashi, Cécile Viboud, Jasmine Wang, Derek A. T. Cummings, Amy Wesolowski
Journal: Nature Human Behaviour (2025)
General anaesthesia decreases the uniqueness of brain functional connectivity across individuals and species
Authors: Andrea I. Luppi, Daniel Golkowski, Andreas Ranft, Rudiger Ilg, Denis Jordan, Danilo Bzdok, Adrian M. Owen, Lorina Naci, Emmanuel A. Stamatakis, Enrico Amico, Bratislav Misic
Journal: Nature Human Behaviour (2025)

Abstract The human brain is characterized by idiosyncratic patterns of spontaneous thought, rendering each brain uniquely identifiable from its neural activity. However, deep general anaesthesia suppresses subjective experience. Does it also suppress what makes each brain unique? Here we used functional MRI scans acquired under the effects of the general anaesthetics sevoflurane and propofol to determine whether anaesthetic-induced unconsciousness diminishes the uniqueness of the human brain, both with respect to the brains of other individuals and the brains of another species. Using functional connectivity, we report that under anaesthesia individual brains become less self-similar and less distinguishable from each other. Loss of distinctiveness is highly organized: it co-localizes with the archetypal sensory–association axis, correlating with genetic and morphometric markers of phylogenetic differences between humans and other primates. This effect is more evident at greater anaesthetic depths, reproducible across sevoflurane and propofol and reversed upon recovery. Providing convergent evidence, we show that anaesthesia shifts the functional connectivity of the human brain closer to the functional connectivity of the macaque brain in a low-dimensional space. Finally, anaesthesia diminishes the match between spontaneous brain activity and cognitive brain patterns aggregated from the Neurosynth meta-analytic engine. Collectively, the present results reveal that anaesthetized human brains are not only less distinguishable from each other, but also less distinguishable from the brains of other primates, with specifically human-expanded regions being the most affected by anaesthesia.
Prodigiosin Loaded SN‐PB@PG NPs‐Based Multimodal Therapy for the Healing of Bacterial Infected Chronic Wounds
Authors: Zhou Wu, Li Chang, Changling Li, Pengxiang Xu, Liuying Liu, Aidi Tong, Yilong Li, Chunyi Tong, Bin Liu
Journal: Advanced Healthcare Materials (2025)

Abstract Healing of infected chronic wounds faces dual challenges: persistent inflammation and impaired angiogenesis. To address these, SN‐PB@PG nanocomplexes were prepared by hybridisation of nitroprusside (SNP) with Prussian blue (SN‐PB NPs) and loaded with prodigiosin (PG). Under near‐infrared (NIR) irradiation, SN‐PB NPs generated mild hyperthermia, facilitating the release of nitric oxide (NO) and PG to combat bacterial biofilms and multidrug‐resistant pathogens. The in vivo assay using diabetic infected wounds demonstrated that SN‐PB@PG NPs with NIR reduced the wound area to 10.6% by the 11th day, which is superior to that of control group (29.6%). In the flap transplantation experiments, the data showed SN‐PB@PG NPs with NIR group only have a necrobiosis of 3.8% of flaps on the 8th day, which is superior to 31.3% of the control group. Additionally, the release of NO promoted vascular regeneration by up‐regulating vascular endothelial growth factor (VEGF) and platelet endothelial cell adhesion molecule‐1 (CD31), and regenerated sarcomeric tissue by down‐regulating MMP‐9. The results indicated that the combination of SN‐PB@PG NPs with gas and photothermal therapy exerted a combined antibacterial and wound healing effect. Compared to traditional clinical methods such as surgical debridement and hyperbaric oxygen therapy, this new strategy efficiently addresses issues of infection and healing, which is convenient for clinical application.
Real-time genomic characterization of pediatric acute leukemia using adaptive sampling
Authors: Julie Geyer, Kofi B. Opoku, John Lin, Lori Ramkissoon, Charles Mullighan, Nickhill Bhakta, Thomas B. Alexander, Jeremy R. Wang
Journal: Leukemia (2025)

Abstract Effective treatment of pediatric acute leukemia is dependent on accurate genomic classification, typically derived from a combination of multiple time-consuming and costly techniques such as flow cytometry, fluorescence in situ hybridization (FISH), karyotype analysis, targeted PCR, and microarrays [1–3]. We investigated the feasibility of a comprehensive single-assay classification approach using long-read sequencing, with real-time genome target enrichment, to classify chromosomal abnormalities and structural variants characteristic of acute leukemia. We performed whole genome sequencing on DNA from diagnostic peripheral blood or bone marrow for 57 pediatric acute leukemia cases with diverse genomic subtypes. We demonstrated the characterization of known, clinically relevant karyotype abnormalities and structural variants concordant with standard-of-care clinical testing. Subtype-defining genomic alterations were identified in all cases following a maximum of 48 h of sequencing. In 18 cases, we performed real-time analysis— concurrent with sequencing—and identified the driving alteration in as little as 15 min (for karyotype) or up to 6 h (for complex structural variants). Whole genome nanopore sequencing with adaptive sampling has the potential to provide genomic classification of acute leukemia specimens with reduced cost and turnaround time compared to the current standard of care.
Correlation of progression-free survival and overall survival after treatment for relapsed Hodgkin lymphoma: individual patient data analysis of randomized German Hodgkin Study Group (GHSG) Trials
Authors: P. J. Bröckelmann, H. Müller, M. Fuchs, S. Gillessen, D. Eichenauer, S. Borchmann, A. S. Robertz, K. Behringer, J. Welters, J. Ferdinandus, B. Böll, H. Tharmaseelan, X. Yang, C. Kobe, H. -T. Eich, C. Baues, W. Klapper, P. Borchmann, B. von Tresckow
Journal: Leukemia (2025)
M1-macrophage membrane-camouflaged nanoframeworks activate multiple immunity via calcium overload and photo-sonosensitization
Authors: Yinjing Shen, Nuo Yu, Wenjing Zhao, Shining Niu, Pu Qiu, Haiyan Zeng, Zhigang Chen, Wei Men, Dong Xie
Journal: Biomaterials (2025)
Longitudinal paired liver biopsies and transcriptome profiling in alcohol-associated hepatitis reveal dynamic changes in cellular senescence
Authors: Daniel Rodrigo-Torres, Alastair M Kilpatrick, Sofia Ferreira-Gonzalez, Rhona E Aird, Stephen Rahul Atkinson, Victoria L Gadd, Tak Yung Man, Luke D Tyson, Gopal Krishna R Dhondalay, Nikhil Vergis, Gavin E Arteel, Mark R Thursz, Laura Martinez-Gili, Stuart J Forbes
Journal: Gut (2025)

Background and aims Alcohol-associated hepatitis (AH) is an acute form of alcohol-related liver disease (ALD) with high mortality rate. AH is histologically characterised by cellular processes, including steatosis, inflammation and cell death. Apoptosis is the most studied form of cell death in AH; however, the role of cellular senescence, another response to cellular injury, in AH is unknown. Here, we explore the mechanisms of ALD pathophysiology and describe the role of senescence in AH. Methods We performed RNA sequencing and bioinformatics analysis of 0- and 28-day transjugular liver biopsies (n=65) from patients with AH participating in the IL-1 Signal Inhibition In Alcoholic Hepatitis (ISAIAH) clinical trial. Additional bioinformatics reanalysis of existing AH transcriptomic datasets was conducted to confirm our findings. We also performed multiomic analysis of an in vitro model of AH with ethanol-treated hepatocytes overexpressing ethanol-metabolising enzymes. Results Our longitudinal analysis revealed that senescence and inflammation were reduced at transcriptomic level following AH resolution; the expression of hepatocyte markers was increased. We identified two senescence-associated protein complexes, cytochrome c oxidase and the proteasome, which may act as senescence-induction mechanisms. We confirmed that senescence markers and pathways were increasingly expressed in hepatocytes as ALD progressed towards AH; this was partially reversed following AH resolution. Our in vitro model revealed that ethanol directly induces senescence and was dependent on ethanol metabolism. Conclusions Our results suggest a possible pathogenic role for senescence in AH and indicate cellular senescence as a potential therapeutic target in early ALD to limit AH severity.
Association between asthma and type 2 diabetes in a Swedish adult population: a register-based cross-sectional study
Authors: Mwenya Mubanga, Tong Gong, Awad I Smew, Amanda Wikström, Emma Caffrey Osvald, Katarina Eeg-Olofsson, Christer Janson, Cecilia Lundholm, Catarina Almqvist
Journal: Thorax (2025)

Objective Asthma and type 2 diabetes are two important causes of morbidity globally. We examined both the association of type 2 diabetes with asthma in Swedish adults and the familial co-aggregation of the diseases. Methods We conducted a cross-sectional study of all adults aged 25–85 in Sweden between 2009 and 2013. Asthma and type 2 diabetes status were ascertained from the health registers. Models were adjusted for sex, age, education level, income and country of birth and in a subset, for body mass index (BMI). We further conducted a familial coaggregation analysis to determine if shared familial factors could explain any observed findings. Results The study included 5 299 245 participants, 25 292 (0.5%) had both asthma and type 2 diabetes. In the total population, the OR for the association between type 2 diabetes and asthma was 1.47 (95% CI 1.45 to 1.49); in the population of men (1.30 (95% CI 1.27 to 1.32)) and women (1.63 (95% CI 1.60 to 1.66)). The ORs were slightly higher among men (1.51 (95% CI 1.45 to 1.56)) and women (2.04 (95% CI 1.96 to 2.11)) for whom BMI measurements were available but attenuated with adjustment for BMI (1.45 (95% CI 1.40 to 1.51)) and (1.76 (95% CI 1.68 to 1.84)). Diabetes was more likely if a full sibling had asthma than if the sibling did not (1.13 (95% CI 1.10 to 1.15)). Conclusions We found an association between asthma and type 2 diabetes that was sustained after adjusting for BMI, indicating that BMI alone does not explain this relationship. We also found that the two conditions coaggregate in siblings, indicating that the association is partly due to shared familial genetic and environmental risk factors.
Microbial Ecosystem Therapeutics 4 (MET4) elicits treatment-specific IgG responses associated with changes in gut microbiota in immune checkpoint inhibitor recipients with advanced solid tumors
Authors: Matthew K Wong, Giselle M Boukhaled, Eric Armstrong, Rachel Liu, Alya A Heirali, Noelle R Yee, Jinny Tsang, Pavlina Spiliopoulou, Pierre H H Schneeberger, Ben X Wang, Kyla Cochrane, Keith Sherriff, Emma Allen-Vercoe, Lillian L Siu, Anna Spreafico, Bryan Coburn
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Gut microbiome modulation has shown promise in its potential to treat cancer in combination with immunotherapy. Mechanistically, the pathways and routes by which gut microbiota may influence systemic and antitumor immunity remain uncertain. Here, we used blood and stool samples from Microbial Ecosystem Therapeutic 4 (MET4)-IO, an early-phase trial testing the safety and engraftment of the MET4 bacterial consortium in immune checkpoint inhibitor recipients, to assess how MET4 may affect systemic immunity. Methods Circulating antibody responses induced by MET4 were assessed using an antimicrobial antibody flow cytometry assay on pretreatment and post-treatment plasma. Antibody responses were associated with taxonomic changes in stool identified by metagenomic sequencing. Mass cytometry was performed on peripheral blood mononuclear cells to identify shifts in circulating immune subsets associated with antibody responses. Results Increases in circulating anti-MET4 immunoglobulin G (IgG) responses were measured by flow cytometry post-consortium treatment in MET4 recipients, but not untreated control participants, with five individuals displaying notably higher antibody responses. Stronger IgG responses were associated with greater increases in multiple taxa, including MET4 microbe Collinsella aerofaciens , which was previously linked with immune checkpoint response. However, these taxa were not enriched in the IgG-bound fraction post-MET4 treatment. Greater increases in circulating B cells and FoxP3 + CD4 + T cells post-MET4 treatment were observed in the blood of high IgG responders, while CD14 + and CD16 + monocyte populations were decreased in these individuals. Conclusion These results demonstrate the induction of treatment-specific circulating humoral immunity by a bacterial consortium and suggest potential mechanisms by which gut microbes may contribute to antitumor immunity.
Depletion of tumor-derived CXCL5 improves T cell infiltration and anti-PD-1 therapy response in an obese model of pancreatic cancer
Authors: Richard McKinnon Walsh, Joseph Ambrose, Jarrid L Jack, Austin E Eades, Bailey A Bye, Mariana Tannus Ruckert, Fanuel Messaggio, Appolinaire A Olou, Prabhakar Chalise, Dong Pei, Michael N VanSaun
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background CXCR1/2 inhibitors are being implemented with immunotherapies in PDAC clinical trials. CXC-ligands are a family of cytokines responsible for stimulating these receptors; while typically secreted by activated immune cells, fibroblasts, and even adipocytes, they are also secreted by immune-evasive cancer cells. CXC-ligand release is known to occur in response to inflammatory stimuli. Adipose tissue is an endocrine organ and a source of inflammatory signaling peptides. Importantly, adipose-derived cytokines and chemokines are implicated as potential drivers of tumor cell immune evasion; cumulatively, these findings suggest that targeting CXC-ligands may be beneficial in the context of obesity. Methods RNA-sequencing of human PDAC cell lines was used to assess influences of adipose conditioned media on the cancer cell transcriptome. The adipose-induced secretome of PDAC cells was validated with ELISA for induction of CXCL5 secretion. Human tissue data from CPTAC was used to correlate IL-1β and TNF expression with both CXCL5 mRNA and protein levels. CRISPR-Cas9 was used to knockout CXCL5 from a murine PDAC KPC cell line to assess orthotopic tumor studies in syngeneic, diet-induced obese mice. Flow cytometry and immunohistochemistry were used to compare the immune profiles between tumors with or without CXCL5. Mice-bearing CXCL5 competent or deficient tumors were monitored for differential tumor size in response to anti-PD-1 immune checkpoint blockade therapy. Results Human adipose tissue conditioned media stimulates CXCL5 secretion from PDAC cells via either IL-1β or TNF; neutralization of both is required to significantly block the release of CXCL5 from tumor cells. Ablation of CXCL5 from tumors promoted an enriched immune phenotype with an unanticipatedly increased number of exhausted CD8 T cells. Application of anti-PD-1 treatment to control tumors failed to alter tumor growth, yet treatment of CXCL5-deficient tumors showed response by significantly diminished tumor mass. Conclusions In summary, our findings show that both TNF and IL-1β can stimulate CXCL5 release from PDAC cells in vitro, which correlates with expression in patient data. CXCL5 depletion in vivo alone is sufficient to promote T cell infiltration into tumors, increasing efficacy and requiring checkpoint blockade inhibition to alleviate tumor burden.
Inhibition of stromal MAOA leading activation of WNT5A enhance prostate cancer immunotherapy by involving the transition of cancer-associated fibroblasts
Authors: Zhite Zhao, Yaohua Hu, Hui Li, Tong Lu, Xinglin He, Yifan Ma, Minli Huang, Mengyao Li, Lijun Yang, Changhong Shi
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background The interaction between stromal cells and the tumor immune microenvironment (TIME) is acknowledged as a critical driver in the progression of prostate cancer (PCa). Monoamine oxidase A (MAOA), a mitochondrial enzyme that catalyzes the degradation of monoamine neurotransmitters and dietary amines, has been linked to the promotion of prostate tumorigenesis, particularly when upregulated in stromal cells. However, the detailed mechanisms of MAOA’s interaction with TIME have not been fully elucidated. Methods We reanalyzed a single-cell sequencing dataset to evaluate the role of MAOA in the stroma, verify the impact of stromal MAOA alterations on CD8 + T cell responses by co-culturing stromal cells and immune cells in vitro. Furthermore, C57BL/6J mouse subcutaneous transplant tumor models and dual humanized mouse models were established to investigate the function of MAOA in vivo and the potential of its inhibitors for immunotherapy. Results Our study demonstrates that inhibiting MAOA in stromal cells facilitates the conversion of myofibroblastic cancer-associated fibroblasts (myCAFs), thereby improving the immunosuppressive environment of PCa. The strategic combination of MAOA inhibition with immune checkpoint inhibitors elicits a synergistic antitumor effect. Specifically, MAOA inhibition in stromal cells leads to increased production of WNT5A, which subsequently activates the cytotoxic capacity of CD8 + T cells through the Ca 2+ -NFATC1 signaling pathway. Conclusions Our findings highlight the critical role of MAOA in modulating cancer-associated fibroblasts within the PCa immune microenvironment, presenting a novel therapeutic strategy to augment the efficacy of immunotherapy for PCa.
PLS-α-GalCer: a novel targeted glycolipid therapy for solid tumors
Authors: Julian Burks, Shweta Tiwary, David M Stevens, Sarah L Skoczen, Ruvanthi N Kularatne, Stephan T Stern, Jay A Berzofsky
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background The prototypical type I natural killer T (NKT) cell agonist, α-galactosylceramide (α-GalCer), has shown only minimal effects against solid tumors in the clinic. The most promising clinical application of α-GalCer currently entails ex vivo priming of patient-derived dendritic cells; however, this technology suffers from cost, logistical concerns, and safety issues. As a parenteral dendritic cell-targeted alternative, we demonstrate that poly(L-lysine succinylated) (PLS)-α-GalCer, a novel scavenger receptor-A1 targeted α-GalCer prodrug has enhanced antitumor activity compared with α-GalCer. Methods To compare the antitumor activity of PLS-α-GalCer and α-GalCer, we used mouse syngeneic subcutaneous pancreatic and cervical tumor models using Panc02 and TC-1 cells, respectively. Intratumoral immune cell infiltration was evaluated using flow cytometry and immunohistochemistry whole-slide scan analysis. Serum cytokine levels were examined by ELISA and LEGENDplex analysis. Type I NKT cell intracellular interferon-gamma (IFN-γ) levels were determined by flow cytometry. Immunofluorescence was used to test the uptake and processing of PLS-α-GalCer and α-GalCer in antigen-presenting cells (APCs). Results The scavenger receptor A1 (SR-A1)-mediated targeting of α-GalCer to APCs by PLS-α-GalCer significantly improves the antitumor function against solid tumors compared with α-GalCer. The Panc02 and TC-1 tumor models demonstrated that PLS-α-GalCer increases intratumoral antigen-specific T, NKT and T cells, and increases the M1/M2 macrophage ratio. In the TC-1 tumor model, we demonstrated that PLS-α-GalCer synergizes with an E7 tumor vaccine to significantly suppress tumor growth and increase the survival of mice. Furthermore, the antitumor function of PLS-α-GalCer is dependent on type I NKT cells and requires SR-A1 targeting. In addition, using SR-A1 knockout RAW cells, a murine macrophage cell line, we showed that PLS-α-GalCer uptake and processing in APCs are more efficient compared with α-GalCer. PLS-α-GalCer also induces significantly less serum Th2 and Th17 cytokines while stimulating significantly more IFN-γ for a longer period and increases Th1:Th2 cytokine ratios compared with α-GalCer. Conclusions PLS-α-GalCer is a promising immunotherapy for the treatment of solid tumors that has superior antitumor activity compared with α-GalCer and could be combined with tumor vaccines and potentially other immunotherapies such as immune checkpoint inhibitors.