Citations

Ultrafast oscillations (UFOs) are brief bursts of high-frequency (2–8 kHz) activity recorded using depth electrodes in epileptic brain tissue. While reliably detected at small scales using microelectrodes, UFOs have thus far likely not been observed at larger scales using macroelectrodes. Here we show that faint echoes of these bursting patterns can be detected in macroelectrode signals using a model of cross-scale propagation. To model this cross-scale effect, we extend the classical damped wave equation to include an explicit scale coordinate governed by the dilation operator. We then use Green's functions to obtain an expression for the spectral echo expected at the macroelectrode scale. This echo takes the form of a carrier envelope modulated by the temporal structure of the original microscale bursting event. We test the predicted signature echo pattern in human intracranial recordings from eleven epilepsy patients implanted with both micro- and macroelectrodes. Statistically significant echoes are confirmed in two out of eleven patients, appearing in 2% of all tested micro-macro pairs.

Background: Noninvasive tests are well validated in metabolic dysfunction–associated steatotic liver disease, but evidence in metabolic dysfunction and alcohol-associated liver disease (MetALD) and alcohol-associated liver disease (ALD) is limited. We evaluated noninvasive test–based clinical care pathways for fibrosis risk stratification in MetALD and ALD. Methods: This is a multinational, multicenter, cross-sectional study across 35 centers in 16 countries (2013–2025), including adults with MetALD or ALD. Fibrosis was assessed by liver biopsy and/or vibration-controlled transient elastography (VCTE). In biopsy-proven participants, we analyzed the sequential pathway (Fibrosis-4 [FIB-4] first, followed by VCTE for indeterminate FIB-4) to identify advanced fibrosis (≥F3). Diagnostic accuracy was assessed using the AUC. Results: Among 893 participants (41.3% MetALD and 58.7% ALD), the median age was 52 [43.0–61.0] years, and 79.4% were male. The estimated prevalence of advanced fibrosis was 45% (32.2% in MetALD and 54.0% in ALD). Participants with MetALD had a more dysmetabolic profile but lower fibrosis stages than ALD. Among biopsy-proven participants, FIB-4 AUC was 0.720, and VCTE AUC was 0.833. FIB-4 performed better in MetALD than ALD (AUC 0.773 vs. 0.540), while VCTE accuracy was similar across groups. In the sequential pathways, the false-negative rate for advanced fibrosis (misclassified as low risk) was 6.8% (4.9% MetALD and 11.3% ALD). Conclusions: In biopsy-proven patients, FIB-4 performance was acceptable in MetALD but substantially weaker in ALD. The standard 2-step pathway performed adequately in MetALD but missed a clinically meaningful proportion of advanced fibrosis in ALD.

Patients in the liso-cel plus ibrutinib cohort of the phase 1/2, open-label TRANSCEND CLL 004 study had relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and received liso-cel (50×106 [dose level (DL)1] or 100×106 [DL2] chimeric antigen receptor-positive T cells) with concurrent ibrutinib from enrollment through 90 days after liso-cel infusion or longer per investigator discretion. Primary end point was complete response/remission (CR)/CR with incomplete marrow recovery (CRi) by investigator assessment. Among 56 patients who received ibrutinib plus liso-cel (DL1, n=5; DL2, n=51), median (range) age was 64.5 years (44‒77), 98% had high-risk cytogenetics, 55% had progression on Bruton tyrosine kinase inhibitor and venetoclax failure, and median (range) number of prior therapies was 5 (1‒13). Median (range) follow-up was 24.8 months (3.1‒51.8). At DL2, CR/CRi rate was 45% (95% confidence interval [CI], 31‒60) and overall response rate was 86% (95% CI, 74‒94). Median (95% CI) duration of response was not reached (NR; 28.7‒NR) for patients with CR/CRi and 41.4 months (23.3‒NR) for all responders. Median (95% CI) progression-free survival was 31.4 months (20.1‒NR). In DL1+DL2, most common grade ≥3 treatment-emergent adverse events (TEAE) were neutropenia (52%) and anemia (41%). Cytokine release syndrome was reported in 80% of patients (grade 3, 4%; no grade 4/5), and neurological events in 41% (grade 3/4, 11%; no grade 5). Ibrutinib-related TEAEs were reported in 68% of patients (grade 3/4, 43%; no grade 5). Liso-cel plus ibrutinib demonstrated notable efficacy in patients with relapsed/refractory CLL/SLL with predictable and manageable safety. Clinicaltrials.gov: NCT03331198; NCT03435796.

➢ Periprosthetic joint infection (PJI) remains the most common cause of failure after total joint arthroplasty, with current standard therapies associated with failure rates between 10% and 30%. ➢ The 2025 International Consensus Meeting in Istanbul, Türkiye, highlighted the potential benefits of bacteriophage (phage) therapy in managing PJI. ➢ One of the barriers to integrating phage therapy into standard clinical PJI care is the knowledge gap between preclinical research and clinical practice. ➢ This Expert Review summarizes the key therapeutic advantages of using phages as an adjuvant therapeutic platform for PJI. It also highlights the current challenges that are continuing to limit the integration of phages into standard PJI care.

Abstract Introduction Immunotherapy has achieved remarkable success in hematologic malignancies, but its efficacy in solid tumors remains limited due to tumor heterogeneity, immune suppression within the tumor microenvironment, and inefficient T cell infiltration. I hypothesize that enhancing tumor cell sensitivity to cytokine-mediated killing can potentiate paracrine killing, in which T cell—derived cytokines induce tumor cell death even without direct cell—cell contact. This mechanism can overcome antigen heterogeneity and limited T cell penetration, broadening the therapeutic reach of immunotherapy. Methods I propose targeting ADAR1, an RNA-editing enzyme that suppresses innate immune activation, to enhance paracrine killing. Loss of ADAR1 leads to dsRNA accumulation and activation of PKR, MDA5, and RIG-I, sensitizing tumor cells to T cell—derived cytokines such as IFNγ and TNF. To test this, I performed in vitro paracrine killing co-culture assays using T cells from healthy donor PBMCs, antigen-positive tumor targets, and GFP-labeled antigen-negative ADAR1KO tumor targets. GFP signal loss in ADAR1KO cells will indicate enhanced paracrine killing independent of antigen recognition. Results My data show that ADAR1 inhibition sensitizes tumor cells to cytokine-mediated cytotoxicity, though how dsRNA sensor and cytokine receptor signaling intersect remains unclear. Supernatant from antigen-positive T cell—tumor co-cultures induced cell death in ADAR1KO but not WT tumor targets, indicating selective cytokine sensitivity. Consistently, Western blot analysis revealed increased cleaved Caspase-3 and PARP in ADAR1KO cells. The paracrine killing assay is ongoing. Conclusion This study aims to elucidate the interplay between dsRNA sensing and cytokine signaling in the absence of ADAR1 and to define how this crosstalk shapes the efficacy of paracrine killing in solid tumors. These insights could inform new therapeutic strategies to enhance the potency of immunotherapy against resistant and heterogeneous solid tumors. Funding Source n/a Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Abstract Introduction Alzheimer’s disease (AD) is characterized by pathologies including amyloid, tau, neurodegeneration reflected in established blood biomarkers and track with clinical changes. However, the association between peripheral cell-specific signatures and AD-related phenotypes remain poorly characterized. Methods We analyzed bulk blood transcriptome data from the Mayo Clinic Study of Aging (MCSA) and Emory University Vascular study. We used BayesPrism, CIBERSORTx, and an in-house pipeline CNNreg to deconvolute these data and obtain peripheral cell proportions. Cell type specific transcripts were estimated with BayesPrism. We compared cell proportions between cases (AD/MCI) and controls. Association analysis was performed between cell type specific transcripts and AD-related phenotypes including diagnosis and cognition. Meta-analysis of transcripts associations and gene ontology analysis were conducted to assess the enriched pathways for significant genes. Results In MCSA, B and CD4+ T cells proportions are significantly lower while that of myeloid cells higher in cases. The Emory cohort had similar trends. We identified transcripts associated with AD-related phenotypes in CD4+ T and CD8+ T cells. In CD4+ T cells, transcripts downregulated in case are enriched in response to stimulus pathway, whereas those upregulated in negative regulation of immune response. Downregulation of CD4+ T genes enriched in extracellular matrix disassembly and epigenetic regulation and upregulation of those in protein localization associate with better cognition. In CD8+T cells, genes pertinent to vascular development were downregulated while those to metabolic processes were upregulated in cases. Downregulation of CD8+T genes involved in lipid transportation and upregulation of those in mitochondria associate with better cognition. Conclusion We identified peripheral cellular transcriptional changes associated with AD/MCI phenotypes and involved in important biological pathways, revealing potential disease mechanisms in AD. Funding Source RF1 AG051504 Topic Categories Neuroimmunology (NEUR)

Abstract Introduction Primary sclerosing cholangitis (PSC) is an immune-mediated chronic fibrotic liver disease with no effective medical therapies. We showed that bile duct epithelial cells, called cholangiocytes, express IL-17C, a cytokine that modulates immune responses. Mucosal-associated invariant T cells (MAITs) have been implicated in fibrosis, but their mechanistic role in PSC remains unknown. SPARC (secreted protein acidic and rich in cysteine) is an extracellular matrix protein whose role in hepatic fibrosis is unexplored. Methods Flow cytometry, RNAscope, ELISA, RNA sequencing, immunofluorescence, immunocytochemistry, spheroid culture. Results Flow cytometry of bile duct brushings from PSC patients (n = 8) revealed that 41.32% of T cells were MAITs, indicating their proximity to cholangiocytes within the epithelial-immune niche. MAITs co-cultured with PSC patients-derived cholangiocytes showed increased activation than with normal human cholangiocytes (p = 0.018, n = 4). RNAscope on human livers identified increased IL17C expression in PSC cholangiocytes compared to controls (p = 0.064, n = 3), and IL-17C levels were elevated in PSC bile (p = 0.035, n = 25). Surprisingly, the receptor of IL-17C is enriched in MAITs in PSC (re-analysis of single cell-RNA seq, PMID: 33774059). Bulk RNA sequencing of IL-17C-treated peripheral blood MAITs revealed upregulation of T cell activation markers and pathways associated with hepatic fibrosis. Moreover, IL-17C-treated MAITs increased SPARC secretion (p = 0.025, n = 7), an effect attenuated by IL-17C blockade. Consistently, conditioned media from IL-17C—treated MAITs activated hepatic fibroblasts (HF), evidenced by increased PDGFRβ expression (p = 0.048, n = 6). SPARC directly promoted HF activation, marked by increased α-SMA (p = 0.039, n = 5). Co-culture of primary human HF, MAITs and cholangiocytes in the presence of IL-17C enhanced HF activation. Conclusion IL-17C drives MAITs toward a profibrogenic phenotype in PSC, promoting HF activation through SPARC. Funding Source C-SIG P30DK084567 Topic Categories Immune Mechanisms of Human Disease (HUM)

Abstract Introduction Cancer immunotherapy has transformed the treatment landscape by leveraging the immune system to eradicate malignant cells. Among immune effectors, CD8+ T cells play a pivotal role in tumor clearance through recognition and destruction of cancer cells. To effectively counter the rapid proliferation and continuous evolution of cancer, robust effector function of cytotoxic CD8+ T cells is essential. The expression of effector genes in CD8+ T cells is tightly regulated, ensuring that cytotoxic molecules are expressed only at appropriate times and in relevant contexts. We previously reported that upregulation of the gene NKG7 following immunotherapy is critical for clinical response and demonstrated that NKG7 expression is both necessary and sufficient for T cell cytotoxicity. However, the mechanisms governing NKG7 expression in CD8+ T cells remain poorly defined. Methods We performed a cytokine screen to identify potential drivers of NKG7 expression at both the transcriptional and protein levels in cell lines and healthy donor peripheral blood mononuclear cells (PBMC). We employed quantitative RT-PCR, flow cytometry, and Western blotting to determine and validate the expression level of NKG7 and relevant signal molecules. We validated the signal pathways identified in single cell RNAseq data analysis in PD-1 therapy-responsive CD8+ T cells. Results In PBMC derived CD8+ T cells, we found that IL-2 increases NKG7 mRNA levels, correlating with a dose dependent increase in NKG7 protein expression. IL-2—induced NKG7 expression is associated with elevated levels of T-bet, a transcription factor essential for effector T cell differentiation. Consistent with this, scRNA-seq analysis revealed enrichment of the IL-2 signaling pathway in CD8+ T cells responsive to anti—PD-1 therapy. Conclusion Our results suggest that NKG7 is upregulated by IL-2 and T-bet signaling. Due to the critical role of this signaling axis during effector CD8+ T cell differentiation, NKG7 expression may be determined during this phase. Funding Source n/a Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Abstract Introduction The ability of the adaptive immune system to have memory of previous pathogen encounters is the basis for vaccination as one of the most successful medical interventions. With increasing age, the ability to develop protective immunity after vaccination declines. Differentiation into T memory cells is at least in part determined during the early cell divisions after activation when cells undergo assymmetric cell division (ACD). Fate decisions depend on the uneven distribution of signaling molecules and transcription factors with accumulation of mTORC1 activity biasing for an effector and TCF1 for a memory state. We explored whether ACD of naïve CD4 T cells is impaired in older adults. Methods We used human primary cells from young and older adults. Human naive CD4 T cells were isolated and cultured in RPMI, 10% FBS and antibiotics on plates coated with anti-CD3 Ab, anti-CD28 Ab and huICAM1 for 3 days. We used transfection by electroporation to modify gene expression. Read out systems included confocal microscopy, flow cytometry and lysosome function assays. Results were compared by t-test with values of p < 0.05 considered significant. Results Naive CD4 T cell responses from older adults is characterized by increased activation of the AKT-mTORC1 pathway and reduced ACD of mTORC1 activity. Increased RICTOR expression resulting in increased mTORC2 activity in naive CD4 T cells from older individuals accounted for the activation of the AKT-mTORC1 pathway. AKT inhibition or silencing of RICTOR restores ACD of mTORC1 activity as well as of TCF1. Conversely, ACD was also improved through inducing WNT signaling by GSK3β inhibition irrespective of RICTOR expression. Conclusion Our data show that increased RICTOR expression in naïve T cells from older adults at least in part accounts for defective memory cell generation. Silencing of RICTOR or downstream AKT inhibition can enforce both mTORC1 ACD and TCF1 ACD suggesting that mTORC2 is a promising target to improve vaccine responses. Funding Source n/a Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)