Citations

Abstract The INFORM trial (NCT01670500) was a randomized, two-arm Phase II neoadjuvant study comparing the efficacy of a platinum-based regimen (cisplatin) versus an anthracycline (AC)-based regimen in participants with germline BRCA1/2 mutations and early-stage, HER2-negative breast cancer. MicroRNAs (miRNAs) are emerging as promising non-invasive biomarkers for disease detection and treatment monitoring. The initial aim of this study was to evaluate whether pretreatment plasma miRNA profiles were associated with treatment outcomes in the INFORM trial cohort. Pretreatment plasma samples from 97 INFORM participants (n=53 cisplatin and n=44 AC) were screened for 352 miRNAs commonly implicated in cancer using the qPCR-based ID3EALTM Cancer Panel. Twenty out of 53 participants achieved residual cancer burden (RCB) score of 0 or 1 with cisplatin and 20/44 with AC. Higher plasma miR-362-3p expression was associated with a favorable response to cisplatin (1.7-fold; p<0.01), but not to AC. MiR-362-3p expression in paired pretreatment tumor biopsies (n=79) did not significantly correlate with plasma expression and was not associated with RCB 0/1 (p>0.05). In TCGA, miR-362-3p expression was higher in breast tumors than in adjacent normal tissue, and higher in triple negative breast cancers (TNBCs) compared with hormone receptor-positive tumors (both FDR<0.001), independent of BRCA mutation or Single Base Substitution Signature 3 (SBS3) status. The miR-362-3p findings in INFORM did not replicate in a sister trial, TBCRC 030 (NCT01982448; 11 out of 46 cisplatin-treated patients achieved RCB 0/1, p=0.46). These results suggest that while miR-362-3p is unsuitable as a circulating biomarker for cisplatin response, it may play an important biological role in mediating cisplatin sensitivity in TNBCs, independent of BRCA1/2 mutations. Functional studies demonstrated that miR-362-3p is expressed and secreted by TNBC cell lines, operates as a tumor suppressor, and generally correlates with cisplatin sensitivity. Overexpression of miR-362-3p rendered MDA-MB-231 and CAL-51 cells cisplatin sensitive, while knockdown induced resistance in MDA-MB-436 cells. Ongoing studies are testing whether these effects translate in xenograft models. In silico and functional assays identified BCLAF1, a DNA damage response (DDR) regulator, as a direct target of miR-362-3p. Overexpression of miR-362-3p suppresses BCLAF1 mRNA and protein levels. Our findings demonstrate that miR-362-3p enhances cisplatin responsiveness by targeting BCLAF1. A miR-362-3p-based therapeutic may be useful as a co-agent to enhance tumor responses to platinum-based chemotherapy. Citation Format: Zhaoji Liu, Shizhong Ke, Xiaohui Li, Catherine Wu, Madison M. Uyemura, Brian R. Sardella, Erica S. Massicott, Lin Wang, Emily K. Aronson, Dimitra Karagkouni, Nikolas Kalavros, Ioannis S. Vlachos, Felipe Batalini, Cristina S. Bogsan, Jit Kong Cheong, Lihan Zhou, He Cheng, Phillip Munson, Erica L. Mayer, Judy E. Garber, Stuart J. Schnitt, Nadine M. Tung, Andrea L. Kasinski, Frank J. Slack, Gerburg M. Wulf, Yujing J. Heng. MiR-362-3p enhances platinum response in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7903.

Abstract Platinum-based chemotherapy remains a cornerstone of treatment for triple-negative breast cancer (TNBC), yet the molecular determinants governing platinum response remain poorly defined. By leveraging the randomized Phase II INFORM trial, which compared neoadjuvant cisplatin to anthracycline-based therapy in BRCA1/2 -mutant breast cancer—we identified miR-362-3p as a specific regulator of cisplatin sensitivity. Higher plasma miR-362-3p expression was exclusively associated with favorable clinical outcome in the cisplatin arm, with no association observed in the AC arm, decoupling platinum-specific vulnerability from general chemotherapy response. We used gain- and loss-of-function TNBC models to establish that miR-362-3p functions as a potent sensitizer to cisplatin in vitro and in vivo . Integrated TCGA analysis and experimental validation identified BCLAF1, a key regulator of DNA damage response, as a direct repression target of miR-362-3p. We uncovered a novel role for the miR-362-3p/ BCLAF1 axis in overcoming platinum resistance in TNBC.

Objective To quantitatively examine immune cell markers and spatial distribution in human diabetic kidney disease (DKD) to enhance understanding of the inflammatory landscape contributing to injury. Maladaptive inflammation is an underrecognized contributor to DKD pathogenesis and progression and remains undertreated. Patients and methods NanoString GeoMx™ Digital Spatial Profiling technology targeted antibodies labeled with unique oligonucleotide barcode in kidney biopsy [DKD (n=5), tubulointerstitial nephritis (TIN; n=4), and normal (n=2)] with regions of interest selection of compartments (glomeruli, tubules, interstitium). Inflammation-related proteins were analyzed with differential expression through linear mixed modeling. Results Compared to normal tissue, inflammatory cell surface protein markers were increased in DKD tubules and interstitium. Markers of T cells (CD4, CD44), macrophages (CD68; proinflammatory), and antigen-presenting cells (APCs; CD40 and CD11c) were increased across all DKD compartments (vs. normal). Macrophage (CD163; prorepair) marker was increased in DKD tubules and interstitium (vs. normal). Fewer differences were observed in glomeruli for normal vs. DKD or TIN vs. DKD groups. CD66b+ (granulocytes) cell marker was higher in DKD (vs. TIN). As expected, TIN had higher levels of T cell and macrophage markers in tubules and interstitium (vs. DKD). Interestingly, CD34, a hematopoietic stem cell and endothelial cell marker, was lower in DKD tubules and interstitium (vs. normal) but higher in DKD (vs. TIN). Conclusion NanoString GeoMx DSP technology may fulfil a role in enhancing the understanding the inflammatory landscape engaged in DKD pathogenesis as well as measuring response to therapy. Moreover, additional investigations of CD34 progenitor cell depletion in DKD may be warranted.

Abstract Introduction: T-PLL is a rare, aggressive leukemia with poor prognosis and limited therapies. Previous studies on T-PLL patients receiving an allogeneic stem cell transplant (alloSCT) are limited by small numbers with limited data on disease and transplant characteristics. Further, recent data from our large national cohort of patients demonstrated significant survival difference between TCL1A+ and TCL1A- T-PLL, and CD8+ T-PLL vs CD8- T-PLL. In this large multi-center series, utilizing comprehensive disease subtype and alloSCT clinical data, we evaluated prognostic and survival therapeutic outcomes in T-PLL patients that had an alloSCT with a particular focus on T-PLL disease subtypes. Methods: We retrospectively evaluated 572 diagnosed with T-PLL at 21 academic cancer centers throughout the USA between 2000-2023, of which we performed a further evaluation on the169 that proceeded with alloSCT. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier methods and Cox proportional hazard models. Results: Among n=169 alloSCT recipients with T-PLL, the median follow-up time was 20.9 months post-alloSCT (range: 0.2-182.9), the median age at transplant was 59 years (range: 35-77) and 52% were male. In evaluated patients (n=109), TCL1A was positive by cytogenetics or FISH in 69%. As our recent analysis demonstrated significant differences in survival among specific subtypes of T-PLL, we evaluated outcomes in patients with CD4+CD8- T-PLL (n=90, 53%), CD4-CD8+ (n=17, 10%) T-PLL, and CD4+CD8+ T-PLL (n=52, 31%). 53% (87/164) had known nodal involvement at diagnosis identified by PET or CT scan and 45% (43/96) of known patients had minimal residual disease (MRD) at the time of transplant [defined as <5% T-PLL in marrow by flow, or +cytogenetics (e.g. TCL1A)] prior to alloSCT. At the time of alloSCT, 136 (80%) patients were in CR and 23 (14%) patients were in PR. Forty-nine (30%) had a myeloablative (MAC)conditioning regimen and 114 (70%) had a reduced intensity chemotherapy (RIC) conditioning regimen. Eighty (49%) patients had TBI as part of their regimen. The most common regimens were fludarabine (flu)/melphalan based regimens (n=44; 26.0%), flu/cyclophosphamide (cy) based regimens (n=33; 19.5%), flu/busulfan based regimens (n=22; 13.0%), flu/total body irradiation (TBI) (n=8; 4.7%), and cy/TBI (n=4; 2.4%). Across the whole cohort, the median OS and PFS post-alloSCT was 32.6 months (95% CI: 21.0-41.9) and 20.8 months (95% CI: 14.4-30.5) months while the 1-year cumulative incidences (CI) of NRM and relapse were 17% and 20%, respectively. The incidences of grade II-IV acute GVHD and cGVHD were 19% and 23%. There was no difference between patients with myeloablative conditioning (MAC) (n=49, 29%) when compared to patients that received reduced intensity conditioning (RIC) (n=114, 67%) in OS (33.1 vs 29.2; p=0.68) and PFS (20.2 vs 20.8; p=0.97). Patients that were MRD+ (n=31) had worse OS (22.2 vs 48.6; p=0.1) and PFS (14.1 vs 32.5; p=0.04) and higher rates of relapse (1-year relapse 20% vs 8%; p=0.08) than patients that were MRD- (n=50). PFS was improved in those who received alloSCT though only trended towards significance due to low numbers (HR 0.76, p=0.09). In subtype analysis, TCL1A+ T-PLL had significantly worse outcomes compared to TCL1A negative T-PLL. TCL1A+ disease had significantly worse OS (21.6 vs 63.1; p=0.01) and PFS (12.4 vs 50.7; p=0.01) compared to TCL1A-. Additionally, in TCL1A+ disease CI of NRM (24% vs 3%; p=0.02) and relapse (25% vs 12%; p=0.86) was higher vs TCL1A- PLL. CD4+CD8-, CD4-CD8+, and CD4+CD8+ disease had no difference in survival via either OS (28.0 vs 34.4 vs 21.0; p=0.17) or PFS (29.4 vs 23.5 vs 13.6; p=0.09) as well as no difference 1-year CI of NRM ( 11.6 vs 23.5 vs 26.2; p=0.35) and relapse (18.5 vs 23.5 vs 20.0; p=0.67).Conclusions: AlloSCT significantly improved outcomes for patients with T-PLL compared to those who did not proceed to alloSCT and remains he only curative therapy for those with T-PLL. OS, PFS, and CI relapse were significantly worse for patients with TCL1A+ subtype of T-PLL, or those with MRD positivity or PR prior to alloSCT. Novel strategies to decrease relapse such as post-alloSCT maintenance therapy to improve outcomes are urgently needed in these patients.

Key Points Activin A is implicated in profibrotic and prosenescent kidney injury and correlates with kidney injury markers in animals and humans. Follistatin, through activin A antagonism, reduces senescence burden, macrophage infiltration, and proinflammatory pathway activation in murine diabetic kidney disease. Follistatin and other antagonists of activin A signaling pathways may be promising, novel therapeutics for diabetic kidney disease. Background Circulating activin A, an inflammatory mediator implicated in profibrotic kidney injury and cellular senescence-induced adipose tissue dysfunction, is increased in human diabetic kidney disease (DKD) and directly correlates with kidney dysfunction. We tested the hypothesis that activin A increases kidney injury, senescent cell abundance, and macrophage infiltration in DKD and antagonism through follistatin (FS) therapy diminishes these effects. Methods An accelerated nephropathy type 2 diabetes (db/db) mouse model was generated by implantation of angiotensin II-loaded osmotic minipumps resulting in increased albuminuria and glomerular and tubular injury. Kidney repair effects of FS (5 µ g intraperitoneal; two doses) were assessed through markers of kidney injury, fibrosis, inflammation, cellular senescence, and macrophage infiltration. In vitro studies examined antiactivin effects of FS on high glucose-exposed human monocytes, renal fibroblasts, and renal tubule epithelial cells. Results Activin A antagonism with FS reduced senescence (p19), proinflammatory (including senescence-associated secretory phenotype), and profibrotic markers including activin A. FS improved kidney morphology, restored podocyte markers (nephrin and Wilms tumor-1), and reduced kidney injury biomarkers, albuminuria and kidney fibrosis. FS decreased kidney macrophage and leukocyte infiltration and absent in melanoma 2 inflammasome activation. FS seemed to suppress inflammation through the toll-like receptor-4/NF kappa-light-chain-enhancer of activated B cells pathway in vivo further supported in human macrophages in vitro . In addition, FS reduced hyperglycemia-induced renal fibroblast activation and renal tubule epithelial cell senescence in vitro . Conclusions Activin A is a mediator of kidney injury through macrophage-associated inflammation in murine DKD. FS acts through senomorphic activities which inhibit profibrotic, proinflammatory, and prosenescence signaling by activin A. Hence, antiactivin targeting may aid in the development of a promising, novel therapeutic for DKD.

Introduction: Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (CNS), traditionally referred to as primary CNS lymphoma (PCNSL), is a rare type of primary large B-cell lymphoma of immune-privileged sites with significantly poorer prognosis than systemic DLBCL. Genetic profiles of PCNSL were widely studied, whereas the tumor microenvironment has not been well characterized. Patients and Methods: A series of molecular analyses were performed using DLBCL FFPE tissues collected by the International Lymphoma Consortium. First, multiplex fluorescent immunohistochemistry (mfIHC) using antibodies for CD20, PAX5, CD3, CD4, CD8, FOXP3, CD45RO, CD68, CD56, PD-1, PD-L1, PD-L2, and CTLA-4 was performed on PCNSL tissues from 121 immunocompetent patients and de novo systemic DLBCL tissues from 405 patients. Digital quantification results for 405 patients with EBV-negative systemic DLBCL or primary testicular (PT) DLBCL have been reported previously. The preliminary mfIHC results of PCNSL will be presented. Second, mfIHC for multiple B cell biomarkers, CD3, CD4, CD8, CD68, CD163, CD11c, and CD31 were performed for 10 PCNSL validation cases, 24 PT-DLBCL and 451 systemic DLBCL tissues (unpublished). Third, RNA samples were extracted and sequenced for the targeted 1408 cancer-associated genes, successfully in 142 PCNSL cases, including 102 cases evaluated by either of these two mfIHC panels and additional 40 PCNSL cases, Results: First, in the first large mfIHC cohort, PCNSLs compared with de novo systemic nodal or extranodal DLBCL had significantly higher mean/median CD56+ cell densities whereas lower T cell densities (consistent with the immune privilege), as well as lower CD45RO+, PD-1+, and FOXP3+ percentages in T cells whereas higher CD4¯CD8¯ double-negative percentages in T cells. Prognostic analysis in the PCNSL cohort showed that high CD56+ cell densities and high CD45RO+CD8+ T cell densities were associated with significantly poorer and better patient survival, respectively, which are opposite to their prognostic effects in systemic DLBCL as previously reported. Twelve patients had very high PD-L1 expression in B cells and significantly poorer survival in the PCNSL cohort. Second, as validation, the 10 PCNSL cases in the second mfIHC study showed significantly less T cells than systemic DLBCL and PT-DLBCL cases, and low CD8 T cell densities and having low percentage of CD8 T cells adjacent to tumor cells were associated with significantly poorer survival. Immunofluorescence landscapeand spatial analysisrevealed significant differences in immune privilege between PCNSL and PT-DLBCL. Third, gene expression profiling analysis by targeted RNA-seq identified 282 significantly differentially expressed genes between PCNSL and systemic DLBCL, referred to as the PCNSL signature. Unsupervised clustering analysis divided the PCNSL cohort into two clusters, which had no significant difference in MYD88 mutation frequencies analyzed at the mRNA level. Importantly, the cluster with higher expression of many neural glial genes in the PCNSL signature had significantly poorer survival, which remained significant in multivariate analysis adjusting for clinical factors and/or treatments, two PCNSL subcohorts (as training and validation cohorts), and methotrexate-treated patients. NCAM1 (Neural Cell Adhesion Molecule 1, encoding CD56) was among the upregulated PCNSL signature genes, explaining the poorer prognosis associated with higher CD56+ cell densities in PCNSL by the mfIHC analysis. Summary: Our studies represent the largest immunophenotypic and gene expression profiling studies currently in PCNSL, a rare type of primary DLBCL of immune-privileged sites. Multiplex immunofluorescence revealed the immune landscape in PCNSL in comparison with systemic and testicular DLBCL, and identified prognostic immune biomarkers. Targeted RNA-seq identified a PCNSL gene signature enriched with neuronal-glial genes and showing significant prognostic effect in PCNSL. These novel findings in the PCNSL microenvironment warrant further studies.

AbstractLiver fibrosis is a pathological process resulting from prolonged exposure to various injury factors. It is characterized by the abnormal proliferation and activation of hepatic stellate cells and excessive deposition of extracellular matrix. If left untreated, it can progress to cirrhosis, liver failure, and even liver cancer. There is currently no efficient and accurate clinical diagnostic method for early liver fibrosis. Therefore, there is an urgent need to address the challenge of accurate staging and early diagnosis of liver fibrosis in clinical practice. Recently, nanomaterials have demonstrated significant potential for enhancing the diagnosis of liver fibrosis. Nanomaterials possess the ability to precisely identify and target the microenvironment associated with liver fibrosis. By enhancing their enrichment in the target area, nanomaterials can improve imaging contrast of fibrosis lesions in the liver, thereby enabling accurate diagnosis of liver fibrosis. Accordingly, this review delves into the latest research and advancements concerning nanomaterials in liver fibrosis diagnosis.

Neutrophil accumulation is a key feature of ARDS, but their contribution to the pathogenesis is still uncertain. We investigated the effect of reducing neutrophils in a clinically relevant mouse model of pneumococcal pneumonia treated with antibiotics. When appropriate antibiotics were administered, neutrophil reduction with Ly6G antibody markedly attenuated lung injury and improved oxygenation. In the early phase of bacterial pneumonia, neutrophils contribute to the severity of lung injury, although they also participate in host defense.

Diabetic kidney disease (DKD) is the worldwide leader in end-stage kidney failure and has limited treatment options. Cellular senescence abundance and inflammation contribute to DKD pathogenesis. We previously demonstrated that activin A, an inflammatory mediator of pro-fibrotic kidney injury and cellular senescence, is increased in DKD and correlates with DKD injury and kidney function. We hypothesized that activin A contributes to DKD injury causing pro-fibrotic, pro-inflammatory, and cellular senescence effects in vitro, and that antagonism of activin A is achieved with follistatin. An in vitro model of DKD injury was applied with high-glucose (HG) and transforming growth factor-β (TGFβ) exposure for 24 hours in U-937-derived macrophages and renal epithelial (HK2) cells. Prior to exposure, U-937 cells were converted to M0 macrophages with phorbol myristate acetate (PMA). To examine the potential of reducing activin A release by DKD injured cells, follistatin, an activin A antagonist, was added to the media of cells at the time of injury for 24 hours. Additionally, an activin A neutralizing antibody was added to the collected supernatant of DKD injured cells. Activin A, senescence (p16), pro-fibrotic (collagen I), and pro-inflammatory (monocyte chemoattractant protein [MCP]-1, tumor necrosis factor [TNF]-alpha, interleukin [IL]-6) markers were measured through qPCR, ELISA (activin A), and immunofluorescence staining (activin A). DKD injury in renal epithelial cells increased protein expression of activin A, increased gene expression of activin A, p16, and collagen I, but did not significantly increase MCP-1 expression at 24 hour exposure (Figure 1). Furthermore, DKD injury led to increased activin A release in conditioned medium vs. control renal epithelial cells. Administration of follistatin reduced activin A release by renal epithelial cells. Application of neutralizing antibody reduced activin A levels in collected medium after cell injury. After DKD injury in U-937 derived macrophages, activin A gene expression was increased. Injured macrophages had increased gene expression of TNF-alpha and IL-6, demonstrating a pro-inflammatory phenotype. In conclusion, diabetic kidney injury increases activin A release, inflammation markers, and senescence markers in kidney cells and macrophages, therein contributing to downstream effects that further propagate disease. As shown, follistatin antagonism reduces activin A release by injured cells. Additional studies are needed to explore activin A as a promising therapeutic target and follistatin as a possible treatment in DKD. NIH 5TL1TR002380-07, AG076537, DK123492, DK109134. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.