Citations

Abstract Invasive lobular breast carcinoma (ILC) is the most common special histological subtype of breast cancer, which accounts for 10-15% of all cases. To study the phenotype characteristics, metastatic growth kinetic and immune microenvironment of ILC, we developed an orthotopically transplantable cell line model from the spontaneous mammary fat pad tumor of CDH1-PTEN dual knockout C57BL/6 mouse with Cre-loxP system, designated CPT6. CPT6 recapitulates single-file growth pattern of human ILC, with pleomorphic features and a high mitotic index. RNA sequencing together with whole exome sequencing reveals a luminal A subtype with targetable driver mutations such as Kras G12C. As a novel orthotopically transplantable ILC model in immune competent mice, CPT6 shows robust in vivo growth and metastatic rate, and has moderate immunogenicity which appears to be T-cell independent. We also profiled the immune microenvironment of CPT6, revealing a myeloid-rich environment with dominant M2-macrophage population, which is concordant with human ILC. In summary, this model recapitulates human ILC phenotype and represents a valuable preclinical platform for evaluating immunotherapy and other therapeutic strategies for invasive lobular breast carcinoma.

TRAIL is a TNF family ligand that trimerizes TRAIL-R1 (DR4) or TRAIL-R2 (DR5) to induce apoptosis, necroptosis, and/or NF-κB activation in receptor-bearing cells. We previously identified TRAILshort as a splice variant of TRAIL that lacks cysteine 230, cannot trimerize, and acts as a dominant-negative ligand that blocks TRAIL-mediated apoptosis. TRAILshort is expressed on cell surfaces and within extracellular vesicles, enabling it to confer TRAIL resistance to both producing and bystander cells. In this study, we showed that elevated TRAILshort levels were associated with chronic viral infections, cancer, and autoimmune diseases, suggesting a link to impaired immune regulation. Using unbiased phosphoproteomics and mechanistic studies, we demonstrated that TRAILshort binding to DR5 recruited and activated the phosphatase Src homology region 2 domain–containing phosphatase 1 (SHP-1), leading to zeta-chain-associated protein kinase 70 (ZAP-70) dephosphorylation, disruption of ZAP-70–CD3ζ interactions, and impaired T cell receptor signaling, thereby reducing T cell activation, proliferation, and cytokine production in response to antigen or CD3/CD28 ligation. Genetic or pharmacologic SHP-1 inhibition reverses these effects. In humanized mouse models, TRAILshort promoted the persistence of transformed mouse embryonic fibroblasts (MEFs) and L428 and antagonized CD19-directed CAR T cell activity, revealing TRAILshort as an immunomodulator of T cell function with therapeutic implications, including blocking TRAILshort to restore T cell immunity or delivering TRAILshort to enforce tolerance. TRAILshort, a variant of TRAIL, suppresses T cell function and immune responses in cancer and infectious diseases, highlighting its potential as a therapeutic target.

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is commonly encountered in older individuals. MGUS, by definition, is a benign finding where an expanded population of clonal plasma and B-cells produces a monoclonal antibody that is a biologically inactive. Even in patients with overt plasma cell neoplasms such as multiple myeloma, the monoclonal antibody is often a marker of disease burden but not pathogenic except in light chain cast nephropathy. However, there is a growing recognition that, in rare cases, clonal cells and/or monoclonal gammopathy not meeting criteria for hematologic malignancy can be pathogenic drivers of disease. These MGUS syndromes have been termed monoclonal gammopathies of clinical significance (MGCS), a larger umbrella under which sits the monoclonal gammopathies of renal significance (MGRS). In this review, we focus on MGCS entities beyond standard MGRS and provide a mechanism-based classification centered on the pathogenic nature of the paraprotein rather than on clonal disease burden. We highlight MGCS entities of relevance to nephrologists, including POEMS syndrome, TEMPI syndrome, monoclonal gammopathy-associated systemic capillary leak syndrome, and hematologic autoantibody-mediated disorders. Awareness and recognition of these rare processes are ultimately essential for accurate diagnosis and patient management.

Objective: To evaluate factors associated with the conversion of robotic-assisted partial nephrectomy (RAPN) to open partial nephrectomy (OPN) and radical nephrectomy (RN). Methods: We retrospectively reviewed 775 consecutive RAPNs from a single surgeon. Perioperative factors were evaluated for association with RAPN conversion such as Mayo Adhesive Probability (MAP) score, length of stay (LOS), and operative time (OT). A logistic regression model was utilized to evaluate factors associated with conversion and reported as odds ratio (OR) with 95% confidence intervals. Continuous and categorical variables were analyzed through the Wilcoxon rank-sum and chi-square tests. Results: Thirty-two (4.1%) patients had a conversion including 19 (2.5%) to OPN and 13 (1.7%) to RN. OPN conversions were related to bleeding ( n = 7), inability to dissect perinephric fat ( n = 4), liver retraction ( n = 1), and failure to secure renal hilum/progress ( n = 7). In contrast, conversions to RN were due to tumor involvement of the renal vein ( n = 3) or ureter ( n = 5) and inability to achieve negative margins ( n = 5). Patients in the conversion cohort were more likely to have larger tumor size (3.7 vs 2.8 cm; p < 0.001) and higher MAP score (3.0 vs 2.0; p = 0.04). Median LOS was higher in the conversion group (3.0 vs 2.0 days; p = 0.003). Conversions were associated with postoperative complications (28.1% vs 13.7%; p = 0.023). After adjusting tumor size in our regression model, longer OT and dissection time were statistically higher in the conversion group (OR = 2.19 [1.50–3.21]; p < 0.001 and OR = 2.67 [1.82–3.94]; p < 0.001, respectively). Conclusions: Larger tumor size and higher MAP score were associated with conversions during RAPN. Conversions were associated with higher LOS, longer OT, and postoperative complications.

Abstract Objective Anterior nucleus of the thalamus (ANT) deep brain stimulation (DBS) is an effective therapy for frontotemporal and limbic drug‐resistant focal epilepsies. The pulvinar nucleus (PUL) is an emerging neuromodulation target for seizure networks involving the posterior quadrant and temporal lobe. This study evaluates the safety and effectiveness of combined bilateral ANT plus PUL DBS for posterior quadrant and temporal lobe epilepsies. Methods We conducted a single‐center retrospective cohort study of patients receiving combined ANT/PUL DBS between 2021 and 2025. Outcomes included median seizure rate reduction (MSR), responder rate (RR; >50% seizure frequency reduction), and stimulation‐related side effects, assessed across ANT, PUL, and concurrent ANT/PUL stimulation settings. Acute surgical complications were evaluated. Statistical significance was assessed using two‐sided Wilcoxon signed‐rank tests with Holm–Bonferroni correction. Results Nine patients with combined ANT/PUL DBS were identified, and eight patients had sufficient follow‐up for inclusion (median follow‐up = 20 months). Posterior predominant structural abnormalities were present in eight of nine patients. There were no acute surgical complications. Three instances of transient stimulation‐related side effects resolved with parameter adjustments, whereas one patient required rescue antiseizure medication in addition to programming changes. Eight patients received periods of ANT stimulation, six PUL stimulation, and seven combined ANT/PUL stimulation. Regarding overall outcome, at last follow‐up, there was a significant 80.8% MSR ( p = .0078) and 87.5% RR, with two patients receiving ANT and six ANT/PUL stimulation. Regarding target‐specific MSR, concurrent ANT/PUL DBS (68.8% MSR) showed a trend toward superior performance relative to ANT (43.3%) and PUL DBS (17.5%) alone, although subgroup analysis of target‐specific performance did not reach statistical significance. Significance Combined four‐lead ANT/PUL DBS appears safe and effective for patients with drug‐resistant posterior quadrant and temporal lobe epilepsies. Dual‐network neuromodulation may provide greater flexibility to individually optimize neuromodulation for complex seizure networks.

ABSTRACT Background Long‐term health effects of thymectomy in adults remain uncertain. Previous reports suggested associations with increased mortality, cancer incidence, and autoimmune disease, although these findings may reflect differences in patient selection, surgical indication, or follow‐up duration. We aimed to examine long‐term outcomes following adult thymectomy. Methods We performed a propensity score‐matched retrospective study of patients who underwent thymectomy or comparator cardiothoracic procedures, with follow‐up extending to 10 years. Primary outcomes were all‐cause mortality, new‐onset malignancy, and autoimmune disease. Findings were compared with those reported in a recent study that has raised caution regarding thymic excision. Results We identified 425 patients who underwent thymectomy and 5401 controls who underwent coronary artery bypass or valve surgery. After matching, 398 patients remained in each group. Thymectomy was not associated with increased mortality at 5 years ( HR = 0.63; 95% CI , 0.38–1.04) or 10 years ( HR = 0.78; 95% CI , 0.54–1.13). Excluding reclassified thymic cancers, 5‐year extrathymic malignancy incidence was 2.3% versus 1.8% ( p = 0.54); no significant differences were observed in immune‐related disease. Mortality was higher among patients with thymic malignancy. Among MG patients, only one event occurred, precluding reliable estimation. Conclusions Thymectomy was not associated with excess mortality or malignancy at 10 years compared with matched cardiothoracic controls. Indication‐stratified analyses within the thymectomy cohort showed higher mortality for thymic malignancy, with insufficient events to assess outcomes in MG patients. These findings do not support a generalized survival penalty from thymectomy, though caution is warranted for incidental thymic removal.

Heart transplantation remains the definitive treatment for end-stage heart failure. Preservation of donor hearts is a critical determinant of graft function and post-transplant outcomes. Traditional static cold storage (SCS) has limitations in ischemia tolerance and functional assessment, particularly for marginal and donation after circulatory death (DCD) hearts. Emerging strategies, including normothermic ex vivo perfusion (NEHP) and hypothermic oxygenated perfusion (HOPE), enable extended preservation, functional evaluation, and improved utilization of high-risk donor organs. This review summarizes current preservation techniques, discusses mechanistic strategies to mitigate ischemia-reperfusion injury, highlights emerging trends and controversies, and identifies future research directions to optimize outcomes in heart transplantation.

Scientific evidence regarding AKI and acute kidney care has advanced in recent years. However, a knowledge gap remains on the implementation of these evidence-based practices (EBPs) into clinical care. Implementation science (IS) is focused on ensuring that this knowledge is translated in an effective, efficient and sustainable fashion. Objectives: 1) Define the current status of IS; 2) Define a roadmap for accelerating IS with a focus on patient/care partner advocacy, digital tool application, social determinants of health, and resource-limited settings; and 3) Develop a robust and broad research agenda incorporating IS methodology into the programs. Evidence Review: ADQI XXXV was conducted through a modified Delphi process with virtual meetings preceding an in-person meeting. Five workgroups were determined a priori to focus on 1) IS definitions and methods applicable to AKI and acute kidney care; 2) IS literature in AKI and acute kidney care; 3) Innovations in IS to accelerate the adoption, adherence to, and sustainment of EBPs in AKI and acute kidney care; 4) IS methods in resource-limited settings; and 5) Recommendations to identify and evaluate EBPs that are ready for implementation or de-implementation. Prior to the in-person meeting, each workgroup met virtually to review the literature and develop framework questions to address their objectives. During the two-day in person meeting, through iterative discussions, questions and supporting statements were finalized. These questions and statements were agreed upon through voting to achieve consensus, defined as agreement of ≥80%. Conclusions and Relevance: We report a structured multidisciplinary consensus for defining the role of IS in AKI and acute kidney care. Future programs should address these consensus questions and apply these statements along with IS methodology in the translation of science into clinical practice and the implementation/de-implementation of EBPs in clinical care.