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 Background Invasive listeriosis remains a leading cause of foodborne infection–related mortality in the United States and is associated with substantial case fatality despite appropriate antimicrobial therapy. Owing to the relative rarity of invasive disease, contemporary data evaluating clinical characteristics, optimal antimicrobial strategies, and predictors of mortality remain limited. Methods We conducted a retrospective cohort study of adults with laboratory-confirmed invasive Listeria monocytogenes infection at Mayo Clinic Health System sites from 1980 to 2024. Clinical syndromes were categorized into four mutually exclusive categories, namely bloodstream infection, central nervous system infection, pregnancy-associated infection, and other focal infections. The primary outcome was 1-year all-cause mortality. Secondary outcomes included 90-day mortality and residual neurological deficits among patients with neurolisteriosis. Results Fifty patients were included (median age, 72 years; 56% immunocompromised). The most common clinical presentations were bacteremia (44%) and neurolisteriosis (36%), followed by endovascular infection (12%) and peritonitis (6%). Most patients received a beta-lactam–based regimen, 46% aminopenicillin monotherapy, and 30% received combination therapy with gentamicin. Thirty-day, 90-day, and 1-year mortality were 10%, 12%, and 20%, respectively. Immunocompromised status and intensive care unit admission were associated with an increased risk of 1-year mortality, whereas adjunctive gentamicin therapy was not associated with improved survival. Conclusion Invasive listeriosis is associated with substantial morbidity and mortality, particularly among immunocompromised hosts. Host factors and severity of illness at presentation appear to be key drivers of unfavorable outcomes. Larger multicenter studies are needed to define optimal management strategies.

Abstract Treatment resistance and metastases occur in 10–20% of patients with invasive lobular carcinoma (ILC), the most common special histological subtype of breast cancer. ILC metastasizes to the ovary more frequently than no special type (NST) tumors, also known as invasive ductal carcinoma (IDC). To characterize the genomic landscape of breast cancer ovarian metastases, we analyzed 15,613 local breast cancers, 22,010 non-ovarian metastases, and 246 ovarian metastases sequenced using FoundationOne®CDx or FoundationOne® assays. Ovarian metastases had enriched CDH1 , PIK3CA , and TBX3 mutations and depleted TP53 and MYC alterations relative to local breast cancers, with additional depletion of ESR1 mutations compared to non-ovarian metastases. CDH1 mutations were less frequent in ovarian metastases (47%) than local ILC (81.3%), with reduced 16q loss (64% vs 84%), indicating that ovarian metastases also arise from non-ILC tumors. We extended these findings to a UPMC cohort of 27 ovarian metastases (13 ILC, 8 IDC, 6 mixed ductal-lobular carcinoma) with patient-matched primary tumors in most cases. In both cohorts, patients with ovarian metastases were significantly younger than those with other metastatic sites. In the UPMC cohort, the most frequent mutations were in PIK3CA , CDH1 , KMT2C , FOXA1 , and RUNX1 . Transcriptomic analysis identified upregulated G protein-coupled receptor (GPCR) pathways, including metabotropic glutamate receptor signaling. Functional studies showed that calcium-sensing receptor (CaSR), a GPCR overexpressed in ovarian metastases, drives MEK/ERK-dependent migration and F-actin reorganization in ILC cell lines, enhanced by estrogen and blocked by calcilytic, MEK, or anti- estrogen treatment. Our findings inform future therapeutic targeting of ovarian metastasis.

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.

Abstract Among 1141 inpatients from Arizona with community-acquired pneumonia, 865 (75.8%) were tested for Coccidioides infection and 85 (9.8%) had positive results. Patients more commonly underwent testing if they had concerning radiographs, fever, dyspnea, or fatigue. Patients with night sweats, rash, headache, or eosinophilia more commonly had positive results.

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.