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ImportanceThe rates of suicide and suicide attempts are rising precipitously among early adolescents aged 10 to 14 years in the US. While suicide attempts in this age group are more common and associated with lower lethality than in older age groups, very little is known about these individuals’ long-term social and psychiatric outcomes.ObjectivesTo examine the adult outcomes of individuals making index suicide attempts that came to medical attention between the ages of 10 and 14 years.Design, Setting, and ParticipantsThis population-based cohort constitutes a subsample (n = 164) of a previously reported retrospective-prospective study examining individuals who made index suicide attempts during a 22-year period (1986-2007) in Olmsted County, Minnesota.Main Outcomes and MeasuresTo collect outcome measures, the medical records of all individuals were queried until March 31, 2023, comprising up to 36 years of follow-up data after the index attempt. Measures included current social, psychiatric, and mortality outcomes as well as lifetime measures of psychiatric hospitalizations and repeat suicide attempts. K-means clustering generated adult groupings based on aggregates of psychiatric hospitalizations and repeat attempts. Multivariable logistic regression identified index attempt factors associated with poor adult outcomes.ResultsOf 164 individuals aged 10 to 14 years who made index attempts (128 [78.0%] female; mean [SD] age at index attempt, 13.7 [1.1] years), 3 (1.8%) died on the index attempt. In the follow-up period, no individuals died by suicide. K-means clustering generated a 2-group solution reflecting low (120 [80%]) and high (30 [20%]) rates of adult psychopathology. While a minority of the sample belonged to the high-rate group, characterized by multiple repeat attempts and hospitalizations, the majority had favorable social indicators and fewer reattempts and hospitalizations. Poor adult outcomes were associated with being male (odds ratio, 2.44; 95% CI, 1.00-5.80; P = .04) and having a psychiatric diagnosis prior to the index attempt (odds ratio, 3.27; 95% CI, 1.42-8.07; P = .007).Conclusions and RelevanceIn this sample of early adolescents with index suicide attempts followed into adulthood, all who died by suicide did so on the index attempt. While a small number of individuals went on to develop chronic severe psychopathology, the majority demonstrated little evidence of long-term impairment. Given this discrepancy, future studies should focus on using risk stratification after index attempts to direct postvention resources toward adolescents more susceptible to poor outcomes.

Human immune system (HIS) mice constructed in various ways are widely used for investigations of human immune responses to pathogens, transplants, and immunotherapies. In HIS mice that generate T cells de novo from hematopoietic progenitors, T cell-dependent multisystem autoimmune disease occurs, most rapidly when the human T cells develop in the native NOD.Cg- Prkdc scid Il2rg tm1Wjl (NSG) mouse thymus, where negative selection is abnormal. Disease develops very late when human T cells develop in human fetal thymus grafts, where robust negative selection is observed. We demonstrate here that PD-1 + CD4 + peripheral (Tph) helper-like and follicular (Tfh) helper-like T cells developing in HIS mice can induce autoimmune disease. Tfh-like cells were more prominent in HIS mice with a mouse thymus, in which the highest levels of IgG were detected in plasma, compared to those with a human thymus. While circulating IgG and IgM antibodies were autoreactive to multiple mouse antigens, in vivo depletion of B cells and antibodies did not delay the development of autoimmune disease. Conversely, adoptive transfer of enriched Tfh- or Tph-like cells induced disease and autoimmunity-associated B cell phenotypes in recipient mice containing autologous human APCs without T cells. Tfh/Tph cells from mice with a human thymus expanded and induced disease more rapidly than those originating in a murine thymus, implicating HLA-restricted T cell-APC interactions in this process. Since Tfh, Tph, autoantibodies, and lymphopenia-induced proliferation (LIP) have all been implicated in various forms of human autoimmune disease, the observations here provide a platform for the further dissection of human autoimmune disease mechanisms and therapies.

Abstract Gliomas are highly malignant brain tumors with poor prognosis and short survival. Nicotinamide adenine dinucleotide (NAD+) plays a critical role in cancer progression, yet anti-cancer therapies targeting NAD+ synthesis have had limited clinical success due to an incomplete understanding of its mechanisms. Here, we demonstrate the essential role of the NAD+ synthase nicotinamide mononucleotide adenylyltransferase (NMNAT) in glioma progression and its novel contribution to nuclear atypia. Analysis of the patient glioma transcriptomics dataset (GAPIA) indicated a strong correlation between high NMNAT transcription levels and poorer disease-free survival in low grade glioma (LGG) and glioblastoma multiforme (GBM). Utilizing quantitative statistical analysis to assess the size and circularity of about 3 million cells in glioma tissue samples from 19 patients, we identified the significant association between NMNAT1 protein level and increased nuclear atypia in different types of gliomas. Mechanistic studies in human glioma cells and a Drosophila glial neoplasia model revealed that NMNAT enhances glioma growth by promoting NAD+-dependent post-translational modifications poly(ADP-ribosyl)ation (PARylation) and deacetylation of p53, thereby attenuating the pro-apoptotic activity of p53. Additionally, NMNAT1 disrupts nuclear lamina integrity by altering lamin A/C distribution, further contributing to nuclear atypia and glioma progression. These findings uncover a novel tumorigenic mechanism involving NMNAT's regulation of nuclear architecture and NAD+-mediated metabolic signaling pathways, highlighting its roles in glioma growth and nuclear atypia. This study underscores NMNAT as a potential therapeutic target in glioma treatment. Citation Format: Jiaqi Liu, Xianzun Tao, Yi Zhu, Xiang Gao, Tijana Canic, Kai Ruan, Zoraida Diaz-Perez, Sakir Humayun Gultekin, Priyamvada Rai, Qunfeng Dong, Grace Zhai. NMNAT-mediated NAD+ metabolism promotes glioma growth by modulating p53 post-translational modifications and nuclear atypia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB060.

Abstract Chimeric antigen receptor T (CART) cell therapy has shown clinical successes in B cell hematological malignancies. Two B cell maturation antigen (BCMA)-directed CART cell therapies treating multiple myeloma (MM) were approved by FDA but most patients relapse within 1-2 years. Ex vivo-expanded antigen specific T cells as cancer treatment rely on TCR-mediated killing of tumors. We hypothesized that arming ex vivo enriched tumor-specific T cells with CARs targeting a different antigen improves T cell functions. First, we expanded mucin 1 (MUC1)-activated T cells from patients with MM through ex vivo stimulation by MUC1 peptides-loaded autologous PBMCs for 19 days. Then, we engineered MUC1-activated T cells with 4-1BB-co-stimulated BCMA CAR to generate MUC1 TCR+BCMA CAR+ T cells. Baseline T cells without MUC1 stimulation were engineered with BCMA CAR as control. Baseline T cells, MUC1 T cells, baseline BCMA CART cells, or MUC1 BCMA CART cells were cocultured with luc+ RPMI-8226, a MUC1+BCMA+ MM cell line, for 3 days. MUC1 BCMA CART cells showed stronger tumor killing than BCMA CART or MUC1 T cells in all 3 patients (p<0.0001). MUC1 BCMA CART showed improved proliferation than BCMA CART or MUC1 T cells (p=0.0765, p<0.0001, respectively) after a 5-day stimulation by RPMI-8226. To exclude possibility of metabolic alterations by 19-day PBMC incubation leading to better T cell functions in MUC1 BCMA CART, baseline and MUC1-stimulated T cells from 3 healthy donors were processed for the same assays. Day-19 BCMA CART cells showed inferior tumor killing compared to baseline BCMA CART in all 3 donors (p<0.0001). Lower T cell proliferation was also observed in day-19 BCMA CART (p=0.0838). Our data indicate that improved T cell functions in MUC1 BCMA CART were unlikely due to metabolic changes and required stimulation by tumor antigens prior to CAR engineering likely through MUC1 TCR. Additionally, MUC1 T cells, BCMA CART, or MUC1 BCMA CART cells from tested patients were stimulated by RPMI-8226 for bulk RNA sequencing. Both BCMA CART and MUC1 T cells had distinct transcriptomic features from MUC1 BCMA CART cells. Differential gene expression analysis showed upregulation of T cell function-associated genes (RYR2, ITGA1, GNLY, GZMA, etc.) in MUC1 BCMA CART vs BCMA CART. Enrichment of T cell function-associated pathways was also observed in MUC1 BCMA CART. Analysis between MUC1 T cell and MUC1 BCMA CART showed upregulation of T cell function-associated genes (CSF2, CRTAM, IFNG, GZMB, etc.) and enrichment of immune response pathways in MUC1 BCMA CART. Our findings suggest that equipping ex vivo-enriched tumor-specific T cells with CARs targeting a different antigen improves T cell functions in vitro. Importantly, this provides a rationale for a therapeutic regimen where patients receive ex vivo-enriched tumor-induced T cells followed by CAR engineering. Persistence of the engineered T cells is being investigated Citation Format: Kun Yun, R. Leo Sakemura, Ismail Can, Omar Gutierrez Ruiz, Ekene J. Ogbodo, Truc N. Huynh, Claudia Manriquez Roman, Olivia Sirpilla, Carli M. Stewart, Jennifer M. Feigin, Grace E. DeFranco, Sophia Y. Goldberg, Dominic A. Skeele, Mariam Stein, Dara Missan, Latha Pathangey, Long Mai, Hong Xia, Brooke Kimball, Lionel A. Kankeu Fonkoua, Mehrdad Hefazi, Michael W. Ruff, Elizabeth L. Siegler, Leif Bergsagel, Michael Gustafson, Sandra Gendler, Saad S. Kenderian. BCMA CAR engineering arms T cells with superior functions post ex vivo stimulation by MUC1 peptide-loaded autologous PBMCs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6103.

Background: Prostate cancer is the most common cancer in men in the United States with an estimated 288,300 new cases diagnosed in 2023. The treatment strategies include androgen deprivation therapies (ADTs) for metastatic prostate cancer (mPC) but 10-20% of patients eventually progress to castration-resistant prostate cancer (CRPC). However, nearly all patients develop primary and acquired resistance overtime, and developing therapies and identifying novel molecular targets are essential in enhancing the clinical outcomes of patients with prostate cancer. In this study, we report a small molecule that belongs to a class of tricyclic quinolones, QL47 that was previously screened among various other compounds in prostate PDX organoid models and showed a potent anti-proliferative activity. Methods: QL47 was tested on prostate cancer cell lines (22Rv1, 22RV1 abiraterone-resistant and DU145) for its anti-proliferative potential. Further, we used the biotinylated QL47 (QL47B) to pulldown its potential targets and we identified the targets through immunoprecipitation-mass spectrometry (IP-MS) technique followed by Western blot analysis. Cell cycle and cell death analyses were performed after staining the cells with propidium iodide and Annexin V followed by flow cytometry analysis. Oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) was investigated using the Seahorse assay. Results: The initial screening of QL47 in prostate cancer cell lines showed that it inhibits the proliferation at an IC50 of 50-200 nM. Through IP-MS and Western blot analysis, we identified a member of the pyruvate dehydrogenase complex dihydrolipoamide S-acetyltransferase (DLAT) as a direct target of QL47. Mechanistically, we found that QL47 does not increase cell death or affect cell cycle, but inhibits metabolic function, with a decrease in both oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Conclusion: We have identified a novel mechanism of action of QL47 on the pyruvate dehydrogenase complex, and we plan to further validate the safety and efficacy for the treatment of prostate cancer. Citation Format: Grace Nirmala Jesuthankaraj, August John, Huanyao Gao, Arun Kanakkanthara, Richard Weinshilboum, Liewei Wang. Targeting metabolic dysfunction in prostate cancer: the anti-proliferative effects of ql47 through inhibition of dlat [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4297.

OBJECTIVE The optimal dose for triazoles in pediatric patients may substantially vary given the dynamic changes in pharmacokinetics and pharmacodynamics, based on disease severity. Therapeutic drug monitoring has been a valuable tool to help guide management and avoid potential toxicities associated with treatment of invasive fungal infections (IFIs). Goal azole serum concentrations are based on specific drug, indication, and minimum inhibitory concentration when known. This study aimed to determine the optimal pediatric azole doses needed to achieve targeted serum concentrations of isavuconazole, itraconazole, posaconazole, and voriconazole. METHODS This is a single center, retrospective chart review of pediatric patients who received isavuconazole, itraconazole, posaconazole, or voriconazole between January 1, 2011, and August 31, 2021. RESULTS A total of 273 pediatric patients received isavuconazole, itraconazole, posaconazole, or voriconazole in the inpatient or outpatient setting during the study period. Of the 273 patients, only 122 met criteria for inclusion in the analysis. Eighty-three percent of patients reached a goal serum concentration. Patients younger than 12 years required a higher dose (mg/kg/day) to achieve goal serum concentrations. Patients who received an azole in the form of an oral tablet or intravenously were more likely to reach a goal concentration than those not receiving these formulations. Median time to goal concentration occurred at 20 days for isavuconazole, 34 days for itraconazole, 11 days for posaconazole, and 10 days for voriconazole. CONCLUSIONS Higher starting azole doses are needed to obtain goal concentrations quickly, especially for children younger than 12 years.

Background: Cardiac rehabilitation (CR) is essential to secondary cardiovascular disease prevention and management of cardiac patients. Despite its proven benefits, CR remains underutilized with enrollment and completion rates ranging from 10-30% in the US. Yet, there is a scarcity of nationally representative data among diverse populations on socioeconomic differences in barriers and beliefs of CR participation and delivery mode preferences. Hypothesis: The perceptions (barriers, beliefs), CR delivery mode preferences, and CR utilization (prior enrollment) varies by socioeconomic status (SES) among CR-eligible individuals. Methods: We conducted an anonymous national electronic survey from March 2023 to January 2024 of individuals self-reporting a prior CR-eligible diagnosis. The 22-item CR Barriers Scale assessed perceived barriers to CR enrollment and participation using a 5-point Likert scale (strongly disagree to strongly agree). A 13-item, validated questionnaire assessed 4 subscales pertaining to patients’ beliefs about CR, each rated on a 5-point Likert scale (strongly disagree to strongly agree): perceived necessity, concerns about exercise, practical barriers and perceived suitability. CR delivery mode preferences were ascertained (eg, virtual, at-home, etc.). Mean barriers and belief scores as well as delivery mode preferences were stratified by SES. Low SES was defined as ≤ high school education, Medicaid insurance, or uninsured. High SES was defined as > high school education and non-Medicaid health insurance. Responses were analyzed using descriptive statistics with R software. Results: A total of 466 participants completed the survey (38.1% women, 30.6% minoritized racial/ethnic group, 29.6% low SES, 95% response rate) ( Table 1 ). The majority indicated prior enrollment in CR (81.5%) with no difference by SES. CR barrier scores did not differ significantly by SES (p=0.331) ( Table 2 ). Beliefs about CR perceived necessity and perceived suitability differed by SES (p<0.001 and p=0.025), but beliefs regarding concerns about exercise and practical barriers did not. The low SES group reported a higher preference for completely at-home CR compared to the high SES group (33.6% vs 7.4%, p<0.001). Conclusion: Our findings suggest that CR beliefs varied by SES while utilization did not. For CR-eligible patients experiencing socioeconomic disadvantage, at-home CR may be a preferred alternative to center-based CR to increase CR participation and adherence.

Herein described is an eight-year-old female patient presenting with bilateral external ear canal duplication and a history of recurrent postauricular abscesses, otorrhea, and moderate left-sided conductive hearing loss. Previous incision and drainage of the postauricular abscesses yielded little long-term success. Medical history was otherwise unremarkable. Physical examination revealed a cystic mass in the right ear and postauricular fibrosis, likely a result of previous surgical interventions. An audiogram revealed asymmetric hearing function, with mild-to-moderate conductive hearing loss in the left ear contrasting normal hearing in the right ear, while tympanometry confirmed an intact right tympanic membrane but was precluded on the left due to purulent otorrhea. A head CT scan revealed postauricular soft tissue swelling and well-pneumatized mastoid air cells. Both ears were explored intraoperatively via postauricular incisions. Surgical excision included removal of a cyst, cartilaginous remnants, and fibrotic tissue. The patient was followed up to assess for postsurgical complications. The surgical site healed uneventfully; no new symptoms or recurrences of past symptoms of otorrhea, cyst formation, or abscesses had developed within the twelve weeks post-surgery. Although external ear canal duplications are rare, it is imperative that early, accurate diagnoses be made to ensure optimal patient outcomes.

PURPOSE Adjuvant endocrine therapy (ET) improves overall survival (OS) in estrogen receptor (ER)–positive early-stage breast cancer (BC). However, the benefit of ET for those with ER-low BC (ER 1%-10%) is unclear. METHODS Using the National Cancer Database, we studied patients with high-risk stage I to III, ER-low BC (defined as immunohistochemistry 1%-10%) who received (neo)adjuvant chemotherapy and did or did not initiate ET. OS was analyzed with ET initiation as a time-dependent covariate using Cox proportional hazards regression. RESULTS Of 10,362 patients with stage I to III ER-low BC, 7,018 received chemotherapy and met inclusion criteria. ET omission was 42% at 12 months and more common in patients with tumors that were progesterone receptor–negative, human epidermal growth factor receptor 2–negative, higher-grade (grade 2/3) and higher Ki-67 (≥20%; all P < .001) and those who received neoadjuvant chemotherapy (NAC; P < .001). With a median follow-up of 3 years, 586 deaths were observed. In a multivariable analysis, ET omission was associated with a higher risk of death (hazard ratio [HR], 1.23 [95% CI, 1.04 to 1.46]; P = .02), with a greater impact in those with higher ER levels: ER 1%-5% (HR, 1.15 [95% CI, 0.91 to 1.45]; P = .24) versus ER 6%-10% (HR, 1.42 [95% CI, 1.00 to 2.02]; P = .048). Among patients treated with NAC (n = 4,377, 62%), ET omission was associated with worse OS in those with residual disease (RD; HR, 1.26 [95% CI, 1.00 to 1.57]; P = .046) but not in those who achieved a pathologic complete response (HR, 1.06 [95% CI, 0.62 to 1.80]; P = .84). CONCLUSION In ER-low, early-stage BC, ET omission is associated with significantly worse OS, especially in patients with RD after NAC and those with higher (6%-10%) ER levels. Until prospective data are available, patients with ER-low BC should be counseled regarding the potential benefit of ET.