Citations

Abstract Introduction Breast cancer is uncommon in men. Almost all male breast cancers are hormone receptor-positive, HER2-negative, although the pathogenesis is not always attributable to an endocrine condition. A few studies have compared biological characteristics or molecular signatures with breast cancers in women. We sought to evaluate whether hormone receptor-related gene expression is different in cancers from men compared to equivalent cancers from women. SET2,3 index measures non-proliferative hormone receptor-related transcriptional activity in the cancer (SET-ER/PR index) and adjusts this for a Baseline Prognosis Index (BPI) that combines the measurements of tumor and nodal stage with a 4-gene molecular subtype (ESR1, PGR, ERBB2, and AURKA). Methods We received aliquots of total RNA from male patients with breast cancer included in the retrospective cohort study of the EORTC 10085/BCG/TBCRC/BIG/NCTN International Male Breast Cancer Program (NCT01101425). SET2,3 assay was performed using the QuantiGene assay (Thermo Fisher) using bead-based hybridization and laser spectroscopy (Luminex). The statistical analyses were performed by the EORTC statistician. The primary objective of the study was the assessment of the prognostic value of the SET2,3 index score in patients with early-stage hormone receptor-positive, HER2-negative male breast cancer, treated with endocrine therapy. Clinical outcomes (recurrence-free survival – RFS; overall survival – OS) were estimated by Kaplan-Meier curves and secondarily compared using multivariable Cox models adjusted for continuous SET2,3 index, tumor size, nodal status, age, and chemotherapy and radiotherapy use. An exploratory analysis to compare the SET2,3 index scores distribution in female and male breast cancer patients was also performed using results from the same assay performed on cancers from women selected on the same inclusion criteria. Due to the low numbers of male patients treated with neoadjuvant treatment (N=6), this analysis was restricted to patients treated with adjuvant treatment (n=315 male and 660 female). Results Of the 321 male patients with breast cancer analyzed, treated between 1990 and 2010, 211 (65.7%) were categorized as high SET2,3 index score, reflecting a high endocrine activity in the cancer and low risk of recurrence, and 110 patients (34.3%) categorized as being low score, reflecting low endocrine activity and high risk of recurrence. At 5 years, the RFS was 75.0% (95% CI, 67.4-81.1) in the high SET2,3 group versus 60.7% (95% CI, 49.1-70.5) in the low SET2,3 group (HR univariate, 0.49; 95% CI, 0.34-0.70; P< 0.0001). The 5-year OS rate among patients with a high SET2,3 index was 84.3% (95% CI, 45.5-73.8), in contrast of 67.8% (95% CI, 56.6-76.7) in the low SET2,3 group (HR univariate, 0.44; 95% CI, 0.30-0.65; P< 0.0001). SET2,3 was independently prognostic for OS, but not RFS in multivariable Cox models. In patients classified as low SET2,3, the addition of neo/adjuvant chemotherapy to adjuvant endocrine therapy was associated with 5-year OS of 76.0% (95% CI, 59.5-86.4) and in patients who received endocrine therapy alone the 5-year OS was 61.3% (95% CI, 45.5-73.8), an absolute difference of 14.7 percentage points. Overall, we did not observe a difference in the distributions (median, interquartile range) of SET2,3 index between men (2.4, 1.9–2.6) and women (2.3, 2.0–2.7). Conclusion SET2,3 index measurements of endocrine-related transcriptional activity in male patients with breast cancer were not different from measurements in female patients with breast cancer. SET2,3 was prognostic in male breast cancer and our exploratory analysis suggests that chemotherapy might improve the poor prognosis for men with breast cancer that has low SET2,3 index. This study was funded by the Breast Cancer Research Foundation (BCRF). Citation Format: Danielle B. Zakon, Coralie Poncet, Fatima Cardoso, Neven Anouk, Vicente Valero, Stefan Aebi, Kim Benstead, Oliver Bogler, Lissandra Dal Lago, Judith Fraser, Carmela Caballero, Ingrid A. Hedenfalk, Larissa A. Korde, Barbro Linderholm, John WM Martens, Lavinia P. Middleton, Melissa Murray, Catherine M. Kelly, Cecilia Nilsson, Monika Nowaczyk, Stephanie Peeters, Melanie Beauvois, Peggy Porter, Carolien P. Schroder, Isabel T. Rubio, Kathryn Ruddy, Christi van Asperen, Danielle Van Den Weyngaert, Carolien HM van Deurzen, Elise van Leeuwen-Stok, Joanna M. Vermeij, John MS Bartlett, Antonio C. Wolff, Sharon H. Giordano, W. Fraser Symmans. PD6-11 Evaluation of the Sensitivity to Endocrine Therapy Index (SET2,3) in Early Male Breast Cancer: Results from an analysis in the EORTC 10085/TBCRC/BIG/NCTN International Male Breast Cancer Program [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD6-11.

Abstract Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2,367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response — defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������

Abstract After activation, CD4+ T cells undergo metabolic modifications in order to orchestrate successful immune responses. In particular, naïve T cells shift to a more glycolysis-heavy metabolic program that produces the necessary metabolites for growth, division, and exertion of effector function. Histone Deacetylase 3 (HDAC3) has been shown to epigenetically regulate many T cell fate decisions and is also capable of post-translationally modifying non-histone proteins. Deletion of HDAC3 in mature CD4+ T cells using a distal Lck-Cre HDAC3 cKO mouse revealed a reduction in differentiated T-helper cell populations in vivo. In contrast, in vitro differentiation of HDAC3-deficient CD4+ T cells occurred normally, however, the numbers of T cells present within each culture was greatly diminished. CD3/CD28-stimulated HDAC3-deficient cells exhibited poor proliferation with decreased blastogenesis, decreased CD25 expression, and decreased IL-2 production. Signaling downstream of TCR is disrupted in the HDAC3-deficient T cells. HDAC3-deficient CD4+ T cells have an overabundance of Foxo1 protein, and diminished signaling downstream of mTOR, including reduced phosphorylation of Ribosomal Protein S6, and decreased expression of Egr2. Key transporters involved in cholesterol efflux, ABCA1 and ABCG1, were upregulated in HDAC3-deficient CD4+ T cells. Strikingly, the proliferation and blasting defects of HDAC3-deficient CD4+ T cells are restored with the addition of exogenous cholesterol, but the signaling defects remain. Thus, the failure of HDAC3-deficient CD4+ T cells to proliferate is due to alterations in cholesterol homeostasis.

Abstract Inhibitory receptors have a critical role in the regulation of immunity. Siglecs are a family of primarily inhibitory receptors expressed by immune cells, which recognize specific sialic acid modifications on cell surface glycans. Sialyltransferases are the enzymes that catalyzing the addition of sialic acids onto glycoproteins and glycolipids. Siglec-E binds to α2,8-linked disialic acids, generated by the enzyme ST8Sia6 on O-linked glycoproteins and functions to inhibit activation of innate immune cells. Many tumors have increased sialic acid incorporation. Overexpression of the sialyltransferase ST8Sia6 on tumors led to altered macrophage polarization and increased tumor growth through engagement of ligands generated by ST8Sia6 with Siglec-E. Here, we examine the role of ST8Sia6 on immune cells in regulating anti-tumor immunity. The loss of ST8Sia6 in tumor bearing mice reduced tumor growth, increased survival, and altered the immune response as compared to ST8Sia6 sufficient tumor bearing mice. Using MC38, B16, and B16-OVA flank tumor mouse models, tumor growth was decreased in ST8Sia6 KO mice as compared to C57Bl/6 mice. Within the tumor microenvironment of tumors present in ST8Sia6 KO mice compared to tumors present in C57Bl/6 mice, macrophages and dendritic cells altered their phenotype towards enhanced immune activation. Tregs from tumors in ST8Sia6 KO mice also displayed an increase in RORγt and a reduction in TNFRII, suggesting a possible shift to a less suppressive Treg. These alterations in the immune response to tumors were due to the loss of ST8Sia6 in macrophages and dendritic cells and not T-cells. Thus, ST8Sia6 generates ligands for Siglecs that dampen anti-tumor immunity. Supported by grants from NIH (R01CA243545, 2T32AI007425) and Mayo Clinic Center of Biomedical Discovery

Abstract Signaling lymphocyte activation molecule (Slamf1) is a T cell co-stimulatory molecule and a regulator of cytokine production by macrophages and dendritic cells. Because Slamf1 positively regulates microbicidal mechanisms in macrophages, we evaluate whether Slamf1 would affect enterocolitis. To induce colitis, mouse CD45RBhi CD4+ T cells were transferred into RAG-/- or Slamf1-/- RAG-/- recipient mice. In a second set of experiments, an agonistic αCD40 antibody was administered to the same recipient strains to induce colitis. Whilst the absence of Slamf1 in RAG-/- recipients mitigated colitis, the function of disease-causing effector or regulatory T cells was not affected by the ablation of the receptor. Surprisingly, in Slamf1-/- mice monocyte / macrophage migration into the inflamed tissue was impaired not only in αCD40-induced colitis but also in two other in vivo models of inflammation: thioglycolate induced peritonitis and in an “air pouch” model in response to TNFα. Administering αSlamf1 to RAG-/- mice ameliorated enterocolitis and altered this migration. Slamf1 is a key contributor to the innate immune responses during experimental colitis by affecting the migration of monocytes / macrophages to the sites of inflammation. As αSlamf1 also mitigates the pathogenesis of colitis, SLAMF1 should be a plausible therapeutic target in treating inflammatory bowel diseases.

Leukemia cells accumulate DNA damage but altered DNA repair mechanisms protect them from apoptosis. We showed here that formaldehyde generated by serine/one-carbon cycle metabolism contributed to accumulation of toxic DNA-protein crosslinks (DPCs) in leukemia cells, especially in driver clones harboring oncogenic tyrosine kinases [OTKs: FLT3(ITD), JAK2(V617F), BCR/ABL1]. To counteract this effect, OTKs enhanced the expression of DNA polymerase theta (POLq) by ERK1/2 serine/threonine kinase-dependent inhibition of c-CBL E3 ligase-mediated ubiquitination of POLq and its proteasomal degradation. Overexpression of POLq in OTK-positive cells resulted in efficient repair of DPC-containing DNA double-strand breaks (DSBs) by POLq-mediated end-joining (TMEJ). Transforming activity of OTKs and other leukemia-inducing oncogenes, especially of those causing inhibition of BRCA1/2 -mediated homologous recombination (HR) with and without concomitant inhibition of DNA-PK -dependent non-homologous end-joining (D-NHEJ), was abrogated in Polq-/- murine bone marrow cells. Genetic and pharmacological targeting of POLq polymerase and helicase activities revealed that both activities are promising targets in leukemia cells. Moreover, OTK inhibitor or DPC-inducing drug etoposide enhanced anti-leukemia effect of POLq inhibitor (POLqi) in vitro and in vivo. In conclusion, we demonstrated that POLq plays an essential role in protecting leukemia cells from metabolically induced toxic DNA lesions triggered by formaldehyde and that it can be targeted to achieve therapeutic effect.

Abstract Background Hepatitis B virus (HBV) vaccine seroprotection rates with conventional aluminum adjuvanted recombinant HBV vaccines (HepB-alum) among people with HIV (PWH) are varied. HepB-CpG, a novel adjuvanted recombinant HBV vaccine, has shown higher seroprotection rates in immunocompetent patients but is not well studied in PWH. There are no published studies comparing seroprotection rates between HepB-alum and HepB-CpG in PWH. The purpose of this study was to evaluate and compare the seroprotection incidence of HepB-CpG versus HepB-alum in adults at least 18 years of age with HIV. Methods This retrospective, observational, cohort study screened for inclusion adults diagnosed with HIV who received a 3-dose series of HepB-alum or a 2-dose series of HepB-CpG between January 1, 2015 through December 31, 2021 at a community health center in Phoenix, Arizona. Patients who had a confirmed diagnosis of HIV and a hepatitis B surface antibody &lt; 10 IU/L at the time of the first vaccine dose were included until an adequate sample size was achieved. The primary outcome was to compare seroconversion incidence of HepB-CpG and HepB-alum in PWH. Secondary outcomes included identifying factors associated with an increased likelihood of response to HBV vaccination. Seroconversion incidence data was analyzed using Fisher’s exact test using BlueSky Statistics. Results A total of 121 patients were included in this study, 59 in the HepB-alum cohort and 61 in the HepB-CpG cohort. In the HepB-alum cohort, 57.6% (34/59) achieved seroconversion, compared to 93.4% (57/61) in the HepB-CpG group (p &lt; 0.001). Univariate comparisons of comorbidities among the vaccine cohorts found no significant differences in sex, body mass index, diabetic status, kidney/liver disease, CD4 count, HIV viral load, or active/prior history of substance use. Conclusion Among PWH at a single community health center, HepB-CpG provided a statistically higher incidence of seroprotection against HBV compared to HepB-alum. The higher seroprotection rate for HepB-CpG versus HepB-alum patients is not due to differences in group demographics or reported comorbidities. Disclosures Carlos Hartmann, MD, Viiv Pharmaceuticals: Speaker.

Motivation: The price of medical treatment continues to rise due to (i) an increasing population; (ii) an aging human growth; (iii) disease prevalence; (iv) a rise in the frequency of patients that utilize health care services; and (v) increase in the price. Objective: Artificial Intelligence (AI) is already well-known for its superiority in various healthcare applications, including the segmentation of lesions in images, speech recognition, smartphone personal assistants, navigation, ride-sharing apps, and many more. Our study is based on two hypotheses: (i) AI offers more economic solutions compared to conventional methods; (ii) AI treatment offers stronger economics compared to AI diagnosis. This novel study aims to evaluate AI technology in the context of healthcare costs, namely in the areas of diagnosis and treatment, and then compare it to the traditional or non-AI-based approaches. Methodology: PRISMA was used to select the best 200 studies for AI in healthcare with a primary focus on cost reduction, especially towards diagnosis and treatment. We defined the diagnosis and treatment architectures, investigated their characteristics, and categorized the roles that AI plays in the diagnostic and therapeutic paradigms. We experimented with various combinations of different assumptions by integrating AI and then comparing it against conventional costs. Lastly, we dwell on three powerful future concepts of AI, namely, pruning, bias, explainability, and regulatory approvals of AI systems. Conclusions: The model shows tremendous cost savings using AI tools in diagnosis and treatment. The economics of AI can be improved by incorporating pruning, reduction in AI bias, explainability, and regulatory approvals.

ImportanceLate-onset meningitis (LOM) has been associated with adverse neurodevelopmental outcomes in children born extremely preterm.ObjectiveTo report the incidence of LOM during birth hospitalization and neurodevelopmental outcomes at 18 to 26 months’ corrected age.Design, Setting, and ParticipantsThis cohort study is a secondary analysis of a multicenter prospective cohort of children born at 22 to 26 weeks’ gestation between 2003 and 2017 with follow-up from 2004 to 2021. The study was conducted at 25 Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers.ExposuresCulture-confirmed LOM.Main Outcomes and MeasuresIncidence and microbiology of LOM (2003-2017); lumbar puncture (LP) performance in late-onset sepsis (LOS) evaluations (2011-2017); composite outcome of death or neurodevelopmental impairment (NDI; 2004-2021).ResultsAmong 13 372 infants (median [IQR] gestational age, 25.4 [24.4-26.1] weeks; 6864 [51%] boys), LOM was diagnosed in 167 (1%); LOS without LOM in 4564 (34%); and neither LOS nor LOM in 8641 (65%). The observed incidence of LOM decreased from 2% (95% CI, 1%-3%) in 2003 to 0.4% (95% CI, 0.7%-1.0%) in 2017 (P &amp;lt; .001). LP performance in LOS evaluations decreased from 36% (95% CI, 33%-40%) in 2011 to 24% (95% CI, 21%-27%) in 2017 (P &amp;lt; .001). Among infants with culture-confirmed LOS, LP performance decreased from 58% (95% CI, 51%-65%) to 45% (95% CI, 38%-51%; P = .008). LP performance varied by center among all LOS evaluations (10%-59%, P &amp;lt; .001) and among those with culture-confirmed LOS (23%-79%, P &amp;lt; .001). LOM occurred in the absence of concurrent LOS in 27 of 167 cases (16%). The most common LOM isolates were coagulase-negative Staphylococcus (98 [59%]), Candida albicans (38 [23%]), and Escherichia coli (27 [16%]). Death or NDI occurred in 22 of 46 children (48%) with LOM due to coagulase-negative Staphylococcus, 43 of 67 (64%) due to all other bacterial pathogens, and 26 of 33 (79%) due to fungal pathogens. The adjusted relative risk of death or NDI was increased among children with LOM (aOR, 1.53; 95% CI, 1.04-2.25) and among those with LOS without LOM (aOR, 1.41; 95% CI, 1.29-1.54) compared with children with neither infection.Conclusions and RelevanceIn this cohort study, LP was performed with decreasing frequency, and the observed incidence of LOM also decreased. Both LOM and LOS were associated with increased risk of death or NDI; risk varied by LOM pathogen. The full association of LOM with outcomes of children born extremely preterm may be underestimated by current diagnostic practices.