Cumulative Lifetime Violence and Bacterial Vaginosis Infection in Sexually Transmitted Infections: Findings From a Retrospective Cohort Study Among Black Women at Risk for HIV.

Introduction: Bacterial vaginosis is the most common vaginal condition among women of reproductive age and has been associated with sexually transmitted infections. This study examines the association between cumulative lifetime violence exposure, bacterial vaginosis, and sexually transmitted infections among Black women at risk for HIV. Methods: HIV-negative Black women in a retrospective cohort study (N=230) completed survey questions on cumulative violence (exposure to sexual or physical abuse before age 18 years and exposure to intimate partner violence or sexual violence [partner or other] after age 18 years and past year), bacterial vaginosis (lifetime and past year), and sexually transmitted infection diagnosis (lifetime and past year). Logistic regression models estimated the associations between cumulative violence, bacterial vaginosis, and sexually transmitted infections. Bacterial vaginosis was examined as a moderator in the association between cumulative violence and sexually transmitted infections. Results: Many women reported cumulative violence exposure (40%), lifetime bacterial vaginosis diagnosis (53%), and lifetime sexually transmitted infection diagnosis (73%). Cumulative violence experience was significantly associated with increased adjusted odds of lifetime bacterial vaginosis diagnosis (AOR=1.98; 95% CI=1.10, 3.54). Lifetime bacterial vaginosis diagnosis (AOR=2.76; 95% CI=1.45, 5.22) and past-year bacterial vaginosis diagnosis (AOR=2.16; 95% CI=1.14, 4.10) were significantly associated with increased odds of lifetime sexually transmitted infection diagnosis. Lifetime bacterial vaginosis diagnosis (AOR=2.10; 95% CI=1.19, 3.70) and past-year bacterial vaginosis diagnosis (AOR=3.00; 95% CI=1.70, 5.31) were significantly associated with past-year sexually transmitted infection diagnosis. Lifetime bacterial vaginosis infection significantly increased the odds of lifetime sexually transmitted infection diagnosis with increasing cumulative violence exposure. Conclusions: Our findings support educating and screening Black women who experience cumulative violence for bacterial vaginosis to reduce the risk of untreated bacterial vaginosis and sexually transmitted infections.

moPepGen: Rapid and Comprehensive Proteoform Identification.

Gene expression is a multi-step transformation of biological information from its storage form (DNA) into functional forms (protein and some RNAs). Regulatory activities at each step of this transformation multiply a single gene into a myriad of proteoforms. Proteogenomics is the study of how genomic and transcriptomic variation creates this proteoform diversity, and is limited by the challenges of modeling the complexities of gene-expression. We therefore created moPepGen, a graph-based algorithm that comprehensively enumerates proteoforms in linear time. moPepGen works with multiple technologies, in multiple species and on all types of genetic and transcriptomic data. In human cancer proteomes, it detects and quantifies previously unobserved noncanonical peptides arising from germline and somatic genomic variants, noncoding open reading frames, RNA fusions and RNA circularization. By enabling efficient identification and quantitation of previously hidden proteins in both existing and new proteomic data, moPepGen facilitates all proteogenomics applications. It is available at: https://github.com/uclahs-cds/package-moPepGen.

Enhancing immunotherapy efficacy against MHC-I deficient triple-negative breast cancer using LCL161-loaded macrophage membrane-decorated nanoparticles.

Current cytotoxic T lymphocyte (CTL) activating immunotherapy requires a major histocompatibility complex I (MHC-I)-mediated presentation of tumor-associated antigens, which malfunctions in around half of patients with triple-negative breast cancer (TNBC). Here, we create a LCL161-loaded macrophage membrane decorated nanoparticle (LMN) for immunotherapy of MHC-I-deficient TNBC. SIRPα on the macrophage membrane helps LMNs recognize CD47-expressing cancer cells for targeted delivery of LCL161, which induces the release of high mobility group protein 1 and proinflammatory cytokines from cancer cells. The released cytokines and high mobility group protein 1 activate antitumor immunity by increasing the intratumoral density of the phagocytic macrophage subtype by 15 times and elevating the intratumoral concentration of CTL lymphotoxin by 4.6 folds. LMNs also block CD47-mediated phagocytosis suppression. LMNs inhibit the growth of MHC-I-deficient TNBC tumors, as well as those resistant to combined therapy of anti-PDL1 antibody and albumin-bound paclitaxel, and prolong the survival of animals, during which process CTLs also play important roles. This macrophage membrane-decorated nanoparticle presents a generalizable platform for increasing macrophage-mediated antitumor immunity for effective immunotherapy of MHC-I-deficient cancers.

Chemical conjugation mitigates immunotoxicity of chemotherapy via reducing receptor-mediated drug leakage from lipid nanoparticles.

Immunotoxicity remains a major hindrance to chemotherapy in cancer therapy. Nanocarriers may alleviate the immunotoxicity, but the optimal design remains unclear. Here, we created two variants of maytansine (DM1)-loaded synthetic high-density lipoproteins (D-sHDL) with either physically entrapped (ED-sHDL) or chemically conjugated (CD-sHDL) DM1. We found that CD-sHDL showed less accumulation in the tumor draining lymph nodes (DLNs) and femur, resulting in a lower toxicity against myeloid cells than ED-sHDL via avoiding scavenger receptor class B type 1 (SR-B1)-mediated DM1 transportation into the granulocyte-monocyte progenitors and dendritic cells. Therefore, higher densities of lymphocytes in the tumors, DLNs, and blood were recorded in mice receiving CD-sHDL, leading to a better efficacy and immune memory of CD-sHDL against colon cancer. Furthermore, liposomes with conjugated DM1 (CD-Lipo) showed lower immunotoxicity than those with entrapped drug (ED-Lipo) through the same mechanism after apolipoprotein opsonization. Our findings highlight the critical role of drug loading patterns in dictating the biological fate and activity of nanomedicine.

Zeb1-controlled metabolic plasticity enables remodeling of chromatin accessibility in the development of neuroendocrine prostate cancer.

Cell plasticity has been found to play a critical role in tumor progression and therapy resistance. However, our understanding of the characteristics and markers of plastic cellular states during cancer cell lineage transition remains limited. In this study, multi-omics analyses show that prostate cancer cells undergo an intermediate state marked by Zeb1 expression with epithelial-mesenchymal transition (EMT), stemness, and neuroendocrine features during the development of neuroendocrine prostate cancer (NEPC). Organoid-formation assays and in vivo lineage tracing experiments demonstrate that Zeb1+ epithelioid cells are putative cells of origin for NEPC. Mechanistically, Zeb1 transcriptionally regulates the expression of several key glycolytic enzymes, thereby predisposing tumor cells to utilize glycolysis for energy metabolism. During this process, lactate accumulation-mediated histone lactylation enhances chromatin accessibility and cellular plasticity including induction of neuro-gene expression, which promotes NEPC development. Collectively, Zeb1-driven metabolic rewiring enables the epigenetic reprogramming of prostate cancer cells to license the adeno-to-neuroendocrine lineage transition.

The N6-methyladenosine Epitranscriptomic Landscape of Lung Adenocarcinoma.

Comprehensive m6A epitranscriptome profiling of primary tumors remains largely uncharted. Here, we profiled the m6A epitranscriptome of 10 non-neoplastic lung (NL) tissues and 51 lung adenocarcinoma (LUAD) tumors, integrating the corresponding transcriptome, proteome and extensive clinical annotations. We identified distinct clusters and genes that were exclusively linked to disease progression through m6A modifications. In comparison with NL tissues, we identified 430 transcripts to be hypo-methylated and 222 to be hyper-methylated in tumors. Among these genes, EML4 emerged as a novel metastatic driver, displaying significant hyper-methylation in tumors. m6A modification promoted the translation of EML4, leading to its widespread overexpression in primary tumors. Functionally, EML4 modulated cytoskeleton dynamics through interacting with ARPC1A, enhancing lamellipodia formation, cellular motility, local invasion, and metastasis. Clinically, high EML4 protein abundance correlated with features of metastasis. METTL3 small molecule inhibitor markedly diminished both EML4 m6A and protein abundance, and efficiently suppressed lung metastases in vivo.

ADORA2A-driven proline synthesis triggers epigenetic reprogramming in neuroendocrine prostate and lung cancers.

Cell lineage plasticity is one of the major causes for the failure of targeted therapies in various cancers. However, the driver and actionable drug targets in promoting cancer cell lineage plasticity are scarcely identified. Here, we found that a G protein-coupled receptor, ADORA2A, is specifically upregulated during neuroendocrine differentiation, a common form of lineage plasticity in prostate cancer and lung cancer following targeted therapies. Activation of the ADORA2A signaling rewires the proline metabolism via an ERK/MYC/PYCR cascade. Increased proline synthesis promotes deacetylases SIRT6/7-mediated deacetylation of histone H3 at lysine 27 (H3K27), and thereby biases a global transcriptional output toward a neuroendocrine lineage profile. Ablation of Adora2a in genetically engineered mouse models inhibits the development and progression of neuroendocrine prostate and lung cancers, and, intriguingly, prevents the adenocarcinoma-to-neuroendocrine phenotypic transition. Importantly, pharmacological blockade of ADORA2A profoundly represses neuroendocrine prostate and lung cancer growth in vivo. Therefore, we believe that ADORA2A can be used as a promising therapeutic target to govern the epigenetic reprogramming in neuroendocrine malignancies.