The Droplet Creeping-Sliding Dynamic Wetting Mechanism on Bionic Self-Cleaning Surfaces.

The dynamic wetting behavior of droplets has been of wide concern due to the hazards of accretion/icing of supercooled droplets on engineering components/systems served in low temperature freezing rain environment; thus, it is urgent to establish the relationship between droplet depinning/removing behaviors and surface characteristics. In this article, the actual rotation conditions of moving components such as wind turbine blades are simulated. The self-cleaning hydrophobic coating surface(S1) and bionic superhydrophobic coating surface(S2) show outstanding droplet removal performance compared to hydrophilic bare steel surface(S0), and the average speed of the droplet removal is increased by 400-500%. The "creeping-sliding" behavior of droplets on self-cleaning coatings is investigated by the change of droplet displacement(ΔD). The effect of the energy storage caused by the droplet creeping process provides initial kinetic energy for the droplet removal. Combined with the experimental data and theoretical model, the critical depinning resistance is calculated. The difference of the wetting interface free energy(ΔEx) during the dynamic wetting process of the droplets on the bionic superhydrophobic self-cleaning surface is researched. And the influence mechanism of the droplet embedded depth(x) on the creeping/sliding behavior in the nanotexture is clarified. Thus, the mechanical criterion of droplet depinning is proposed (the error is about 10%). The results can provide a theoretical basis for the design principle of antifreezing rain coatings on moving components.

Targeting PELP1 oncogenic signaling in TNBC with the small molecule inhibitor SMIP34.

PURPOSE: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Oncogenic PELP1 is frequently overexpressed in TNBC, and it has been demonstrated that PELP1 signaling is essential for TNBC progression. The therapeutic utility of targeting PELP1 in TNBC, however, remains unknown. In this study, we investigated the effectiveness of SMIP34, a recently developed PELP1 inhibitor for the treatment of TNBC. METHODS: To ascertain the impact of SMIP34 treatment, we used seven different TNBC models for testing cell viability, colony formation, invasion, apoptosis, and cell cycle analysis. Western blotting and RT-qPCR were used to determine the mechanistic insights of SMIP34 action. Using xenograft and PDX tumors, the ability of SMIP34 in suppressing proliferation was examined both ex vivo and in vivo. RESULTS: TNBC cells' viability, colony formation, and invasiveness were all decreased by SMIP34 in in vitro cell-based assays, while apoptosis was increased. SMIP34 treatment promoted the degradation of PELP1 through the proteasome pathway. RT-qPCR analyses confirmed that SMIP34 treatment downregulated PELP1 target genes. Further, SMIP34 treatment substantially downregulated PELP1 mediated extranuclear signaling including ERK, mTOR, S6 and 4EBP1. Mechanistic studies confirmed downregulation of PELP1 mediated ribosomal biogenesis functions including downregulation of cMyc and Rix complex proteins LAS1L, TEX-10, and SENP3. The proliferation of TNBC tumor tissues was decreased in explant experiments by SMIP34. Additionally, SMIP34 treatment markedly decreased tumor progression in both TNBC xenograft and PDX models. CONCLUSIONS: Together, these findings from in vitro, ex vivo, and in vivo models show that SMIP34 may be a useful therapeutic agent for inhibiting PELP1 signaling in TNBC.

Methods to detect and characterize introgression.

Introgression, also known as introgressive hybridization, refers to the process that genetic components from the gene pool of one population transfer to the other via constant backcrossing. Introgression is widespread in nature, which plays important roles in increasing genetic diversity and improving adaptability to the environment, and in turn, influences the evolutionary progress of animals, plants and humans. Being as an important evolutionary event, researchers pay great attention to the detection of introgression, the introgression direction, the introgression timing, the pattern of introgression and so on. With the rapid development of high-throughput sequencing technologies, methods to detect and characterize introgression based on genome-wide data are continuously developed. In this review, we summarize a series of methods for introgression detection, and introduce the design principles and applications of these methods. We also discuss the maintenance and selection of gene segments after introgression. This review provides a relatively comprehensive reference for the studies on introgression.

SETDB1 interactions with PELP1 contributes to breast cancer endocrine therapy resistance.

BACKGROUND: Methyltransferase SETDB1 is highly expressed in breast cancer (BC), however, the mechanisms by which SETDB1 promotes BC progression to endocrine therapy resistance remains elusive. In this study, we examined the mechanisms by which SETDB1 contribute to BC endocrine therapy resistance. METHODS: We utilized therapy sensitive (MCF7 and ZR75), therapy resistant (MCF7-TamR, MCF7-FR, MCF7-PELP1cyto, MCF7-SETDB1) estrogen receptor alpha positive (ER+)BC models and conducted in vitro cell viability, colony formation, 3-dimensional cell growth assays to investigate the role of SETDB1 in endocrine resistance. RNA-seq of parental and SETDB1 knock down ER+ BC cells was used to identify unique pathways. SETDB1 interaction with PELP1 was identified by yeast-two hybrid screen and confirmed by immunoprecipitation and GST-pull down assays. Mechanistic studies were conducted using Western blotting, reporter gene assays, RT-qPCR, and in vitro methylation assays. Xenograft assays were used to establish the role of PELP1 in SETDB1 mediated BC progression. RESULTS: RNA-seq analyses showed that SETDB1 regulates expression of a subset of estrogen receptor (ER) and Akt target genes that contribute to endocrine therapy resistance. Importantly, using yeast-two hybrid screen, we identified ER coregulator PELP1 as a novel interacting protein of SETDB1. Biochemical analyses confirmed SETDB1 and PELP1 interactions in multiple BC cells. Mechanistic studies confirmed that PELP1 is necessary for SETDB1 mediated Akt methylation and phosphorylation. Further, SETDB1 overexpression promotes tamoxifen resistance in BC cells, and PELP1 knockdown abolished these effects. Using xenograft model, we provided genetic evidence that PELP1 is essential for SETDB1 mediated BC progression in vivo. Analyses of TCGA datasets revealed SETDB1 expression is positively correlated with PELP1 expression in ER+ BC patients. CONCLUSIONS: This study suggests that the PELP1/SETDB1 axis play an important role in aberrant Akt activation and serves as a novel target for treating endocrine therapy resistance in breast cancer.

Genome-wide analysis suggests multiple domestication events of Chinese local pigs.

Chinese local pigs have abundant phenotypes as a result of different cultures and habits of Chinese populations, geographic constraints and the long history of pig domestication. A comprehensive investigation of local Chinese pigs will benefit biodiversity research and future breeding practices. However, their classification and demographic history are not yet clear. We studied 91 Chinese local pigs from 14 breeds and 15 Chinese wild boars to reveal the dispersal of Chinese pigs, genetic groups and the demographic history. Based on spatial feature analyses, we believe that the geographic landscape played an important role in the dispersal of local pigs. According to genetic studies, Chinese pigs are divided into three groups where each group appears to have a distinct background. The nucleotide diversity, observed heterozygosity, runs of homozygosity and inbreeding coefficient varied among the groups and widespread migration also existed between the groups. Furthermore, demographic models have been constructed to explain the evolutionary relationship between the groups using the approximate Bayesian computation approach. These suggested that Chinese local pigs are inherited from an extinct Sus scrofa population from ~22 000 years ago. Then, the three groups diverged from ancestors ~16 000, ~11 000 and ~8700 years ago respectively. This study advances our understanding of the genetic variation and demographic history of Chinese local pigs.

The suitable biomass carbon source for improving nitrogen removal in surface flow constructed wetland system: Fresh vs. withered.

Plant biomass can be used as a carbon source to enhance the nitrogen removal effect. Related researches mainly focused on withered biomass, while little on fresh biomass. In this study, batch experiments revealed that the carbon release rate (60.5 mg TOC g-1) of fresh biomass was significantly higher than that of withered biomass (44.9 mg TOC g-1), while the nitrogen release rate showed the opposite trend. Compared with withered biomass, fresh biomass could release more sugar and less refractory humic acid, which means higher bioavailability. After adding fresh biomass, TN removal rate increased from 18.65% to 51.59%. The TN removal in the wetland adding withered biomass increased from 13.59% to 42.25%. The biomass addition had a slight impact on the effluent sensory quality in the first two days. After adding fresh biomass and withered biomass, the relative abundance of denitrifying bacteria like Flavobacterium and Pseudomonas in the system significantly increased. In general, fresh biomass was more suitable as a denitrification carbon source for surface flow constructed wetlands.

Approaching Quantum-Limited Metrology with Imperfect Detectors by Using Weak-Value Amplification.

Weak-value amplification (WVA) is a metrological protocol that amplifies ultrasmall physical effects. However, the amplified outcomes necessarily occur with highly suppressed probabilities, leading to the extensive debate on whether the overall measurement precision is improved in comparison to that of conventional measurement (CM). Here, we experimentally demonstrate the unambiguous advantages of WVA that overcome practical limitations including noise and saturation of photodetection and maintain a shot-noise-scaling precision for a large range of input light intensity well beyond the dynamic range of the photodetector. The precision achieved by WVA is 6 times higher than that of CM in our setup. Our results clear the way for the widespread use of WVA in applications involving the measurement of small signals including precision metrology and commercial sensors.

Complete Mitochondrial Genome of Echinostoma hortense (Digenea: Echinostomatidae).

Echinostoma hortense (Digenea: Echinostomatidae) is one of the intestinal flukes with medical importance in humans. However, the mitochondrial (mt) genome of this fluke has not been known yet. The present study has determined the complete mt genome sequences of E. hortense and assessed the phylogenetic relationships with other digenean species for which the complete mt genome sequences are available in GenBank using concatenated amino acid sequences inferred from 12 protein-coding genes. The mt genome of E. hortense contained 12 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes, and 1 non-coding region. The length of the mt genome of E. hortense was 14,994 bp, which was somewhat smaller than those of other trematode species. Phylogenetic analyses based on concatenated nucleotide sequence datasets for all 12 protein-coding genes using maximum parsimony (MP) method showed that E. hortense and Hypoderaeum conoideum gathered together, and they were closer to each other than to Fasciolidae and other echinostomatid trematodes. The availability of the complete mt genome sequences of E. hortense provides important genetic markers for diagnostics, population genetics, and evolutionary studies of digeneans.

The complete mitochondrial genome of Oxyuris equi: Comparison with other closely related species and phylogenetic implications.

The equine pinworm Oxyuris equi (Nematoda: Oxyuridomorpha) is the most common horse nematode, has a worldwide distribution, and causes major economic losses. In the present study, the complete O. equi mitochondrial (mt) genome was sequenced, and the mt genome structure and organization were compared with those of other closely related pinworm species, Enterobius vermicularis and Wellcomia siamensis. The O. equi mt genome is a 13,641-bp circular DNA molecule that encodes 36 genes (12 protein-coding genes, 22 tRNAs, and two rRNAs) and one non-coding region, which is slightly shorter than that of E. vermicularis and W. siamensis. The O. equi mt gene arrangement was consistent with that of GA13-type E. vermicularis but it differs from GA12-type W. siamensis. Phylogenetic analyses using concatenated amino acid sequences of the 12 protein-coding genes with three different computational algorithms (maximum parsimony, maximum likelihood, and Bayesian inference) revealed that there were two distinct clades in Chromadorea nematodes that reflected infraorder. Spiruromorpha formed one clade, whereas Rhabditomorpha, Ascaridomorpha, and Oxyuridomorpha formed another clade. O. equi, E. vermicularis, and W. siamensis represent distinct but closely related species, which indicated that Oxyuridomorpha is paraphyletic. Sequencing the O. equi mt genome provides novel genetic markers for studying the molecular epidemiology and population genetics of pinworms.

The complete mitochondrial genome of Strongylus equinus (Chromadorea: Strongylidae): Comparison with other closely related species and phylogenetic analyses.

The roundworms of genus Strongylus are the common parasitic nematodes in the large intestine of equine, causing significant economic losses to the livestock industries. In spite of its importance, the genetic data and epidemiology of this parasite are not entirely understood. In the present study, the complete S. equinus mitochondrial (mt) genome was determined. The length of S. equinus mt genome DNA sequence is 14,545 bp, containing 36 genes, of which 12 code for protein, 22 for transfer RNA, and two for ribosomal RNA, but lacks atp8 gene. All 36 genes are encoded in the same direction which is consistent with all other Chromadorea nematode mtDNAs published to date. Phylogenetic analysis based on concatenated amino acid sequence data of all 12 protein-coding genes showed that there were two large branches in the Strongyloidea nematodes, and S. equinus is genetically closer to S. vulgaris than to Cylicocyclus insignis in Strongylidae. This new mt genome provides a source of genetic markers for the molecular phylogeny and population genetics of equine strongyles.

Older people's experiences of hospitalization for surgical intervention for hip fracture: A systematic review.

BACKGROUND: Hip fracture always requires hospitalization with high cost, which cause the complicated experiences and feelings. OBJECTIVE: To inform pre- and in-hospital communication practices between healthcare professionals and patients through a systematic review and qualitative research that synthesizes the experiences and feelings of older patients with hip fracture during the perioperative period. METHODS: We searched the Cochrane Library, PubMed, Web of Science, CINAHL, and three Chinese databases for relevant studies. Qualitative studies were included if they were related to the experiences and needs of hospitalization of older patients with hip fracture. Study quality was evaluated using the 2016 Joanna Briggs Institute quality evaluation criteria for qualitative research, and the results were consolidated using an thematic synthesis approach. RESULTS: Sixteen studies were included in our meta-synthesis. We extracted 58 clear research topics. Eight new categories were formed after induction and integration, which were finally merged into three integrated results. Integration result 1: Patients suffered a large amount of physical and psychological trauma. Integration result 2: A balance of proper protection and independence for patients is required. Integration result 3: Adequate pre-discharge preparation is required. CONCLUSIONS: Our review suggests that healthcare professionals should reduce pain catastrophizing and the fear of falling after surgery among older people with hip fracture. Furthermore, adequate pre-discharge preparation should be made jointly with patients. Meeting patients' diverse needs by various methods will promote active and healthy aging.

An Update on MR Spectroscopy in Cancer Management: Advances in Instrumentation, Acquisition, and Analysis.

MR spectroscopy (MRS) is a noninvasive imaging method enabling chemical and molecular profiling of tissues in a localized, multiplexed, and nonionizing manner. As metabolic reprogramming is a hallmark of cancer, MRS provides valuable metabolic and molecular information for cancer diagnosis, prognosis, treatment monitoring, and patient management. This review provides an update on the use of MRS for clinical cancer management. The first section includes an overview of the principles of MRS, current methods, and conventional metabolites of interest. The remainder of the review is focused on three key areas: advances in instrumentation, specifically ultrahigh-field-strength MRI scanners and hybrid systems; emerging methods for acquisition, including deuterium imaging, hyperpolarized carbon 13 MRI and MRS, chemical exchange saturation transfer, diffusion-weighted MRS, MR fingerprinting, and fast acquisition; and analysis aided by artificial intelligence. The review concludes with future recommendations to facilitate routine use of MRS in cancer management. Keywords: MR Spectroscopy, Spectroscopic Imaging, Molecular Imaging in Oncology, Metabolic Reprogramming, Clinical Cancer Management © RSNA, 2024.

Key factors influencing sensory quality of scenic waters and its improvement by constructed wetlands.

Sensory quality is very important for scenic waters. It's necessary to find out the key factors influencing sensory quality of scenic waters and then take corresponding measures to improve it. In this study, transparency, turbidity and surface chroma were chosen as the main sensory quality indexes whose key influencing factors were analyzed by structural equation model (SEM). The results indicated that water's transparency, turbidity and surface chroma were all mainly influenced by suspended solid (SS). Meanwhile, transparency was also influenced by Chlorophyll a (Chl a), pH, dissolved oxygen (DO), particle size and nutrients. Turbidity was influenced by Chl a and particle size as well. To verify this result and improve water's sensory quality, three constructed wetlands (CWs) were set up and operated. CWs could effectively improve the sensory quality of water bodies. When hydraulic retention time (HRT) was 2 days, the water' transparency increased from 18.00 ± 2.83 cm to about 100 cm, the removal rate of turbidity was 56.26% âˆ¼ 97.11%, and the average removal rate of surface chroma of the three CWs was 72.56%, 70.31% and 63.36%, respectively. To get a better improvement effect, planting and extending HRT were feasible measures. The mechanism analysis showed that removing SS, especially large particles in water was the main reason for improving sensory quality by CWs, followed by removing Chl a. The operational results of CWs proved that SS was certainly the key influencing factor of water's sensory quality.

PELP1 inhibition by SMIP34 reduces endometrial cancer progression via attenuation of ribosomal biogenesis.

Endometrial carcinoma (ECa) is the fourth most common cancer among women. The oncogene PELP1 is frequently overexpressed in a variety of cancers, including ECa. We recently generated SMIP34, a small-molecule inhibitor of PELP1 that suppresses PELP1 oncogenic signaling. In this study, we assessed the effectiveness of SMIP34 in treating ECa. Treatment of established and primary patient-derived ECa cells with SMIP34 resulted in a significant reduction of cell viability, colony formation ability, and induction of apoptosis. RNA-seq analyses showed that SMIP34-regulated genes were negatively correlated with ribosome biogenesis and eukaryotic translation pathways. Mechanistic studies showed that the Rix complex, which is essential for ribosomal biogenesis, is disrupted upon SMIP34 binding to PELP1. Biochemical assays confirmed that SMIP34 reduced ribosomal biogenesis and new protein synthesis. Further, SMIP34 enhanced the efficacy of mTOR inhibitors in reducing viability of ECa cells. SMIP34 is also effective in reducing cell viability in ECa organoids in vitro and explants ex vivo. Importantly, SMIP34 treatment resulted in a significant reduction of the growth of ECa xenografts. Collectively, these findings underscore the potential of SMIP34 in treating ECa.

Pharmacological inhibition of KDM1A/LSD1 enhances estrogen receptor beta-mediated tumor suppression in ovarian cancer.

Ovarian cancer (OCa) is the most lethal gynecologic cancer. Emerging data indicates that estrogen receptor beta (ERß) functions as a tumor suppressor in OCa. Lysine-specific histone demethylase 1A (KDM1A) is an epigenetic modifier that acts as a coregulator for steroid hormone receptors. However, it remain unknown if KDM1A interacts with ERß and regulates its expression/functions in OCa. Analysis of TCGA data sets indicated KDM1A and ERß expression showed an inverse relationship in OCa. Knockout (KO), knockdown (KD), or inhibition of KDM1A increased ERß isoform 1 expression in established and patient-derived OCa cells. Further, KDM1A interacts with and functions as a corepressor of ERß, and its inhibition enhances ERß target gene expression via alterations of histone methylation marks at their promoters. Importantly, KDM1A-KO or -KD enhanced the efficacy of ERß agonist LY500307, and the combination of KDM1A inhibitor (KDM1Ai) NCD38 with ERß agonist synergistically reduced the cell viability, colony formation, and invasion of OCa cells. RNA-seq and DIA mass spectrometry analyses showed that KDM1A-KO resulted in enhanced ERß signaling and that genes altered by KDM1A-KO and ERß agonist were related to apoptosis, cell cycle, and EMT. Moreover, combination treatment significantly reduced the tumor growth in OCa orthotopic, syngeneic, and patient-derived xenograft models and proliferation in patient-derived explant models. Our results demonstrate that KDM1A regulates ERß expression/functions, and its inhibition improves ERß mediated tumor suppression. Overall, our findings suggest that KDM1Ai and ERß agonist combination therapy is a promising strategy for OCa.

Demographic reporting across a decade of neuroimaging: a systematic review.

Diversity of participants in biomedical research with respect to race, ethnicity, and biological sex is crucial, particularly given differences in disease prevalence, recovery, and survival rates between demographic groups. The objective of this systematic review was to report on the demographics of neuroimaging studies using magnetic resonance imaging (MRI). The Web of Science database was used and data collection was performed between June 2021 to November 2021; all articles were reviewed independently by at least two researchers. Articles utilizing MR data acquired in the United States, with n ≥ 10 human subjects, and published between 2010-2020 were included. Non-primary research articles and those published in journals that did not meet a quality control check were excluded. Of the 408 studies meeting inclusion criteria, approximately 77% report sex, 10% report race, and 4% report ethnicity. Demographic reporting also varied as function of disease studied, participant age range, funding, and publisher. We anticipate quantitative data on the extent, or lack, of reporting will be necessary to ensure inclusion of diverse populations in biomedical research.

Global Genomic and Proteomic Analysis Identified Critical Pathways Modulated by Proto-Oncogene PELP1 in TNBC.

The PELP1 oncogene is commonly overexpressed in many cancers, including triple negative breast cancer (TNBC). However, the mechanisms by which PELP1 contributes to TNBC progression are not well understood. To elucidate these mechanisms, we generated CRISPR-Cas9 mediated PELP1 knockout TNBC cell lines, and alterations in the proteome were examined using global data-independent acquisition mass spectrometry (DIA-MS). Further mechanistic studies utilized shRNA knockdown, Western blotting, and RNA-seq approaches. TCGA data sets were utilized for determining the status of PELP1 in TNBC patient tumors and for examining its correlation with ribosomal proteins. Global DIA-MS studies revealed that 127 proteins are upregulated while 220 proteins are downregulated upon PELP1-KO. Bioinformatic analyses suggested that the oncogenic activities of PELP1 involve regulation of expression of ribosomal proteins and ribosomal complexes. RNA-seq studies further suggested PELP1 modulates the functions of transcription factor c-Myc in TNBC. TCGA data confirmed PELP1 has high expression in TNBC patient tumors, and this high expression pattern correlates with c-Myc, a regulator of ribosomal proteins. Collectively, our global approach studies suggest that PELP1 contributes to TNBC progression by modulation of cell cycle, apoptosis, and ribosome biogenesis pathways.

Inhibition of LIFR Blocks Adiposity-Driven Endometrioid Endometrial Cancer Growth.

Endometrial cancer (EC) is the fourth most common cancer in women, and half of the endometrioid EC (EEC) cases are attributable to obesity. However, the underlying mechanism(s) of obesity-driven EEC remain(s) unclear. In this study, we examined whether LIF signaling plays a role in the obesity-driven progression of EEC. RNA-seq analysis of EEC cells stimulated by adipose conditioned medium (ADP-CM) showed upregulation of LIF/LIFR-mediated signaling pathways including JAK/STAT and interleukin pathways. Immunohistochemistry analysis of normal and EEC tissues collected from obese patients revealed that LIF expression is upregulated in EEC tissues compared to the normal endometrium. Treatment of both primary and established EEC cells with ADP-CM increased the expression of LIF and its receptor LIFR and enhanced proliferation of EEC cells. Treatment of EEC cells with the LIFR inhibitor EC359 abolished ADP-CM induced colony formation andcell viability and decreased growth of EEC organoids. Mechanistic studies using Western blotting, RT-qPCR and reporter assays confirmed that ADP-CM activated LIF/LIFR downstream signaling, which can be effectively attenuated by the addition of EC359. In xenograft assays, co-implantation of adipocytes significantly enhanced EEC xenograft tumor growth. Further, treatment with EC359 significantly attenuated adipocyte-induced EEC progression in vivo. Collectively, our data support the premise that LIF/LIFR signaling plays an important role in obesity-driven EEC progression and the LIFR inhibitor EC359 has the potential to suppress adipocyte-driven tumor progression.

A First-in-Class Inhibitor of ER Coregulator PELP1 Targets ER+ Breast Cancer.

Most patients with estrogen receptor alpha-positive (ER+) breast cancers initially respond to treatment but eventually develop therapy resistance with disease progression. Overexpression of oncogenic ER coregulators, including proline, glutamic acid, and leucine-rich protein 1 (PELP1), are implicated in breast cancer progression. The lack of small molecules that inhibits PELP1 represents a major knowledge gap. Here, using a yeast-two-hybrid screen, we identified novel peptide inhibitors of PELP1 (PIP). Biochemical assays demonstrated that one of these peptides, PIP1, directly interacted with PELP1 to block PELP1 oncogenic functions. Computational modeling of PIP1 revealed key residues contributing to its activity and facilitated the development of a small-molecule inhibitor of PELP1, SMIP34, and further analyses confirmed that SMIP34 directly bound to PELP1. In breast cancer cells, SMIP34 reduced cell growth in a dose-dependent manner. SMIP34 inhibited proliferation of not only wild-type (WT) but also mutant (MT) ER+ and therapy-resistant breast cancer cells, in part by inducing PELP1 degradation via the proteasome pathway. RNA sequencing analyses showed that SMIP34 treatment altered the expression of genes associated with estrogen response, cell cycle, and apoptosis pathways. In cell line-derived and patient-derived xenografts of both WT and MT ER+ breast cancer models, SMIP34 reduced proliferation and significantly suppressed tumor progression. Collectively, these results demonstrate SMIP34 as a first-in-class inhibitor of oncogenic PELP1 signaling in advanced breast cancer. SIGNIFICANCE: Development of a novel inhibitor of oncogenic PELP1 provides potential therapeutic avenues for treating therapy-resistant, advanced ER+ breast cancer.

Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress.

Triple-negative breast cancer (TNBC) has a poor clinical outcome, due to a lack of actionable therapeutic targets. Herein we define lysosomal acid lipase A (LIPA) as a viable molecular target in TNBC and identify a stereospecific small molecule (ERX-41) that binds LIPA. ERX-41 induces endoplasmic reticulum (ER) stress resulting in cell death, and this effect is on target as evidenced by specific LIPA mutations providing resistance. Importantly, we demonstrate that ERX-41 activity is independent of LIPA lipase function but dependent on its ER localization. Mechanistically, ERX-41 binding of LIPA decreases expression of multiple ER-resident proteins involved in protein folding. This targeted vulnerability has a large therapeutic window, with no adverse effects either on normal mammary epithelial cells or in mice. Our study implicates a targeted strategy for solid tumors, including breast, brain, pancreatic and ovarian, whereby small, orally bioavailable molecules targeting LIPA block protein folding, induce ER stress and result in tumor cell death.