TOP CAR with TMIGD2 as a safe and effective costimulatory domain in CAR cells treating human solid tumors.

Chimeric antigen receptor (CAR)-T cell therapy shows impressive efficacy treating hematologic malignancies but requires further optimization in solid tumors. Here, we developed a TMIGD2 optimized potent/persistent (TOP) CAR that incorporated the costimulatory domain of TMIGD2, a T and NK cell costimulator, and monoclonal antibodies targeting the IgV domain of B7-H3, an immune checkpoint expressed on solid tumors and tumor vasculature. Comparing second- and third-generation B7-H3 CARs containing TMIGD2, CD28, and/or 4-1BB costimulatory domains revealed superior antitumor responses in B7-H3.TMIGD2 and B7-H3.CD28.4-1BB CAR-T cells in vitro. Comparing these two constructs using in vivo orthotopic human cancer models demonstrated that B7-H3.TMIGD2 CAR-T cells had equivalent or superior antitumor activity, survival, expansion, and persistence. Mechanistically, B7-H3.TMIGD2 CAR-T cells maintained mitochondrial metabolism; produced less cytokines; and established fewer exhausted cells, more central memory cells, and a larger CD8/CD4 T cell ratio. These studies demonstrate that the TOP CAR with TMIGD2 costimulation offered distinct benefits from CD28.41BB costimulation and is effective against solid tumors.

Spin Crossover in [Fe(qsal-5-Brq)2]+ Complexes with a Quinoline-Substituted Qsal Ligand.

Using a quinoline substituted Qsal ligand, Hqsal-5-Brq (Hqsal-5-Brq = N-(5-bromo-8-quinolyl)salicylaldimine), four FeIII complexes, [Fe(qsal-5-Brq)2]A·CH3OH (Y = NO3- (1NO3), BF4- (2BF4), PF6- (3PF6), OTf- (4OTf), were prepared and characterized. Structure analysis revealed that complex 2BF4 contained two species (2BF4(P1̅) and 2BF4(C2/c)). In these compounds except 3PF6, the [Fe(qsal-5-Brq)2]+ cations form 1D chains through π-π interactions and other weak interactions. Adjacent chains are connected to form the 2D "Chain Layer" structures and 3D structures through various supramolecular interactions. For 3PF6, a "Dimer Chain" structure is formed from the loosely connected dimers. Magnetic studies revealed that compounds 1NO3 and 2BF4(P1̅) displayed abrupt hysteretic SCO with the transition temperature T1/2↓ = 235 K, T1/2↑ = 240 K for 1NO3 and T1/2↓ = 230 K, T1/2↑ = 235 K for 2BF4(P1̅), while compounds 3PF6 and 4OTf are in the HS state. Desolvation of the complexes significantly modifies their SCO properties: the desolvated 1NO3 and 2BF4 show a gradual SCO, desolvated 3PF6 undergoes a two-step SCO, and desolvated 4OTf exhibits a hysteretic transition. Overall, this work reported the FeIII-SCO complexes of the quinoline-substituted Hqsal ligand and highlighted the potential of these ligands for the development of interesting FeIII-SCO materials.

Corrigendum: Untreated depression and anxiety in patients with common skin diseases: a cross-sectional study in China.

[This corrects the article DOI: 10.3389/fpsyg.2023.1150998.].

Elevated expression of WSB2 degrades p53 and activates the IGFBP3-AKT-mTOR-dependent pathway to drive hepatocellular carcinoma.

Dysregulation of wild-type p53 turnover is a key cause of hepatocellular carcinoma (HCC), yet its mechanism remains poorly understood. Here, we report that WD repeat and SOCS box containing protein 2 (WSB2), an E3 ubiquitin ligase, is an independent adverse prognostic factor in HCC patients. WSB2 drives HCC tumorigenesis and lung metastasis in vitro and in vivo. Mechanistically, WSB2 is a new p53 destabilizer that promotes K48-linked p53 polyubiquitination at the Lys291 and Lys292 sites in HCC cells, leading to p53 proteasomal degradation. Degradation of p53 causes IGFBP3-dependent AKT/mTOR signaling activation. Furthermore, WSB2 was found to bind to the p53 tetramerization domain via its SOCS box domain. Targeting mTOR with everolimus, an oral drug, significantly blocked WSB2-triggered HCC tumorigenesis and metastasis in vivo. In clinical samples, high expression of WSB2 was associated with low wild-type p53 expression and high p-mTOR expression. These findings demonstrate that WSB2 is overexpressed and degrades wild-type p53 and then activates the IGFBP3-AKT/mTOR axis, leading to HCC tumorigenesis and lung metastasis, which indicates that targeting mTOR could be a new therapeutic strategy for HCC patients with high WSB2 expression and wild-type p53.

LILRB3 Supports Immunosuppressive Activity of Myeloid Cells and Tumor Development.

The existing T cell-centered immune checkpoint blockade therapies have been successful in treating some but not all patients with cancer. Immunosuppressive myeloid cells, including myeloid-derived suppressor cells (MDSC), that inhibit antitumor immunity and support multiple steps of tumor development are recognized as one of the major obstacles in cancer treatment. Leukocyte Ig-like receptor subfamily B3 (LILRB3), an immune inhibitory receptor containing tyrosine-based inhibitory motifs (ITIM), is expressed solely on myeloid cells. However, it is unknown whether LILRB3 is a critical checkpoint receptor in regulating the activity of immunosuppressive myeloid cells, and whether LILRB3 signaling can be blocked to activate the immune system to treat solid tumors. Here, we report that galectin-4 and galectin-7 induce activation of LILRB3 and that LILRB3 is functionally expressed on immunosuppressive myeloid cells. In some samples from patients with solid cancers, blockade of LILRB3 signaling by an antagonistic antibody inhibited the activity of immunosuppressive myeloid cells. Anti-LILRB3 also impeded tumor development in myeloid-specific LILRB3 transgenic mice through a T cell-dependent manner. LILRB3 blockade may prove to be a novel approach for immunotherapy of solid cancers.

Eavesdropping on wastewater pollution: Detecting discharge events from river outfalls via fiber-optic distributed acoustic sensing.

Wastewater discharge from outfall pipes can significantly impact river water quality and aquatic ecosystems. Effective outfall monitoring is critical for controlling pollution and protecting public health. This study demonstrates a novel distributed acoustic sensing (DAS) approach for detecting wastewater discharge events from outfall pipes located along rivers. Controlled field experiments were conducted in an industrial park river to systematically evaluate DAS performance. DAS detects vibrational signals imparted to suspended fiber-optic cables by turbulent wastewater flows, predominantly within 10-30 Hz, enabling continuous monitoring along entire river lengths. Vibrational power analysis locates outfalls with meter-level accuracy, while time-frequency techniques discern discharge timing and characteristics. Cable type and outfall-fiber separation influence on detection capability was assessed. Thermoplastic-jacketed tight buffer cables optimized detection through enhanced vibrational coupling. Vibrational energy decreased exponentially with separation, highlighting benefits of proximal deployment for sensitivity. However, detection range scales with discharge flow rate. Frequency centroid proved a robust feature with potential for automated discharge identification. Overall, DAS enables high spatiotemporal resolution monitoring to pinpoint concealed outfalls minimally invasively. This positions DAS as a promising tool supporting improved water governance through early pollution warnings and rapid source localization via outfall vibrational signatures emanating across river networks.

Corrigendum: Untreated depression and anxiety in patients with common skin diseases: a cross-sectional study in China.

[This corrects the article DOI: 10.3389/fpsyg.2023.1150998.].

Syntheses, Structures, and Magnetic Properties of Three Cyano-Bridged FeII-MoIII Single-Molecule Magnets.

Three new cyano-bridged FeII-MoIII complexes assembled from the [MoIII(CN)7]4- unit, FeII ions, and three pentadentate N3O2 ligands, namely {[Fe2H3(dapab)2][Mo(CN)6]}n·2H2O·3.5MeCN (1), [Fe(H2dapb)(H2O)][Fe(Hdapb)(H2O)][Mo(CN)6]·4H2O·3MeCN (2), and [Fe(H2dapba)(H2O)]2[Mo(CN)7]·6H2O (3) (H2dapab = 2,6-diacetylpyridine bis(2-aminobenzoylhydrazone), H2dapb = 2,6-diacetylpyridine bis(benzoylhydrazone), H2dapba = 2,6-diacetylpyridine bis(4-aminobenzoylhydrazone)), have been synthesized and characterized. Single-crystal structure analyses suggest that complex 1 contains a one-dimensional (1D) chain structure where two FeII ions are bridged by the in situ generated [MoIII(CN)6]3- unit through two trans-cyanide groups into trinuclear Fe2IIMoIII clusters that are further linked by the amino of the ligand into an infinite chain. Complexes 2 and 3 are cyano-bridged Fe2IIMoIII trinuclear clusters with two FeII ions connected by the [MoIII(CN)6]3- and [MoIII(CN)7]4- units, respectively. Direct current magnetic studies confirmed the ferromagnetic interactions between the cyano-bridged FeII and MoIII centers and significant easy-axis magnetic anisotropy for all three complexes. Furthermore, complexes 1-3 exhibit slow magnetic relaxation under a zero dc field, with relaxation barriers of 42.3, 21.6, and 14.4 K, respectively, making them the first examples of cyano-bridged FeII-MoIII single-molecule magnets.

Untreated depression and anxiety in patients with common skin diseases: a cross-sectional study in China.

Objective: The study aimed to analyze the current status and reasons for the neglect of the psychological need of patients with common skin diseases. Methods: This cross-sectional study was conducted in China using an online self-assessment questionnaire distributed via social media. Demographic, clinical and psychological data were collected, and the main outcomes, i.e., depression (evaluated using the 9-item Patient Health Questionnaire, PHQ-9) and anxiety (evaluated using Generalized Anxiety Disorder-7, GAD-7). Multivariate regression analysis was used for the prediction of variates of mental health service seeking behaviors. Results: A total of 1,010 patients participated in the survey, and 273 (27.0%) patients met the "with need" criteria, i.e., having the need for mental health intervention but not being treated. In the multivariate regression model, income (OR = 0.80, 95%CI: 0.65-0.99), duration of disease (OR = 0.68, 95%CI: 0.49-0.95) and suicide ideation (OR = 2.10, 95%CI: 1.14-3.87) were significant factors. For patients who did not receive mental health care, the lack of knowledge about the availability of mental health services, lack of knowledge of where to seek help, concerns about the side effects of treatment, failure to seek treatment for severe skin diseases, and absence of current psychological distress were associated with their need for psychological intervention. Conclusion: This study examined the current status of the need for psychological intervention and the reasons why the need was unmet in patients with skin diseases. Due to the confusion and a lack of knowledge about their mental health issues, mental health services are often underutilized.

Syntheses and magnetic properties of a bis-bidentate nitronyl nitroxide radical based on triazolopyrimidine and its metal complexes.

A novel bis-bidentate nitronyl nitroxide radical based on triazolopyrimidine, NIT-2-TrzPm (NIT-2-TrzPm = (2-(2'-triazolopyrimidine)-4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazol-1-oxy-3-oxide)) and six new transition metal complexes of this ligand, namely [M(hfac)2(NIT-2-TrzPm)]·CH2Cl2 (M = Mn (1Mn) and Co (2Co)), [M(hfac)2]2(NIT-2-TrzPm) (M = Mn (3Mn) and Co (4Co)), [Mn(NIT-2-TrzPm)2(MeOH)2](ClO4)2·MeOH (5Mn), and [Co(NIT-2-TrzPm)2(MeOH)2]2(ClO4)4·4MeOH (6Co) were prepared and characterized structurally and magnetically. These complexes can be selectively synthesized by controlling the reaction ratio of M(hfac)2·2H2O to the radical ligand (for 1Mn to 4Co) or using metal perchlorates as the starting materials (for 5Mn and 6Co). Single crystal X-ray crystallographic analyses confirmed that 1Mn and 2Co are isostructural 3d-2p MII-radical complexes, in which the NIT-2-TrzPm radical acts as a terminal bidentate ligand chelating to one 3d ion, while 3Mn and 4Co are isostructural 3d-2p-3d MII-radical-MII complexes with the NIT-2-TrzPm radical acting as a bridging ligand between two 3d ions. For complexes 5Mn and 6Co, two NIT-2-TrzPm ligands from the equatorial positions coordinate with the metal center to form the 2p-3d-2p structures with the axial positions occupied by two methanol molecules. Magnetic analysis on the MnII complexes revealed the existence of a strong antiferromagnetic interaction between the MnII and the NIT radical spin, while weak ferromagnetic coupling for Mn⋯Mn and Rad⋯Rad in the Mn-NIT-Mn and Rad-Mn-Rad spins was confirmed. Interestingly, although the NIT-bridged complexes 3Mn and 4Co possess significantly different magnetic anisotropy, field-induced slow magnetic relaxation can be observed in both complexes, which was assigned to the phonon bottleneck effect for 3Mn and field-induced SMM behavior for 4Co. To the best of our knowledge, 3Mn is the first example of the NIT-bridged binuclear MnII complex undergoing slow magnetic relaxation.

Antibody therapies for the treatment of acute myeloid leukemia: exploring current and emerging therapeutic targets.

INTRODUCTION: Acute myeloid leukemia (AML) is the most common and deadly type of leukemia affecting adults. It is typically managed with rounds of non-targeted chemotherapy followed by hematopoietic stem cell transplants, but this is only possible in patients who can tolerate these harsh treatments and many are elderly and frail. With the identification of novel tumor-specific cell surface receptors, there is great conviction that targeted antibody therapies will soon become available for these patients. AREAS COVERED: In this review, we describe the current landscape of known target receptors for monospecific and bispecific antibody-based therapeutics for AML. Here, we characterize each of the receptors and targeted antibody-based therapeutics in development, illustrating the rational design behind each therapeutic compound. We then discuss the bispecific antibodies in development and how they improve immune surveillance of AML. For each therapeutic, we also summarize the available pre-clinical and clinical data, including data from discontinued trials. EXPERT OPINION: One antibody-based therapeutic has already been approved for AML treatment, the CD33-targeting antibody-drug conjugate, gemtuzumab ozogamicin. Many more are currently in pre-clinical and clinical studies. These antibody-based therapeutics can perform tumor-specific, elaborate cytotoxic functions and there is growing confidence they will soon lead to personalized, safe AML treatment options that induce durable remissions.

Gastroduodenal artery disconnection during liver transplantation decreases non-anastomotic stricture incidence.

BACKGROUND: The hepatic artery is the only blood source nourishing the biliary duct and associated with biliary complication after liver transplantation (LT). Gastroduodenal artery (GDA) disconnection increased proper hepatic artery flow. Whether this procedure attenuates biliary non-anastomotic stricture (NAS) is not clear. METHODS: A total of 241 patients with LT were retrospectively analyzed. The patients were divided into the GDA disconnection (GDA-) and GDA preservation (GDA+) groups. Propensity score matching (PSM) was administrated to reduce bias. Logistic regression was conducted to analyze risk factors for biliary NAS before and after PSM. Postoperative complications were compared. Kaplan-Meier survival analysis and log-rank tests were performed to compare overall survival. RESULTS: In all, 99 patients (41.1%) underwent GDA disconnection, and 49 (20.3%) developed NAS. Multivariate logistic regression revealed that GDA preservation (OR = 2.24, 95% CI: 1.11-4.53; P = 0.025) and model for end-stage liver disease (MELD) score > 15 (OR = 2.14, 95% CI: 1.12-4.11; P = 0.022) were risk factors for biliary NAS. PSM provided 66 pairs using 1:2 matching method, including 66 GDA disconnection and 99 GDA preservation patients. Multivariate logistic regression after PSM also showed that GDA preservation (OR = 3.15, 95% CI: 1.26-7.89; P = 0.014) and MELD score > 15 (OR = 2.41, 95% CI: 1.08-5.36; P = 0.031) were risk factors for NAS. When comparing complications between the two groups, GDA preservation was associated with a higher incidence of biliary NAS before and after PSM (P = 0.031 and 0.017, respectively). In contrast, other complications including early allograft dysfunction (P = 0.620), small-for-size graft syndrome (P = 0.441), abdominal hemorrhage (P = 1.000), major complications (Clavien-Dindo grade ≥ 3, P = 0.318), and overall survival (P = 0.088) were not significantly different between the two groups. CONCLUSIONS: GDA disconnection during LT ameliorates biliary NAS incidence and may be recommended for application in clinical practice.

A perspective on LILRBs and LAIR1 as immune checkpoint targets for cancer treatment.

Immunosuppressive myeloid cells in the tumor microenvironment inhibit anti-tumor immunity and support tumor development. The leukocyte Ig-like receptor subfamily B (LILRB) proteins and the related receptor LAIR1 are immune checkpoint receptors that support the immunosuppressive activity of myeloid cells. All LILRBs and LAIR1 have intracellular immunoreceptor tyrosine-based inhibitory motifs in their signaling domains, but the individual proteins have different functions. The determinants of the distinct functions of these inhibitory receptors likely rest in their interactions with different ligands and other surface proteins, characteristic signaling domains, and expression dynamics in different cell types regulated by various extrinsic cues and transcription factors. Significant advancement of immuno-oncology therapeutic products based on targeting or reprogramming of LILRB- and LAIR1-mediated signaling is anticipated.

The Role of Vesicle Release and Synaptic Transmission in Depression.

Depressive disorder is the leading cause of disability worldwide, yet the mechanisms underlying depression are not fully understood. Vesicle release is essential for synaptic neurotransmission, the abnormalities of vesicle release and synaptic plasticity are associated with various neuropsychiatric disorders. Neural circuits are ensembles of interconnected neurons that collectively perform specific functions. To some extent, depression may be caused by a disruption in the structural and functional connections of the neural circuits underlying emotion regulation. In this review, we summarized the role of abnormalities of vesicle release and synaptic transmission, as well as the related regulatory molecules and signal pathways in the regulation of depression.

Blocking LAIR1 signaling in immune cells inhibits tumor development.

The current immune checkpoint blockade therapy has been successful in treating some cancers but not others. New molecular targets and therapeutic approaches of cancer immunology need to be identified. Leukocyte associated immunoglobulin like receptor 1 (LAIR1) is an immune inhibitory receptor expressing on most immune cell types. However, it remains a question whether we can specifically and actively block LAIR1 signaling to activate immune responses for cancer treatment. Here we report the development of specific antagonistic anti-LAIR1 monoclonal antibodies and studied the effects of LAIR1 blockade on the anti-tumor immune functions. The anti-LAIR1 antagonistic antibody stimulated the activities of T cells, natural killer cells, macrophages, and dendritic cells in vitro. The single-cell RNA sequencing analysis of intratumoral immune cells in syngeneic human LAIR1 transgenic mice treated with control or anti-LAIR1 antagonist antibodies indicates that LAIR1 signaling blockade increased the numbers of CD4 memory T cells and inflammatory macrophages, but decreased those of pro-tumor macrophages, regulatory T cells, and plasmacytoid dendritic cells. Importantly, the LAIR1 blockade by the antagonistic antibody inhibited the activity of immunosuppressive myeloid cells and reactivated T cells from cancer patients in vitro and impeded tumor metastasis in a humanized mouse model. Blocking LAIR1 signaling in immune cells represents a promising strategy for development of anti-cancer immunotherapy.

Transcutaneous auricular vagus nerve stimulation in poststroke cognitive impairment: protocol for a randomised controlled trial.

BACKGROUND: As one of the most common stroke sequelae, poststroke cognitive impairment significantly impacts 17.6%-83% of survivors, affecting their rehabilitation, daily living and quality of life. Improving cognitive abilities among patients in stroke recovery is therefore critical and urgent. Transcutaneous auricular vagus nerve stimulation (TAVNS) is a non-invasive, safe, cost-effective treatment with great potential for improving the cognitive function of poststroke patients. This clinical research will evaluate the effectiveness, and help elucidate the possible underlying mechanisms, of TAVNS for improving poststroke cognitive function. METHODS AND ANALYSIS: A single-centre, parallel-group, allocation concealment, assessor-blinded randomised controlled clinical trial. We will allocate 88 recruited participants to the TAVNS or sham group for an intervention that will run for 8 weeks, 5 days per week with twice daily sessions lasting 30 min each. Blood tests will be performed and questionnaires issued at baseline and 8-week and 12 week follow-ups. Primary outcomes will be changes in cognitive function scores. Secondary outcomes will be changes in activities of daily living, quality of life and serum oxidative stress indicators. ETHICS AND DISSEMINATION: The Ethics Committee of the First Affiliated Hospital of Hunan University of Chinese Medicine has approved the protocol (No. HN-LL-YJSLW-2022200). Findings will be published in peer-reviewed academic journals and presented at scientific conferences. TRIAL REGISTRATION NUMBER: ChiCTR2200057808.

Anion Modified Spin Crossover in [Fe(qsal-4-F)]+ Complexes with a 4-Position Substituted Qsal Ligand.

Four iron(III) complexes, [Fe(qsal-4-F)2]Y·sol (Hqsal-4-F = 4-fluoro-N-(8-quinolyl)salicylaldimine; Y = NO3-, sol = 0.91MeOH·0.57H2O (1NO3); Y = PF6- (2PF6); Y = BF4- (3BF4); Y = OTf-, sol =1.5MeOH (4OTf)), with a new 4-position substituted qsal type ligand Hqsal-4-F have been synthesized and structurally and magnetically characterized. Complexes 1NO3-3BF4 consist of 1D chains formed by the [Fe(qsal-4-F)2]+ cations connected by π-π and C-H···O interactions, which are further linked by more weak interactions to form 2D layers and 3D networks. On the other hand, complex 4OTf has a structure of nearly isolated 1D column where the [Fe(qsal-4-F)2]+ cations are connected by π-π, C-H···π, and C-F···π interactions. Magnetic studies revealed the occurrence of two-step symmetry-breaking SCO in 1NO3 and two-step gradual SCO in 2PF6. Complex 3BF4 undergoes a gradual SCO, whereas 4OTf remains almost high-spin. The smaller anions tend to stabilize the low-spin state, while larger anions tend to stabilize the high-spin state. In addition, the intermediate spin state of 1NO3 could be thermally trapped by quenching from the high temperature, thereby kinetically suppressing the spin transition to the full low-spin state. This work represents a good example that the position of the substituent and the anions plays critical roles in the preparation of SCO materials with tunable properties.

Remimazolam induced cognitive dysfunction in mice via glutamate excitotoxicity.

Objective: Several lines of evidence demonstrated the role of anesthetic drugs in cognitive functions. Some anesthetic agents have been confirmed to be associated with long-term spatial memory and learning in aged animal models. Methods: C57BL/6 mice were divided into four different groups based on different concentrations of remimazolam treatments. Behavioral phenotype was observed by open field, rota rod, Morris water maze, and elevated plus maze test. Western blot was performed to see the expression pattern of different proteins. Confocal microscopy images were taken for neuronal and glial cells to see the effect of remimazolam on CNS cells. Results: We showed that remimazolam, a new anesthetic drug, impaired cognitive behavior. Repetitive doses of remimazolam have been found to induce neuronal loss with a significant change in morphology. Here, we showed that a higher concentration of remimazolam had a significant effect on CNS cell activation. We showed that remimazolam caused memory dysfunction by inducing neuronal apoptosis via glutamate excitotoxicity. It also exhibited amyloid ß plaque in the brain via abnormal phosphorylation of tau protein. Remimazolam-mediated regulation of glial cells in mouse cortex was observed and robust activation of astrocytes and microglial cells was found. Finally, we assessed the behavioral phenotype of mice and found that treatment with remimazolam induced significant behavioral changes and memory dysfunction. Conclusions: This study provides insight into the mechanism of anesthetic drug-induced memory deficits and may help improve the therapeutic effects of anesthesia agents in clinical applications.

YAP inhibits ERα and ER+ breast cancer growth by disrupting a TEAD-ERα signaling axis.

Hippo signaling restricts tissue growth by inhibiting the transcriptional effector YAP. Here we uncover a role of Hippo signaling and a tumor suppressor function of YAP in estrogen receptor positive (ER+) breast cancer. We find that inhibition of Hippo/MST1/2 or activation of YAP blocks the ERα transcriptional program and ER+ breast cancer growth. Mechanistically, the Hippo pathway transcription factor TEAD physically interacts with ERα to increase its promoter/enhancer occupancy whereas YAP inhibits ERα/TEAD interaction, decreases ERα occupancy on its target promoters/enhancers, and promotes ERα degradation by the proteasome. Furthermore, YAP inhibits hormone-independent transcription of ERα gene (ESR1). Consistently, high levels of YAP correlate with good prognosis of ER+ breast cancer patients. Finally, we find that pharmacological inhibition of Hippo/MST1/2 impeded tumor growth driven by hormone therapy resistant ERα mutants, suggesting that targeting the Hippo-YAP-TEAD signaling axis could be a potential therapeutical strategy to overcome endocrine therapy resistance conferred by ERα mutants.