Design, synthesis and biological evaluation of 4-(indolin-1-yl)-6-substituted-pyrido[3,2-d]pyrimidine derivatives as Mnk1/2 inhibitors.

The Mnk-eIF4E axis plays a crucial role in tumor development, and inhibiting Mnk kinases is a promising approach for cancer therapy. Starting with fragment WS23, a series of 4-(indolin-1-yl)-6-substituted-pyrido[3,2-d]pyrimidine derivatives were designed and synthesized. Among these derivatives, compound 15b showed the highest potency with IC50 values of 0.8 and 1.5 nM against Mnk1 and Mnk2, respectively. Additionally, it demonstrated good selectivity among 30 selected kinases. 15b significantly suppressed MOLM-13 and K562 cell lines growth and caused cell cycle arrest. Furthermore, the Western blot assay revealed that 15b effectively downregulated the downstream proteins p-eIF4E, Mcl-1, and c-myc. Additionally, 15b exhibited remarkable stability in rat plasma and rat and human microsomes. In vivo anti-tumor activity study suggested that treatment with 15b suppressed tumor growth in LL/2 syngeneic models. These findings highlight the potential of 15b as a novel and potent Mnks inhibitor, which deserves further investigation.

Inhibition of CDK7 mitigates doxorubicin cardiotoxicity and enhances anticancer efficacy.

AIMS: The anthracycline family of anticancer agents such as doxorubicin (DOX) can induce apoptotic death of cardiomyocytes and cause cardiotoxicity. We previously reported that DOX-induced apoptosis is accompanied by cardiomyocyte cell cycle-reentry. Cell cycle progression requires cyclin-dependent kinase 7 (CDK7)-mediated activation of downstream cell cycle CDKs. This study aims to determine whether CDK7 can be targeted for cardioprotection during anthracycline chemotherapy. METHODS AND RESULTS: DOX exposure induced CDK7 activation in mouse heart and isolated cardiomyocytes. Cardiac-specific ablation of Cdk7 attenuated DOX-induced cardiac dysfunction and fibrosis. Treatment with the covalent CDK7 inhibitor THZ1 also protected against DOX-induced cardiomyopathy and apoptosis. DOX treatment induced activation of the proapoptotic CDK2-FOXO1-Bim axis in a CDK7-dependent manner. In response to DOX, endogenous CDK7 directly bound and phosphorylated CDK2 at Thr160 in cardiomyocytes, leading to full CDK2 kinase activation. Importantly, inhibition of CDK7 further suppressed tumor growth when used in combination with DOX in an immunocompetent mouse model of breast cancer. CONCLUSIONS: Activation of CDK7 is necessary for DOX-induced cardiomyocyte apoptosis and cardiomyopathy. Our findings uncover a novel proapoptotic role for CDK7 in cardiomyocytes. Moreover, this study suggests that inhibition of CDK7 attenuates DOX-induced cardiotoxicity, but augments the anticancer efficacy of DOX. Therefore, combined administration of CDK7 inhibitor and DOX may exhibit diminished cardiotoxicity but superior anticancer activity.

Whole-Exome Sequencing (WES) Reveals Novel Sex-Specific Gene Variants in Non-Alcoholic Steatohepatitis (MASH).

Non-alcoholic steatohepatitis (NASH, also known as MASH) is a severe form of non-alcoholic fatty liver disease (NAFLD, also known as MASLD). Emerging data indicate that the progression of the disease to MASH is higher in postmenopausal women and that genetic susceptibility increases the risk of MASH-related cirrhosis. This study aimed to investigate the association between genetic polymorphisms in MASH and sexual dimorphism. We applied whole-exome sequencing (WES) to identify gene variants in 8 age-adjusted matched pairs of livers from both male and female patients. Sequencing alignment, variant calling, and annotation were performed using standard methods. Polymerase chain reaction (PCR) coupled with Sanger sequencing and immunoblot analysis were used to validate specific gene variants. cBioPortal and Gene Set Enrichment Analysis (GSEA) were used for actionable target analysis. We identified 148,881 gene variants, representing 57,121 and 50,150 variants in the female and male cohorts, respectively, of which 251 were highly significant and MASH sex-specific (p < 0.0286). Polymorphisms in CAPN14, SLC37A3, BAZ1A, SRP54, MYH11, ABCC1, and RNFT1 were highly expressed in male liver samples. In female samples, Polymorphisms in RGSL1, SLC17A2, HFE, NLRC5, ACTN4, SBF1, and ALPK2 were identified. A heterozygous variant 1151G>T located on 18q21.32 for ALPK2 (rs3809983) was validated by Sanger sequencing and expressed only in female samples. Immunoblot analysis confirmed that the protein level of ß-catenin in female samples was 2-fold higher than normal, whereas ALPK2 expression was 0.5-fold lower than normal. No changes in the protein levels of either ALPK2 or ß-catenin were observed in male samples. Our study suggests that the perturbation of canonical Wnt/ß-catenin signaling observed in postmenopausal women with MASH could be the result of polymorphisms in ALPK2.

PSMA-targeted dendrimer as an efficient anticancer drug delivery vehicle for prostate cancer.

Prostate cancer (PCa) is the second leading cause of cancer-related deaths among men in the United States. Although early-stage treatments exhibit promising 5-year survival rates, the treatment options for advanced stage disease are constrained, with short survival benefits due to the challenges associated with effective and selective drug delivery to PCa cells. Even though targeting Prostate Specific Membrane Antigen (PSMA) has been extensively explored and is clinically employed for imaging and radio-ligand therapy, the clinical success of PSMA-based approaches for targeted delivery of chemotherapies remains elusive. In this study, we combine a generation 4 hydroxy polyamidoamine dendrimer (PD) with irreversible PSMA ligand (CTT1298) to develop a PSMA-targeted nanoplatform (PD-CTT1298) for selective intracellular delivery of potent chemotherapeutics to PCa. PD-CTT1298-Cy5 exhibits a PSMA IC50 in the nanomolar range and demonstrates selective uptake in PSMA (+) PCa cells via PSMA mediated internalization. When systemically administered in a prostate tumor xenograft mouse model, PD-CTT1298-Cy5 selectively targets PSMA (+) tumors with significantly less accumulation in PSMA (-) tumors or upon blocking of the PSMA receptors. Moreover, the dendrimer clears rapidly from the off-target organs limiting systemic side-effects. Further, the conjugation of an anti-cancer agent, cabozantinib to the PSMA-targeted dendrimer translates to a significantly enhanced anti-proliferative activity in vitro compared to the free drug. These findings highlight the potential of PD-CTT1298 nanoplatform as a versatile approach for selective delivery of high payloads of potent chemotherapeutics to PCa, where dose related systemic side-effects are a major concern.

Stromal-derived MAOB promotes prostate cancer growth and progression.

Prostate cancer (PC) develops in a microenvironment where the stromal cells modulate adjacent tumor growth and progression. Here, we demonstrated elevated levels of monoamine oxidase B (MAOB), a mitochondrial enzyme that degrades biogenic and dietary monoamines, in human PC stroma, which was associated with poor clinical outcomes of PC patients. Knockdown or overexpression of MAOB in human prostate stromal fibroblasts indicated that MAOB promotes cocultured PC cell proliferation, migration, and invasion and co-inoculated prostate tumor growth in mice. Mechanistically, MAOB induces a reactive stroma with activated marker expression, increased extracellular matrix remodeling, and acquisition of a protumorigenic phenotype through enhanced production of reactive oxygen species. Moreover, MAOB transcriptionally activates CXCL12 through Twist1 synergizing with TGFß1-dependent Smads in prostate stroma, which stimulates tumor-expressed CXCR4-Src/JNK signaling in a paracrine manner. Pharmacological inhibition of stromal MAOB restricted PC xenograft growth in mice. Collectively, these findings characterize the contribution of MAOB to PC and suggest MAOB as a potential stroma-based therapeutic target.

Cholinergic signaling via muscarinic M1 receptor confers resistance to docetaxel in prostate cancer.

Docetaxel is the most commonly used chemotherapy for advanced prostate cancer (PC), including castration-resistant disease (CRPC), but the eventual development of docetaxel resistance constitutes a major clinical challenge. Here, we demonstrate activation of the cholinergic muscarinic M1 receptor (CHRM1) in CRPC cells upon acquiring resistance to docetaxel, which is manifested in tumor tissues from PC patients post- vs. pre-docetaxel. Genetic and pharmacological inactivation of CHRM1 restores the efficacy of docetaxel in resistant cells. Mechanistically, CHRM1, via its first and third extracellular loops, interacts with the SEMA domain of cMET and forms a heteroreceptor complex with cMET, stimulating a downstream mitogen-activated protein polykinase program to confer docetaxel resistance. Dicyclomine, a clinically available CHRM1-selective antagonist, reverts resistance and restricts the growth of multiple docetaxel-resistant CRPC cell lines and patient-derived xenografts. Our study reveals a CHRM1-dictated mechanism for docetaxel resistance and identifies a CHRM1-targeted combinatorial strategy for overcoming docetaxel resistance in PC.

Comparing iodized oil with polyvinyl alcohol for portal vein embolization in promoting liver remnant increase before partial hepatectomy.

BACKGROUND: To compare the efficacy and safety of iodized oil versus polyvinyl alcohol (PVA) particles in portal vein embolization (PVE) before partial hepatectomy. METHODS: From October 2016 to December 2021, 86 patients who planned to undergo hepatectomy after PVE were enrolled, including 61 patients post-PVE with PVA particles + coils and 25 patients post-PVE with iodized oil + coils. All patients underwent CT examination before and 2-3 weeks after PVE to evaluate the future liver remnant (FLR). The intercohort comparison included the degree of liver volume growth, changes in laboratory data, and adverse events. RESULTS: There was no significant difference in the resection rate between the iodized oil group and the PVA particle group (68 % vs. 70 %, p = 0.822). In terms of the degree of hypertrophy (9.52 % ± 13.47 vs. 4.03 % ± 10.55, p = 0.047) and kinetic growth rate (4.07 % ± 5.4 vs. 1.55 % ± 4.63, p = 0.032), the iodized oil group was superior to the PVA group. The PVE operation time in the PVA particle group was shorter than that in the iodized oil group (121. 72 min ± 34.45 vs. 156. 2 min ± 71.58, p = 0.029). There was no significant difference in the degree of hypertrophy between the high bilirubin group and the control group (5.32 % ± 9.21 vs. 6.1 % ± 14.79, p = 0.764). Only 1 patient had a major complication. CONCLUSIONS: Compared with PVA particles, iodized oil PVE can significantly increase liver volume and the degree of hypertrophy without any significant difference in safety.

Binary Metal-Oxide Active Sites Derived from Cu-Doped MIL-88 with Enhanced Electroactivity for Nitrate Reduction.

Nitrate-to-ammonia electrochemical conversion is important for decreasing water pollution and increasing the production of valuable ammonia. However, achieving high ammonium production without undesirable byproducts is difficult. Cu-doped MIL-88-derived bimetallic oxide catalysts with electrocatalytically active Fe-O-Cu bridges, which have high NO3- adsorption energy and facilitate N-intermediate hydrogenation, are developed for NH4+ production. Cu doping promotes hybridization between the O 2p of NO3- and Fe-Cu 3d, facilitating the adsorption and reduction of NO3- with a low Tafel slope (62.1 mV dec-1) and high ammonia yield (1698.8 µg·h-1·cm-2). The cathode efficiency is stable for seven cycles. Cu adjacent to Fe sites inhibits hydrogen evolution, promotes NO3- adsorption, and decreases the intermediate adsorption energy barrier. This study provides new opportunities for fabricating diverse binary metal oxides with new interfaces as efficient cathode materials for selective electroreduction.

Hepatic arterial infusion chemotherapy plus lenvatinib with or without programmed cell death protein-1 inhibitors for advanced cholangiocarcinoma.

Background: New treatment strategies are needed to improve outcomes for patients with advanced cholangiocarcinoma (CCA) due to the limited efficacy of current first-line chemotherapy regimens. Although the combination of hepatic arterial infusion chemotherapy (HAIC), lenvatinib, and programmed cell death protein-1 (PD-1) inhibitors has been extensively evaluated in the treatment of advanced hepatocellular carcinoma, their roles in advanced CCA remain poorly understood. The purpose of this study is to compare the efficacy and safety of HAIC plus lenvatinib with or without PD-1 inhibitors in patients with advanced CCA. Methods: Between March 2019 to June 2022, patients diagnosed with advanced CAA who received HAIC plus lenvatinib with or without PD-1 inhibitors treatment were reviewed for eligibility. Efficacy was evaluated according to survival and tumor response, and safety was evaluated according to the incidence of adverse events (AEs). Results: Fifty-five patients with advanced CCA were included in the study, and they were divided into the HAIC+lenvatinib (LEN)+PD-1 inhibitors (PD-1i) group (n = 35) and HAIC+LEN group (n = 20). The median follow-up time was 14.0 (5-42) months. Patients in the HAIC+LEN+PD-1i group had significantly better PFS (HR = 0.390; 95% CI 0.189-0.806; p = 0.001) and OS (HR = 0.461; 95% CI 0.229-0.927; p = 0.01) than those in the HAIC+LEN group. The HAIC+LEN+PD-1i group showed a higher objective response rate and disease control rate than the HAIC+LEN group but did not find a significant difference. The incidence of grade 1-2 and grade 3-4 AEs was not significantly higher in the HAIC+LEN+PD-1i group compared to the HAIC+LEN group, whereas two patients (5.7%) in the HAIC+LEN+PD-1i group experienced grade 5 immune-mediated pneumonia. Conclusion: HAIC plus lenvatinib with PD-1 inhibitors is safe and well-tolerated, and has the potential to prolong the survival of patients with advanced CCA. The addition of PD-1 inhibitors may enhance the efficacy of HAIC and lenvatinib. Therefore, the combined therapy has the potential to become a treatment option for advanced CCA.

Fast Semantic Segmentation of Remote Sensing Images Using a Network That Integrates Global and Local Information.

Efficient processing of ultra-high-resolution images is increasingly sought after with the continuous advancement of photography and sensor technology. However, the semantic segmentation of remote sensing images lacks a satisfactory solution to optimize GPU memory utilization and the feature extraction speed. To tackle this challenge, Chen et al. introduced GLNet, a network designed to strike a better balance between GPU memory usage and segmentation accuracy when processing high-resolution images. Building upon GLNet and PFNet, our proposed method, Fast-GLNet, further enhances the feature fusion and segmentation processes. It incorporates the double feature pyramid aggregation (DFPA) module and IFS module for local and global branches, respectively, resulting in superior feature maps and optimized segmentation speed. Extensive experimentation demonstrates that Fast-GLNet achieves faster semantic segmentation while maintaining segmentation quality. Additionally, it effectively optimizes GPU memory utilization. For example, compared to GLNet, Fast-GLNet's mIoU on the Deepglobe dataset increased from 71.6% to 72.1%, and GPU memory usage decreased from 1865 MB to 1639 MB. Notably, Fast-GLNet surpasses existing general-purpose methods, offering a superior trade-off between speed and accuracy in semantic segmentation.

A Multi-Step Fusion Network for Semantic Segmentation of High-Resolution Aerial Images.

The demand for semantic segmentation of ultra-high-resolution remote sensing images is becoming increasingly stronger in various fields, posing a great challenge with concern to the accuracy requirement. Most of the existing methods process ultra-high-resolution images using downsampling or cropping, but using this approach could result in a decline in the accuracy of segmenting data, as it may cause the omission of local details or global contextual information. Some scholars have proposed the two-branch structure, but the noise introduced by the global image will interfere with the result of semantic segmentation and reduce the segmentation accuracy. Therefore, we propose a model that can achieve ultra-high-precision semantic segmentation. The model consists of a local branch, a surrounding branch, and a global branch. To achieve high precision, the model is designed with a two-level fusion mechanism. The high-resolution fine structures are captured through the local and surrounding branches in the low-level fusion process, and the global contextual information is captured from downsampled inputs in the high-level fusion process. We conducted extensive experiments and analyses using the Potsdam and Vaihingen datasets of the ISPRS. The results show that our model has extremely high precision.

Monoamine oxidase A: An emerging therapeutic target in prostate cancer.

Monoamine oxidase A (MAOA), a mitochondrial enzyme degrading biogenic and dietary amines, has been studied in the contexts of neuropsychiatry and neurological disorders for decades, but its importance in oncology, as best exemplified in prostate cancer (PC) to date, was only realized recently. PC is the most commonly diagnosed non-skin cancer and the second deadliest malignancy for men in the United States. In PC, the increased expression level of MAOA is correlated with dedifferentiated tissue microarchitecture and a worse prognosis. A wealth of literature has demonstrated that MAOA promotes growth, metastasis, stemness and therapy resistance in PC, mainly by increasing oxidative stress, augmenting hypoxia, inducing epithelial-to-mesenchymal transition, and activating the downstream principal transcription factor Twist1-dictated multiple context-dependent signaling cascades. Cancer-cell-derived MAOA also enables cancer-stromal cell interaction involving bone stromal cells and nerve cells by secretion of Hedgehog and class 3 semaphorin molecules respectively to modulate the tumor microenvironment in favor of invasion and metastasis. Further, MAOA in prostate stromal cells promotes PC tumorigenesis and stemness. Current studies suggest that MAOA functions in PC in both cell autonomous and non-autonomous manners. Importantly, clinically available monoamine oxidase inhibitors have shown promising results against PC in preclinical models and clinical trials, providing a great opportunity to repurpose them as a PC therapy. Here, we summarize recent advances in our understanding of MAOA roles and mechanisms in PC, present several MAOA-targeted strategies that have been nominated for treating PC, and discuss the unknowns of MAOA function and targeting in PC for future exploration.

Frequency-tunable microwave generation with parity-time symmetry period-one laser dynamics.

A novel frequency-tunable microwave signal generation method is proposed by incorporating parity-time (PT) symmetry in period-one (P1) laser dynamics in an optically injected semiconductor laser. In this method, P1 oscillation enables a large frequency tuning range and PT symmetry leads to excellent side-mode suppression and low phase noise. In an experimental demonstration, the side-mode suppression ratio reaches 58.4 dB and the phase noise is -126.2 dBc/Hz at 10 kHz offset when generating a 6.98 GHz signal, which are improved by 44.5 dB and 13.5 dB, respectively, compared with the previously reported optoelectronic oscillator-based P1 oscillation. By simply adjusting the optical injection strength, the frequency of the microwave signal generated by PT symmetry P1 dynamics is tuned from 5.07 GHz to 15.22 GHz, in which the phase noise is kept below 120 dBc/Hz at 10 kHz offset. The proposed method is expected to find applications in high-performance wireless communication and radar systems.

In Vitro and In Vivo Assays Characterizing MAO A Function in Cancers.

Emerging studies, including ours, have revealed the novel essential roles of monoamine oxidase A (MAO A) in mediating the growth and progression of several types of cancers. Recently, we presented the first evidence of MAO A's ability to promote cancer cell perineural invasion, the neoplastic invasion of nerves widely recognized as a significant route for cancer metastasis. Here, we describe a perineural invasion in vitro assay using a 3D coculture with a cancer cell line and an immortalized dorsal root ganglion neuronal cell line for rapid examination of MAO A's roles in cancer-nerve cell crosstalk and evaluating the efficacy of MAO A inhibitors for disrupting perineural invasion. We also summarized the fundamental methods for determining MAO A's effects on cancer cell proliferation in vitro and tumorigenesis in vivo.

Spatiotemporal variation evaluation of water quality in middle and lower Han River, China.

As the water source for the middle route of the South-to-North Water Transfer Project, the Han River in China plays a role of the world's largest inter-basin water transfer project. However, this human-interfered area has suffered from over-standard pollution emission and water blooms in recent years, which necessitates urgent awareness at both national and provincial scales. To perform a comprehensive analysis of the water quality condition of this study area, we apply both the water quality index (WQI) and minimal WQI (WQImin) methods to investigate the spatiotemporal variation characteristics of water quality. The results show that 8 parameters consisting of permanganate index (PI), chemical oxygen demand (COD), total phosphorus (TP), fluoride (F-), arsenic (As), plumbum (Pb), copper (Cu), and zinc (Zn) have significant discrepancy in spatial scales, and the study basin also has a seasonal variation pattern with the lowest WQI values in summer and autumn. Moreover, compared to the traditional WQI, the WQImin model, with the assistance of stepwise linear regression analysis, could exhibit more accurate explanation with the coefficient of determination (R2) and percentage error (PE) values being 0.895 and 5.515%, respectively. The proposed framework is of great importance to improve the spatiotemporal recognition of water quality patterns and further helps develop efficient water management strategies at a reduced cost.

Neuropilin-2 promotes lineage plasticity and progression to neuroendocrine prostate cancer.

Neuroendocrine prostate cancer (NEPC), a lethal subset of prostate cancer, is characterized by loss of AR signaling and resulting resistance to AR-targeted therapy during neuroendocrine transdifferentiation, for which the molecular mechanisms remain unclear. Here, we report that neuropilin 2 (NRP2) is upregulated in both de novo and therapy-induced NEPC, which induces neuroendocrine markers, neuroendocrine cell morphology, and NEPC cell aggressive behavior. NRP2 silencing restricted NEPC tumor xenograft growth. Mechanistically, NRP2 engages in reciprocal crosstalk with AR, where NRP2 is transcriptionally inhibited by AR, and in turn suppresses AR signaling by downregulating the AR transcriptional program and confers resistance to enzalutamide. Moreover, NRP2 physically interacts with VEGFR2 through the intracellular SEA domain to activate STAT3 phosphorylation and subsequently SOX2, thus driving NEPC differentiation and growth. Collectively, these results characterize NRP2 as a driver of NEPC and suggest NRP2 as a potential therapeutic target in NEPC.

N-Acetylcysteine Priming Alleviates the Transplanting Injury of Machine-Transplanted Rice by Comprehensively Promoting Antioxidant and Photosynthetic Systems.

The stress of transplanting injury adversely affects rice growth and productivity worldwide. N-acetylcysteine (NAC), the precursor of glutathione, is a potent ROS scavenger with powerful antioxidant activity. Previous studies on the application of NAC in plants mainly focused on alleviating the stress of heavy metals, UV-B, herbicides, etc. However, the role of NAC in alleviating transplanting injury is still not clear. A barrel experiment was carried out to explain the mechanism of NAC regulating the transplanting injury to machine-transplanted rice during the recovery stage. The results showed that NAC priming shortened the time of initiation of tillering and increased the tiller numbers within 3 weeks after transplanting. In addition, NAC priming increased the chlorophyll content, net photosynthetic rate, and sucrose content, thereby improving the dry weight at the recovery stage, especially root dry weight. At the same time, NAC priming significantly increased the activity of ascorbate peroxidase (APX), glutathione reductase (GR), catalase (CAT), and superoxide dismutase (SOD). In addition, it also regulated flavonoids and total phenols contents to reduce hydrogen peroxide (H2O2) and malondialdehyde (MDA) contents, especially at the initial days after transplanting. These results suggest that NAC priming improves the tolerance of rice seedlings against transplanting injury by enhancing photosynthesis and antioxidant systems at initial days after transplanting, thereby promoting the accumulation of dry matter and tillering for higher yield returns.

KRT13 promotes stemness and drives metastasis in breast cancer through a plakoglobin/c-Myc signaling pathway.

BACKGROUND: Keratins (KRTs) are intermediate filament proteins that interact with multiple regulatory proteins to initiate signaling cascades. Keratin 13 (KRT13) plays an important role in breast cancer progression and metastasis. The objective of this study is to elucidate the mechanism by which KRT13 promotes breast cancer growth and metastasis. METHODS: The function and mechanisms of KRT13 in breast cancer progression and metastasis were assessed by overexpression and knockdown followed by examination of altered behaviors in breast cancer cells and in xenograft tumor formation in mouse mammary fat pad. Human breast cancer specimens were examined by immunohistochemistry and multiplexed quantum dot labeling analysis to correlate KRT13 expression to breast cancer progression and metastasis. RESULTS: KRT13-overexpressing MCF7 cells displayed increased proliferation, invasion, migration and in vivo tumor growth and metastasis to bone and lung. Conversely, KRT13 knockdown inhibited the aggressive behaviors of HCC1954 cells. At the molecular level, KRT13 directly interacted with plakoglobin (PG, γ-catenin) to form complexes with desmoplakin (DSP). This complex interfered with PG expression and nuclear translocation and abrogated PG-mediated suppression of c-Myc expression, while the KRT13/PG/c-Myc signaling pathway increased epithelial to mesenchymal transition and stem cell-like phenotype. KRT13 expression in 58 human breast cancer tissues was up-regulated especially at the invasive front and in metastatic specimens (12/18) (p < 0.05). KRT13 up-regulation in primary breast cancer was associated with decreased overall patient survival. CONCLUSIONS: This study reveals that KRT13 promotes breast cancer cell growth and metastasis via a plakoglobin/c-Myc pathway. Our findings reveal a potential novel pathway for therapeutic targeting of breast cancer progression and metastasis.

Identification of MAP3K15 as a potential prognostic biomarker and correlation with immune infiltrates in osteosarcoma.

BACKGROUND: Osteosarcoma (OS) is a type of primary malignant tumor, and increasing evidence shows the clinical benefits of immunotherapy in treating OS. However, the lack of comprehensive studies on the complex OS immune microenvironment hinders the application of immunotherapy. Thus, this study aimed to systematically explore the immune characteristics of OS and identify novel biomarkers for OS treatment. METHODS: We systematically studied the immune score and proportions of infiltrating immune cells in OS in the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Gene Expression Omnibus (GEO) databases using the ESTIMATE and CIBERSORT algorithms. Differential expression and functional analyses were used to identify dysregulated genes and explore their functions. Survival and Cox regression analyses were applied to establish an immune-related prognostic signature. Additionally, qPCR and immunohistochemistry were performed to validate the results. RESULTS: A total of 103 differentially expressed immune genes (DEIGs) were found in the TARGET-OS and GSE39058 databases, and these DEIGs were mainly enriched in leukocyte proliferation, leukocyte differentiation, osteoclast differentiation, natural killer (NK) cell-mediated cytotoxicity, and the adaptive immune system. A predictive signature was constructed based on the survival analysis, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.65. Moreover, we found that mitogen-activated protein kinase kinase kinase 15 (MAP3K15) can predict the prognosis of patients with OS and is closely related to CD4+ T cells and macrophages. The OS patients with high MAP3K15 expression had a significantly poorer prognosis. CONCLUSIONS: Our study found that MAP3K15, whose expression level is closely related to immune activity in tumors, is a critical immune-related biomarker, and our findings may provide a basis for OS immunotherapy.

Bidirectional Cross-talk between MAOA and AR Promotes Hormone-Dependent and Castration-Resistant Prostate Cancer.

Androgen receptor (AR) is the primary oncogenic driver of prostate cancer, including aggressive castration-resistant prostate cancer (CRPC). The molecular mechanisms controlling AR activation in general and AR reactivation in CRPC remain elusive. Here we report that monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades monoamine neurotransmitters and dietary amines, reciprocally interacts with AR in prostate cancer. MAOA was induced by androgens through direct AR binding to a novel intronic androgen response element of the MAOA gene, which in turn promoted AR transcriptional activity via upregulation of Shh/Gli-YAP1 signaling to enhance nuclear YAP1-AR interactions. Silencing MAOA suppressed AR-mediated prostate cancer development and growth, including CRPC, in mice. MAOA expression was elevated and positively associated with AR and YAP1 in human CRPC. Finally, genetic or pharmacologic targeting of MAOA enhanced the growth-inhibition efficacy of enzalutamide, darolutamide, and apalutamide in both androgen-dependent and CRPC cells. Collectively, these findings identify and characterize an MAOA-AR reciprocal regulatory circuit with coamplified effects in prostate cancer. Moreover, they suggest that cotargeting this complex may be a viable therapeutic strategy to treat prostate cancer and CRPC. SIGNIFICANCE: MAOA and AR comprise a positive feedback loop in androgen-dependent and CRPC, providing a mechanistic rationale for combining MAOA inhibition with AR-targeted therapies for prostate cancer treatment.