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Microseismic source location is crucial for the early warning of rockburst risks. However, the conventional methods face challenges in terms of the microseismic wave velocity and arrival time accuracy. Intelligent techniques, such as the full convolutional neural network (FCNN), can capture spatial information but struggle with complex microseismic sequence. Combining the FCNN with the long short-term memory (LSTM) network enables better time-series signal classification by integrating multi-scale information and is therefore suitable for waveform location. The LSTM-FCNN model does not require extensive data preprocessing and it simplifies the microseismic source location through feature extraction. In this study, we utilized the LSTM-FCNN as a regression learning model to locate the seismic focus. Initially, the method of short-time-average/long-time-average (STA/LTA) arrival time picking was employed to augment spatiotemporal information. Subsequently, oversampling the on-site data was performed to address the issue of data imbalance, and finally, the performance of LSTM-FCNN was tested. Meanwhile, we compared the LSTM-FCNN model with previous deep-learning models. Our results demonstrated remarkable location capabilities with a mean absolute error (MAE) of only 7.16 m. The model can realize swift training and high accuracy, thereby significantly improving risk warning of rockbursts.

Abstract N-Myc is a key driver of neuroblastoma and neuroendocrine prostate cancer (NEPC). One potential way to circumvent the challenge of undruggable N-Myc is to target the protein homeostasis (proteostasis) system that maintains N-Myc levels. Here, we identify heat shock protein 70 (HSP70) as a top partner of N-Myc, which binds a conserved “SELILKR” motif and prevents the access of E3 ubiquitin ligase, STIP1 homology and U-box containing protein 1 (STUB1), possibly through steric hindrance. When HSP70’s dwell time on N-Myc is increased by treatment with the HSP70 allosteric inhibitor, STUB1 is in close proximity with N-Myc and becomes functional to promote N-Myc ubiquitination on the K416 and K419 sites and forms polyubiquitination chains linked by the K11 and K63 sites. Notably, HSP70 inhibition significantly suppressed NEPC tumor growth, increased the efficacy of aurora kinase A (AURKA) inhibitors, and limited the expression of neuroendocrine-related pathways.

Summary: Olaparib is a pioneering PARP inhibitor (PARPi) approved for treating castration-resistant prostate cancer (CRPC) tumors harboring DNA repair defects, but clinical resistance has been documented. To study acquired resistance, we developed Olaparib-resistant (OlapR) cell lines through chronic Olaparib treatment of LNCaP and C4-2B cell lines. Here, we found that IGFBP3 is highly expressed in acquired (OlapR) and intrinsic (Rv1) models of Olaparib resistance. We show that IGFBP3 expression promotes Olaparib resistance by enhancing DNA repair capacity through activation of EGFR and DNA-PKcs. IGFBP3 depletion enhances efficacy of Olaparib by promoting DNA damage accumulation and subsequently, cell death in resistant models. Mechanistically, we show that silencing IGFBP3 or EGFR expression reduces cell viability and resensitizes OlapR cells to Olaparib treatment. Inhibition of EGFR by Gefitinib suppressed growth of OlapR cells and improved Olaparib sensitivity, thereby phenocopying IGFBP3 inhibition. Collectively, our results highlight IGFBP3 and EGFR as critical mediators of Olaparib resistance.

Abstract Visualizing polymer chain growth is always a hot topic for tailoring structure‐function properties in polymer chemistry. However, current characterization methods are limited in their ability to differentiate the degree of polymerization in real‐time without isolating the samples from the reaction vessel, let alone to detect insoluble polymers. Herein, a reliable relationship is established between polymer chain growth and fluorescence properties through polymerization induced emission. (TPE‐C2)2‐Te is used to realize in situ oxidative polymerization, leading to the aggregation of fluorophores. The relationship between polymerization degree of growing polytelluoxane (PTeO) and fluorescence intensity is constructed, enabling real‐time monitoring of the polymerization reaction. More importantly, this novel method can be further applied to the observation of the polymerization process for growing insoluble polymer via surface polymerization. Therefore, the development of visualization technology will open a new avenue for visualizing polymer chain growth in real‐time, regardless of polymer solubility.

Ning et al. report expression of a neural lineage gene signature in enzalutamide-resistant prostate cancer cells and datasets from patients with neuroendocrine prostate cancer. One of these genes, ARHGEF2, is associated with poor overall and disease-free survival in patients with castration-resistant disease and supports cell viability in vitro.

Background: Ventricular septal defects (VSDs) are one of the mechanical complications of acute myocardial infarction (AMI). Because of the high risks of mortality and postoperative complications, a new alternative method is needed. With the development of interventional medicine, transcatheter closure has been increasingly performed for postmyocardial infarction ventricular septal defects (PMIVSDs). The aim of this study is to explore the feasibility and safety of transcatheter closure of PMIVSDs by meta-analysis. Methods: The included studies were mainly single-arm studies of transcatheter closure of PMIVSDs. We compared VSD size, device size, preoperative risk factors and interventions among PMIVSD patients. We analysed the transcatheter closure success rate, the 30-day mortality rate, and the incidence of residual shunts. Results: A total of 12 single‐arm articles (284 patients) were included. The combined incidences of preoperative hypertension, hyperlipidaemia, and diabetes were 66% [95% CI 0.56–0.75], 54% [95% CI 0.40–0.68], and 33% [95% CI] 0.21–0.46], respectively. Multiple studies reported the combined incidences of preoperative PCI, IABP, and CABG, which were 46% [95% CI 0.15–0.80], 60% [95% CI 0.44–0.75], and 8% [95% CI 0.02–0.18]. Eleven studies reported the number of successful closures and the 30-day mortality rate; the success rate was 90% [95% CI 0.86–0.94], and the 30-day mortality rate reached 27% [95% CI 0.86–0.94]. Conclusion: For patients with PMIVSD, transcatheter closure in the acute phase can be used as a rescue measure, while in the chronic phase, it is more effective and has a lower mortality rate, but the effect of selection bias should be considered. Residual shunts are a long-term complication that have a high incidence and long-lasting effects on patients. More large, multicentre, randomized controlled trials are needed in the future to confirm the safety and reliability of transcatheter closure of PMIVSDs.

As an immune checkpoint molecule, CD200 serves a foundational role in regulating immune homeostasis and promoting self-tolerance. While CD200 expression occurs in various immune cell subsets and normal tissues, its aberrant expression patterns in hematologic malignancies and solid tumors have been linked to immune evasion and cancer progression under pathological conditions, particularly through interactions with its cognate receptor, CD200R. Through this CD200/CD200R signaling pathway, CD200 exerts its immunosuppressive effects by inhibiting natural killer (NK) cell activation, cytotoxic T cell functions, and M1-polarized macrophage activity, while also facilitating expansion of myeloid-derived suppressor cells (MDSCs) and Tregs. Moreover, CD200/CD200R expression has been linked to epithelial-to-mesenchymal transition and distant metastasis, further illustrating its role in cancer progression. Conversely, CD200 has also been shown to exert anti-tumor effects in certain cancer types, such as breast carcinoma and melanoma, indicating that CD200 may exert bidirectional effects on cancer progression depending on the specific tumor microenvironment (TME). Regardless, modulating the CD200/CD200R axis has garnered clinical interest as a potential immunotherapeutic strategy for cancer therapy, as demonstrated by early-phase clinical trials. However, further research is necessary to fully understand the complex interactions of CD200 in the tumor microenvironment and to optimize its therapeutic potential in cancer immunotherapy.

Background Emerging data suggest that patients with enzalutamide-treated prostate cancer with increased programmed death-ligand 1 (PD-L1) expression may benefit from anti-PD-L1 treatment. Unfortunately, the Phase III IMbassador250 clinical trial revealed that the combination of atezolizumab (a PD-L1 inhibitor) and enzalutamide failed to extend overall survival in patients with castration-resistant prostate cancer (CRPC). However, the mechanisms underlying treatment failure remain unknown.Methods Human CRPC C4-2B cells and murine Myc-CaP cells were chronically exposed to increasing concentrations of enzalutamide and the cells resistant to enzalutamide were referred to as C4-2B MDVR and Myc-CaP MDVR, respectively. The mechanisms of action in drug-resistant prostate cancer cells were determined using RNA sequencing analyses, RNA interference, real-time PCR, western blotting, and co-culturing technologies. Myc-CaP and Myc-CaP MDVR tumors were established in syngeneic FVB mice, and tumor-infiltrating leukocytes were isolated after enzalutamide treatment. The stained immune cells were determined by flow cytometry, and the data were analyzed using FlowJo.Results Immune-related signaling pathways (interferon alpha/gamma response, inflammatory response, and cell chemotaxis) were suppressed in human enzalutamide-resistant prostate cancer cells. PD-L1 was overexpressed and negatively regulated by androgen receptor signaling in resistant cells and patient with CRPC cohorts. Enzalutamide treatment decreased CD8+ T-cell numbers but increased monocytic myeloid-derived suppressor cell (M-MDSC) populations and PD-L1 expression within murine Myc-CaP tumors. Similarly, chemotaxis and immune response-regulating signaling pathways were suppressed, and PD-L1 expression was also increased using enzalutamide-resistant Myc-CaP MDVR cells. Notably, MDSC populations were significantly increased in Myc-CaP MDVR orthotopic tumors compared with those in Myc-CaP parental tumors. Co-culturing bone marrow cells with Myc-CaP MDVR cells significantly promoted MDSC differentiation and shifted towards M2 macrophage skewing.Conclusions Our study suggests that immunosuppressive signaling can be promoted directly by enzalutamide-resistant prostate cancer cells and may be a potential means by which the efficacy of immune checkpoint inhibitors in enzalutamide-resistant prostate cancer is diminished.

Ubiquitin proteasome activity is suppressed in enzalutamide resistant prostate cancer cells, and the heat shock protein 70/STIP1 homology and U-box-containing protein 1 (HSP70/STUB1) machinery are involved in androgen receptor (AR) and AR variant protein stabilization. Targeting HSP70 could be a viable strategy to overcome resistance to androgen receptor signaling inhibitor (ARSI) in advanced prostate cancer. Here, we showed that a novel HSP70 allosteric inhibitor, JG98, significantly suppressed drug-resistant C4–2B MDVR and CWR22Rv1 cell growth, and enhanced enzalutamide treatment. JG98 also suppressed cell growth in conditional reprogramed cell cultures (CRCs) and organoids derived from advanced prostate cancer patient samples. Mechanistically, JG98 degraded AR/AR-V7 expression in resistant cells and promoted STUB1 nuclear translocation to bind AR-V7. Knockdown of the E3 ligase STUB1 significantly diminished the anticancer effects and partially restored AR-V7 inhibitory effects of JG98. JG231, a more potent analog developed from JG98, effectively suppressed the growth of the drug-resistant prostate cancer cells, CRCs, and organoids. Notably, the combination of JG231 and enzalutamide synergistically inhibited AR/AR-V7 expression and suppressed CWR22Rv1 xenograft tumor growth. Inhibition of HSP70 using novel small-molecule inhibitors coordinates with STUB1 to regulate AR/AR-V7 protein stabilization and ARSI resistance.

The infections and diseases caused by harmful bacteria are regarded as the worldwide health-threatening issue. The most antibiotics-based delivery systems restricted the controlled drug release at specific infection sites due to the stable chemical conjugation, thus largely compromising the treatment effectiveness. Herein, we report the construction of light controlled drug-based supramolecular polymer (LDSP), which is endowed the “switch on” function for realizing the controllable antibiotics released in specific sites. LDSP was first formed based on the host-guest interaction between β-cyclodextrin units grafted hyaluronic acid chain (HA-CD) and azobenzene moiety linked by two enoxacin units (Azo-(Eno)2), and could further self-assemble into light controlled drug-based supramolecular polymer self-assemblies (LDSPSAs). Under the UV light irradiation, the “switch on” function of LDSPSAs could be effectively turned on at the specific infected tissues due to the smartly dissociated host-guest interaction, facilitating the controlled release of the hydrophobic Azo-(Eno)2 to interact with bacteria for efficient antibacterial effect. The biological evaluation demonstrated that LDSPSAs achieved good antibacterial efficiency and well biosafety.

Abstract Niclosamide has preclinical activity against a wide range of cancers. In prostate cancer, it inhibits androgen receptor variant 7 and synergizes with abiraterone. The approved niclosamide formulation has poor oral bioavailability. The primary objective of this phase Ib trial was to identify a maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of a novel reformulated orally-bioavailable niclosamide/PDMX1001 in combination with abiraterone and prednisone in men with castration-resistant prostate cancer (CRPC). Eligible patients had progressing CRPC, adequate end-organ function, and no prior treatment with abiraterone or ketoconazole. Patients were treated with escalating doses of niclosamide/PDMX1001 and standard doses of abiraterone and prednisone. Peak and trough niclosamide plasma levels were measured. Common Terminology Criteria for Adverse Events (CTCAE) v4.0 and Prostate Cancer Working Group 2 criteria were used to evaluate toxicities and responses. Nine patients with metastatic CRPC were accrued, with no dose-limiting toxicities observed at all dose levels. The recommended Phase II dose of niclosamide/PDMX1001 was 1200 mg orally (PO) three times daily plus abiraterone 1000 mg PO once daily and prednisone 5 mg PO twice daily. Trough and peak niclosamide concentrations exceeded the therapeutic threshold of > 0.2 µM. The combination was well tolerated with most frequent adverse effects of diarrhea. Five out of eight evaluable patients achieved a PSA response; two achieved undetectable PSA and radiographic response. A novel niclosamide/PDMX1001 reformulation achieved targeted plasma levels when combined with abiraterone and prednisone, and was well tolerated. Further study of niclosamide/PDMX1001 with this combination is warranted.

Castration-resistant prostate cancer remains as an incurable disease. Exploiting DNA damage repair defects via inhibition of poly (ADP-ribose) polymerase (PARP) is becoming an attractive therapeutic option. The TOPARP-A clinical trial demonstrated that the PARP inhibitor olaparib may be an effective strategy for treating prostate cancer. However, several unanswered questions regarding the use of olaparib remain: 1) How do we best stratify patients for olaparib treatment? 2) Where do we place olaparib in the treatment sequence paradigm? 3) Is there cross-resistance between olaparib and currently used therapies? Here, we tested putative cross-resistance between current therapies and olaparib in treatment-resistant castration-resistant prostate cancer models. Docetaxel-resistant cells exhibited robust resistance to olaparib which could be attributed to blunted PARP trapping in response to olaparib treatment. Upregulated ABCB1 mediates cross-resistance between taxanes and olaparib, which can be overcome through decreasing ABCB1 expression or inhibiting ABCB1 using elacridar or enzalutamide. We also show that combining olaparib with enzalutamide is more effective in olaparib-sensitive cells than either single agent. Our results demonstrate that cross-resistance between olaparib and other therapies could blunt response to treatment and highlight the need to develop strategies to maximize olaparib efficacy.

Prostate cancer is one of the most common malignant tumors in men. Initially, it is androgen-dependent, but it eventually develops into castration-resistant prostate cancer (CRPC), which is incurable with current androgen receptor signaling target therapy and chemotherapy. Immunotherapy, specifically with immune checkpoint inhibitors, has brought hope for the treatment of this type of prostate cancer. Approaches such as vaccines, adoptive chimeric antigen receptor-T (CAR-T) cells, and immune checkpoint inhibitors have been employed to activate innate and adaptive immune responses to treat prostate cancer, but with limited success. Only Sipuleucel-T and the immune checkpoint inhibitor pembrolizumab are approved by the US FDA for the treatment of limited prostate cancer patients. Prostate cancer has a complex tumor microenvironment (TME) in which various immunosuppressive molecules and mechanisms coexist and interact. Additionally, prostate cancer is considered a “cold” tumor with low levels of tumor mutational burden, low amounts of antigen-presenting and cytotoxic T-cell activation, and high levels of immunosuppressive molecules including cytokines/chemokines. Thus, understanding the mechanisms of immunosuppressive signaling activation and immune evasion will help develop more effective treatments for prostate cancer. The purpose of this review is to summarize emerging advances in prostate cancer immunotherapy, with a particular focus on the molecular mechanisms that lead to immune evasion in prostate cancer. At the same time, we also highlight some potential therapeutic targets to provide a theoretical basis for the treatment of prostate cancer.

The AR-V7 isoform is associated with anti-androgen drug resistance in prostate cancer. Here, the authors show that AR-V7 protein stability is regulated by HSP70/STUB1 complex-mediated proteostasis which confers drug resistance in late stage prostate cancer. Inhibition of HSP70 re-sensitizes resistant cells to enzalutamide therapy.

Background and objective It has been proved that methylseleninic acid (MSA) is a kind of artificially developed selenium compound, which appeared to be the best candidate for cancer prevention and therapy. Reduced glutathione is not only critical to MSA metabolism, but also is a kind of protective antioxidant which could remove the oxygen free radical promptly and maintain the intracellular redox status stable. The aim of this study is to explore the anticancer effects of ROS induced by MSA and the molecular mechanisms of MSA on induction of ROS. Methods We confirmed that MSA and selenite have the anticancer effect in the human high-metastatic large cell lung cancer cell line L9981 by growth inhibition detection, we detect the ROS induced by MSA and selenite in L9981 by fluorescence microscopy, and use flow cytometry to quantitate the ROS induced by NAC together with selenium compounds. Results ①MSA 2.5 μM and 5.0 μM selenite could inhibit the L9981 growth, Increasing the concentration resulted in a more pronounced effect. ②MSA and selenite could induce ROS in L9981. ③incubated NAC with selenite could significantly inhibit the ROS but increase the ROS treated by NAC with MSA. Conclusions ①MSA and selenite had anti-L9981 effect. ②Oxidative stress reaction may participate in the induction of apoptosis by MSA and selenite in lung cancer cell line L9981.

Background and objective The aim of this work is to study the tumorigenicity and metastasis ability in human large cell lung caner cell line L9981 by in vivo imaging. Methods We firstly transfected the plasmids with firefly luciferase (luc) gene into L9981 cells and then established the stable transfected L9981-luc cell line with G418. Then the positive L9981-Lue cells were implanted subcutaneously into mice and were monitored for tumor growth and micrometastases with in vivo imaging technique. Results The results showed that the bioluminescence density of the stable transfected L9981-Lue cells correlated to the numbers of the tumor cells in vitro. The L9981-Luc cells still keep the high metastasis characterization. After the L9981-Luc cells were implanted into mice subcutaneously for several weeks, we found the metastasis lesions in the different organs of the mice using in vivo imaging machine and the bioluminescence of the tumor correlated with its size. Furthermore, we confirmed the metastasis lesions by scarifying the mice and analyzing with pathological staining. Conclusion We established a stable L9981-Luc cell line with high metastasis character that can be used to analyze the tumor invasion ad metastasis in animal model by in vivo imaging.

ObjectiveAldehyde dehydrogenase (ALDH) has recently been reported as a marker of cancer stem-like cells in ovarian cancer. However, the prognostic role of ALDH in ovarian cancer still remains controversial. In this study, we aimed to evaluate the association between the expression of ALDH and the outcome of ovarian cancer patients by performing a meta-analysis.MethodsWe systematically searched for studies investigating the relationships between ALDH expression and outcome of ovarian cancer patients. Only articles in which ALDH expression was detected by immunohistochemical staining were included. A meta-analysis was performed to generate combined hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival (OS) and disease-free survival (DFS).ResultsA total of 1,258 patients from 7 studies (6 articles) were included in the analysis. Our results showed that high ALDH expression in patients with ovarian cancer was associated with poor prognosis in terms of Os (HR, 1.25; 95% CI, 1.07-1.47; P = 0.005) and DFS (HR, 1.58; 95% CI, 1.00-2.49; P = 0.052), though the difference for DFS was not statistically significant. In addition, there was no evidence of publication bias as suggested by Begg's and Egger's tests (Begg's test, P = 0.707; Egger's test, P = 0.355).ConclusionThe present meta-analysis indicated that elevated ALDH expression was associated with poor prognosis in patients with ovarian cancer.