SYTL2 promotes metastasis of prostate cancer cells by enhancing FSCN1-mediated pseudopodia formation and invasion.

BACKGROUND: Metastatic prostate cancer (mPCa) has a poor prognosis with limited treatment options. The high mobility of tumor cells is the key driving characteristic of metastasis. However, the mechanism is complex and far from clarified in PCa. Therefore, it is essential to explore the mechanism of metastasis and discover an intrinsic biomarker for mPCa. METHODS: Transcriptome sequencing data and clinicopathologic features of PCa from multifarious public databases were used to identify novel metastatic genes in PCa. The PCa tissue cohort containing 102 formalin-fixed paraffin-embedded (FFPE) samples was used to evaluate the clinicopathologic features of synaptotagmin-like 2 (SYTL2) in PCa. The function of SYTL2 was investigated by migration and invasion assays and a 3D migration model in vitro and a popliteal lymph node metastasis model in vivo. We performed coimmunoprecipitation and protein stability assays to clarify the mechanism of SYTL2. RESULTS: We discovered a pseudopodia regulator, SYTL2, which correlated with a higher Gleason score, worse prognosis and higher risk of metastasis. Functional experiments revealed that SYTL2 promoted migration, invasion and lymph node metastasis by increasing pseudopodia formation in vitro and in vivo. Furthermore, SYTL2 induced pseudopodia formation by enhancing the stability of fascin actin-bundling protein 1 (FSCN1) by binding and inhibiting the proteasome degradation pathway. Targeting FSCN1 enabled rescue and reversal of the oncogenic effect of SYTL2. CONCLUSIONS: Overall, our study established an FSCN1-dependent mechanism by which SYTL2 regulates the mobility of PCa cells. We also found that the SYTL2-FSCN1-pseudopodia axis may serve as a pharmacological and novel target for treating mPCa.

Matrine inhibits the progression of prostate cancer by promoting expression of GADD45B.

BACKGROUND: Matrine is a naturally occurring alkaloid extracted from the Chinese herb Sophora flavescens. It has been demonstrated to exhibit antiproliferative properties, promote apoptosis, and inhibit cell invasion in a number of cancer cell lines by modulating the NF-κB pathway to downregulate the expression of MMP2 and MM9. It has also been shown to improve the efficacy of chemotherapy when it is combined with other chemotherapy drugs. However, the therapeutic potential of matrine for prostate cancer needs to be further studied. METHODS: We analyzed KEGG pathways of differential gene expression between matrine-treated and untreated prostate cancer cell lines and identified GADD45B as one of major target genes of matrine based on its role in apoptosis and prognosis value for prostate cancer patients in TCGA database. We further analyzed the expression of GADD45B protein in a tissue microarray and mRNA in TCGA database, and tested the synergistic impacts of matrine and GADD45B overexpression on proliferation, apoptosis, migration and invasion of prostate cancer cell DU145. RESULTS: Matrine promoted the expression of GADD45B, a tumor suppressive gene that is involved in the regulation of cell cycle, DNA damage repair, cell survival, aging, apoptosis and other cellular processes through p38/JNK, ROS-GADD45B-p38, or other signal pathways. Although GADD45B is elevated in prostate cancer tissues, levels of GADD45B in prostate tumor tissues are reduced at late stage of tumor invasion, and higher levels of GADD45B predict better survivals of prostate cancer patients. CONCLUSIONS: Matrine may be used to treat prostate cancer patients to increase the levels of GADD45B to inhibit tumor invasion and improve patient survivals.

Evaluating the effectiveness of cytoreductive surgery in oligometastatic prostate cancer: insights from quantitative analysis and retrospective cohort studies.

BACKGROUND: Oligometastatic prostate cancer (OmPCa) is characterized by a restricted number of metastatic lesions confined to a limited organ range, presenting a distinct clinical challenge. The role of cytoreductive prostatectomy (CRP) in managing this specific metastatic stage has gained attention but remains controversial. This study aims to assess the effectiveness of CRP in OmPCa by synthesizing outcomes from previous studies and analyzing data from a multicenter, retrospective cohort. METHODS: We focused on evaluating overall survival (OS), progression-free survival (PFS), cancer-specific survival (CSS), and castration-resistant prostate cancer-free survival (CRPCFS) as primary outcomes. A multicenter comparative retrospective analysis was also conducted on OmPCa patients treated with CRP versus those receiving androgen deprivation therapy (ADT) alone from January 2008 to June 2018. We gathered and analyzed data on patient demographics, tumor characteristics, surgical outcomes, and survival metrics. RESULTS: The quantitative analysis included 18 studies(2 randomized controlled trial (RCT) and 16 non-RCT studies),comprising a total of 1733 patients with oligometastatic prostate cancer,this is the largest number of samples included in the same subject research at present.The pooled analysis demonstrated that cytoreductive surgery was associated with significantly improved OS (hazard ratio [HR]: 0.50, 95% confidence interval[CI]: 0.40-0.60) ,PFS (HR: 0.39, 95%[CI]: 0.27-0.51) ,CSS (HR: 0.44, 95%[CI]: 0.23-0.65) and CRPCFS (HR: 0.48, 95%[CI]: 0.36-0.59) compared to non-surgical management.In addition,OS ,PFS and CRPCFS showed better results in the CRP group in all analyses(RCT and non-RCT).Additionally,in our multicenter retrospective research analysis, 64 patients with oligometastatic prostate cancer were included ,32 underwent CRP (50%), and 32 underwent ADT alone (50%).The median follow-up time was 40.1 (18.9-51.3) months.The OS (P=0.0182), PFS (P=0.0297), and CRPCFS (P=0.0125) had statistical difference between the two matched cohorts.Moreover,we observed 8(25%) cases of perioperative complications, with the most common being urinary incontinence(9.4%). CONCLUSIONS: Incorporating CRP alongside ADT in the treatment protocol for OmPCa significantly enhances patient outcomes in terms of OS, PFS, and CRPC-free survival, underscoring the potential benefit of this surgical approach in the specified patient population.

Adjoint Algorithm Design of Selective Mode Reflecting Metastructure for BAL Applications.

Broad-area lasers (BALs) have found applications in a variety of crucial fields on account of their high output power and high energy transfer efficiency. However, they suffer from poor spatial beam quality due to multi-mode behavior along the waveguide transverse direction. In this paper, we propose a novel metasurface waveguide structure acting as a transverse mode selective back-reflector for BALs. In order to effectively inverse design such a structure, a digital adjoint algorithm is introduced to adapt the considerably large design area and the high degree of freedom. As a proof of the concept, a device structure with a design area of 40 × 20 µm2 is investigated. The simulation results exhibit high fundamental mode reflection (above 90%), while higher-order transverse mode reflections are suppressed below 0.2%. This is, to our knowledge, the largest device structure designed based on the inverse method. We exploited such a device and the method and further investigated the device's robustness and feasibility of the inverse method. The results are elaborately discussed.

Prediction and Interpretability of Glass Transition Temperature of Homopolymers by Data-Augmented Graph Convolutional Neural Networks.

Establishing the structure-property relationship by machine learning (ML) models is extremely valuable for accelerating the molecular design of polymers. However, existing ML models for the polymers are subject to scarcity issues of training data and fewer variations of graph structures of molecules. In addition, limited works have explored the interpretability of ML models to infer the latent knowledge in the field of polymer science that could inspire ML-assisted molecular design. In this contribution, we integrate graph convolutional neural networks (GCNs) with data augmentation strategy to predict the glass transition temperature Tg of polymers. It is demonstrated that the data-augmented GCN model outperforms the conventional models and achieves a higher accuracy for the prediction of Tg despite a small amount of training data. Furthermore, taking advantage of molecular graph representations, the data-augmented GCN model has the capability to infer the importance of atoms or substructures from the understanding of Tg, which generally agrees with the experimental findings in the field of polymer science. The inferred knowledge of the GCN model is used to advise on the design of functional polymers with specific Tg. The data-augmented GCN model possesses prominent superiorities in the establishment of structure-property relationship and also provides an efficient way for accelerating the rational design of polymer molecules.

Cerebral glucagon-like peptide-1 receptor activation alleviates traumatic brain injury by glymphatic system regulation in mice.

AIM: We aimed to assess the effects of cerebral glucagon-like peptide-1 receptor (GLP-1R) activation on the glymphatic system and whether this effect was therapeutic for traumatic brain injury (TBI). METHODS: Immunofluorescence was employed to evaluate glymphatic system function. The blood-brain barrier (BBB) permeability, microvascular basement membrane, and tight junction expression were assessed using Evans blue extravasation, immunofluorescence, and western blot. Immunohistochemistry was performed to assess axonal damage. Neuronal apoptosis was evaluated using Nissl staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and western blot. Cognitive function was assessed using behavioral tests. RESULTS: Cerebral GLP-1R activation restored glymphatic transport following TBI, alleviating BBB disruption and neuronal apoptosis, thereby improving cognitive function following TBI. Glymphatic function suppression by treatment using aquaporin 4 inhibitor TGN-020 abolished the protective effect of the GLP-1R agonist against cognitive impairment. CONCLUSION: Cerebral GLP-1R activation can effectively ameliorate neuropathological changes and cognitive impairment following TBI; the underlying mechanism could involve the repair of the glymphatic system damaged by TBI.

SALL4 correlates with proliferation, metastasis, and poor prognosis in prostate cancer by affecting MAPK pathway.

BACKGROUND: The mechanism involved in prostate cancer (PCa) metastasis is still poorly understood, and several oncogenes are known to regulate this process. However, the role of spalt-like transcription factor 4 (SALL4) in PCa metastasis remains unclear. METHODS: We performed RNA-sequencing to compare the mRNA expression profiles of seven localized PCa tissues and six metastatic PCa tissues. SALL4 was then identified and compared in the localized PCa and metastatic PCa. Immunohistochemical studies, qRT-PCR, and Western blot were performed to analyze the expression of SALL4 in PCa patients and cell lines. SALL4 expression and its relevance to clinical traits and prognosis were further explored in the TCGA database and in our 68 clinical samples. Subsequently, we knocked down SALL4 in DU145 and PC3 cells and performed a series of functional assays to explore the effect of SALL4 on PCa progression. Finally, protein levels of SALL4 and core components of the MAPK pathway were measured by Western blot, and cells were treated with PD0325901 to observe proliferation and metastasis. RESULTS: Significantly higher expression of SALL4 was found in metastatic PCa than in localized PCa. In addition, high SALL4 expression was significantly associated with high pathological T stage, N stage, Gleason score, and poor disease-free survival in TCGA database and in our clinical samples. Functional studies indicated that knockdown of SALL4 in DU145 and PC3 inhibited proliferation, migration, and angiogenesis. Furthermore, the ERK and P38 protein phosphorylation significantly reduced after knockdown of SALL4 in DU145 and PC3, indicating the inactivation of the MAPK signaling pathway. Finally, the proliferation and migration ability of DU145 and PC3 cells were significantly decreased after PD0325901 treatment. CONCLUSIONS: SALL4 predicts unfavorable outcome and is closely associated with PCa progression, suggesting that SALL4 may be a promising prognostic marker and potential therapeutic target for PCa.

A Design of High-Efficiency: Vertical Accumulation Modulators Based on Silicon Photonics.

On-chip optical modulators, which are capable of converting electrical signals into optical signals, constitute the foundational components of photonic devices. Photonics modulators exhibiting high modulation efficiency and low insertion loss are highly sought after in numerous critical applications, such as optical phase steering, optical coherent imaging, and optical computing. This paper introduces a novel accumulation-type vertical modulator structure based on a silicon photonics platform. By incorporating a high-K dielectric layer of ZrO2, we have observed an increase in modulation efficiency while maintaining relatively low levels of modulation loss. Through meticulous study and optimization, the simulation results of the final device structure demonstrate a modulation efficiency of 0.16 V·cm, with a mere efficiency-loss product of 8.24 dB·V.

Brain re-expansion predict the recurrence of unilateral CSDH: A clinical grading system.

Objective: Assessing the risk of postoperative recurrence of chronic subdural hematoma (CSDH) is a clinical focus. To screen the main factors associated with the perioperative hematoma recurrence. The brain re-expansion is the core factor of recurrence. A clinical prognostic scoring system was also proposed. Methods: We included 295 patients with unilateral CSDH as the training group for modeling. Factors predicting postoperative recurrence requiring reoperation (RrR) were determined using univariate and multivariate regression analyses, and bivariate Pearson correlation coefficient analysis was used to exclude related factors. Receiver operating characteristic curve analysis evaluates the ability of main factors to predict RrR and determines the cut-off value of brain re-expansion rate. We developed a prognostic scoring system and conducted preliminary verification. A verification group including 119 patients with unilateral CSDH was used to verify the grading systems. Results: The key factors for predicting unilateral CSDH recurrence were cerebral re-expansion rate (≤ 40%) at postoperative days 7-9 (OR 25.91, p < 0.001) and the preoperative CT density classification (isodense or hyperdense, or separated or laminar types) (OR 8.19, p = 0.007). Cerebral atrophy played a key role in brain re-expansion (OR 2.36, p = 0.002). The CSDH prognostic grading system ranged from 0 to 3. An increased score was associated with a more accurate progressive increase in the RrR rate (AUC = 0.856). Conclusions: Our prognostic grading system could screen clinically high-risk RrR patients with unilateral CSDH. However, increased attention should be paid to brain re-expansion rate after surgery in patients with CSDH.

Factors correlated with the postoperative recurrence of chronic subdural hematoma: An umbrella study of systematic reviews and meta-analyses.

BACKGROUND: Chronic subdural hematoma (CSDH) is a common neurological disease, and the surgical evacuation of subdural collection remains the primary treatment approach for symptomatic patients. Postoperative recurrence is a serious complication, and several factors are correlated with postoperative recurrence. METHODS: We searched Embase, Web of Science, PubMed, and Cochrane Library from their establishment to September 2020. Reports on randomized, prospective, retrospective, and overall observational studies on the management of surgical patients with CSDH were searched, and an independent reviewer performed research quality assessment. Factors that affect the postoperative recurrence of CSDH were extracted: social demographics, drugs (as the main or auxiliary treatment), surgical management, imaging, and other risk factors. We evaluated the recurrence rate of each risk factor. A random effect model was used to perform a meta-analysis, and each risk factor affecting the postoperative recurrence of CSDH was then evaluated and graded. FINDINGS: In total, 402 studies were included in this analysis and 32 potential risk factors were evaluated. Among these, 21 were significantly associated with the postoperative recurrence of CSDH. Three risk factors (male, bilateral hematoma, and no drainage) had convincing evidence. The classification of evidence can help clinicians identify significant risk factors for the postoperative recurrence of CSDH. INTERPRETATION: Only few associations were supported by high-quality evidence. Factors with high-quality evidence may be important for treating and preventing CSDH recurrence. Our results can be used as a basis for improving clinical treatment strategies and designing preventive methods. FUNDING: No funding was received.

Evaluation of the prognosis of acute subdural hematoma according to the density differences between gray and white matter.

Objective: Acute subdural hematoma (ASDH) is a common neurological emergency, and its appearance on head-computed tomographic (CT) imaging helps guide clinical treatment. To provide a basis for clinical decision-making, we analyzed that the density difference between the gray and white matter of the CT image is associated with the prognosis of patients with ASDH. Methods: We analyzed the data of 194 patients who had ASDH as a result of closed traumatic brain injury (TBI) between 2018 and 2021. The patients were subdivided into surgical and non-surgical groups, and the non-surgical group was further subdivided into "diffused [hematoma]" and "non-diffused" groups. The control group's CT scans were normal. The 3D Slicer software was used to quantitatively analyze the density of gray and white matter depicted in the CT images. Results: Imaging evaluation showed that the median difference in density between the gray and white matter on the injured side was 4.12 HU (IQR, 3.91-4.22 HU; p < 0.001) and on the non-injured side was 4.07 HU (IQR, 3.90-4.19 HU; p < 0.001), and the hematoma needs to be surgically removed. The median density difference value of the gray and white matter on the injured side was 3.74 HU (IQR, 3.53-4.01 HU; p < 0.001) and on the non-injured side was 3.71 HU (IQR, 3.69-3.73 HU; p < 0.001), and the hematoma could diffuse in a short time. Conclusion: Quantitative analysis of the density differences in the gray and white matter of the CT images can be used to evaluate the clinical prognosis of patients with ASDH.

Multidimensional Assessment of Electroencephalography in the Neuromodulation of Disorders of Consciousness.

In the present study, we aimed to elucidate changes in electroencephalography (EEG) metrics during recovery of consciousness and to identify possible clinical markers thereof. More specifically, in order to assess changes in multidimensional EEG metrics during neuromodulation, we performed repeated stimulation using a high-density transcranial direct current stimulation (HD-tDCS) protocol in 42 patients with disorders of consciousness (DOC). Coma Recovery Scale-Revised (CRS-R) scores and EEG metrics [brain network indicators, spectral energy, and normalized spatial complexity (NSC)] were obtained before as well as fourteen days after undergoing HD-tDCS stimulation. CRS-R scores increased in the responders (R +) group after HD-tDCS stimulation. The R + group also showed increased spectral energy in the alpha2 and beta1 bands, mainly at the frontal and parietal electrodes. Increased graphical metrics in the alpha1, alpha2, and beta1 bands combined with increased NSC in the beta2 band in the R + group suggested that improved consciousness was associated with a tendency toward stronger integration in the alpha1 band and greater isolation in the beta2 band. Following this, using NSC as a feature to predict responsiveness through machine learning, which yielded a prediction accuracy of 0.929, demonstrated that the NSC of the alpha and gamma bands at baseline successfully predicted improvement in consciousness. According to our findings reported herein, we conclude that neuromodulation of the posterior lobe can lead to an EEG response related to consciousness in DOC, and that the posterior cortex may be one of the key brain areas involved in the formation or maintenance of consciousness.

Selective Adsorption of Metal-Organic Framework toward Methylene Blue: Behavior and Mechanism.

In this study, Cu-BTC, a kind of metal-organic framework, was used as an adsorbent to selectively adsorb methylene blue (abbreviated as MB) from dye mixed wastewater. The synthesized Cu-BTC was characterized by scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, and X-ray photoelectron spectroscopy. The results indicated that the synthesized Cu-BTC have an octahedral structure, with its specific surface area at 45.16 m2/g and the pore sizes at 35-40 nm. The influence of various parameters including the initial solution pH, temperature, ionic strength, initial concentration, and contact time on MB adsorption by Cu-BTC was investigated in detail. The adsorption capacity of Cu-BTC toward MB was optimized at the pH value of 8, with a lower temperature and a higher ionic strength. The adsorption isotherm was found to fit well with the Langmuir model, and the kinetic curve was found to be in good agreement with the pseudo-second-order kinetic model. The adsorption mechanism was revealed to be the combined effects of hydrophobicity and electrostatic adsorption. The synthesized Cu-BTC adsorption material showed great potential for recovering MB from dye-mixed wastewater.

Suprapubic Transvesical Repair of Vesicovaginal Fistula Using a Homemade Laparoscopic Single-Port Device: Experience of 42 Patients.

Aim: Vesicovaginal fistula (VVF) is the most common urogenital acquired fistula, and has remained a scourge and of public health importance. VVF can be repaired by transvaginal approach, transabdominal approach or transvesical approach, but the optimal management is still debated. Methods: To demonstrate a suprapubic transvesical approach to repair VVFs using a homemade laparoscopic single-port device. A retrospective review of the medical records of 42 consecutive patients who underwent fistula repair for VVF at our center from January 2012 to March 2018 was performed. VVFs were repaired by a suprapubic transvesical approach using a homemade laparoscopic single-port device. Clinical data, perioperative data and outcomes were collected. The primary outcome was VVF successful closure rate, and secondary outcome was perioperative complications. Results: The mean age of the patients was 44.6 (27-58) yr. The mean follow-up time was 65.6 (32-118) mo. The VVFs were successfully closed in 37 (88.1%) patients after the first surgery, and failure was observed in five patients. Initial failures of all the five patients were cured after a second repair. No major complication occurred as defined by Clavien-Dindo class 2 or greater. Conclusions: Suprapubic transvesical approach to repair VVFs using a homemade laparoscopic single-port device is a simple, effective, and feasible approach offering ideal results without major complications.

Loss of NEIL3 activates radiotherapy resistance in the progression of prostate cancer.

OBJECTIVE: To explore the genetic changes in the progression of castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC) and the reason why these cancers resist existing therapies. METHODS: We employed our CRPC cell line microarray and other CRPC or NEPC datasets to screen the target gene NEIL3. Lentiviral transfection and RNA interference were used to construct overexpression and knockdown cell lines. Cell and animal models of radiotherapy were established by using a medical electron linear accelerator. Flow cytometry was used to detect apoptosis or cell cycle progression. Western blot and qPCR were used to detect changes in the protein and RNA levels. RESULTS: TCGA and clinical patient datasets indicated that NEIL3 was downregulated in CRPC and NEPC cell lines, and NEIL3 was correlated with a high Gleason score but a good prognosis. Further functional studies demonstrated that NEIL3 had no effect on the proliferation and migration of PCa cells. However, cell and animal radiotherapy models revealed that NEIL3 could facilitate the radiotherapy sensitivity of PCa cells, while loss of NEIL3 activated radiotherapy resistance. Mechanistically, we found that NEIL3 negatively regulated the expression of ATR, and higher NEIL3 expression repressed the ATR/CHK1 pathway, thus regulating the cell cycle. CONCLUSIONS: We demonstrated that NEIL3 may serve as a diagnostic or therapeutic target for therapy-resistant patients.

Immune Cytolytic Activity as an Indicator of Immune Checkpoint Inhibitors Treatment for Prostate Cancer.

Immune checkpoint inhibitors (ICIs) treatment is becoming a new hope for cancer treatment. However, most prostate cancer (PCa) patients do not benefit from it. In order to achieve the accuracy of ICIs treatment in PCa and reduce unnecessary costs for patients, we have analyzed the data from TCGA database to find a indicator that can assist the choice of treatment. By analyzing the data of PCa patients with TMB analysis and immune infiltration analysis, we found the expression of immune cells in different immune infiltration groups. Commonly used markers of ICIs, expressed on CD8+ T cell, were highly expressed in the high immune group. Then we used the forimmune cytolytic activity (CYT) to determine its relationship with the target of ICIs treatment. Through the analysis of CYT score and the ligands of immune checkpoints, we found that there was a significant correlation between them. With the increase of CYT score, the expression of CD80/86, PD-L1/L2, TNFSF14, and LGALS9 also increased gradually. Similarly, CD8+ T cells were significantly increased in the CYT high group compared with the CYT low group in PRAD. The present research provides novel insights into the immune microenvironment of PRAD and potential immunotherapies. The proposed CYT score is a clinically promising indicator that can serve as a marker to assist anti-PD-L1 or other ICIs treatment. At the same time, it also provides a basis for the selection of other immune checkpoint drugs.

The metastatic promoter DEPDC1B induces epithelial-mesenchymal transition and promotes prostate cancer cell proliferation via Rac1-PAK1 signaling.

Metastasis is the major cause of prostate cancer (PCa)-related mortality. Epithelial-mesenchymal transition (EMT) is a vital characteristic feature that empowers cancer cells to adapt and survive at the beginning of metastasis. Therefore, it is essential to identify the regulatory mechanism of EMT in metastatic prostate cancer (mPCa) and to develop a novel therapy to block PCa metastasis. Here, we discovered a novel PCa metastasis oncogene, DEP domain containing 1B (DEPDC1B), which was positively correlated with the metastasis status, high Gleason score, advanced tumor stage, and poor prognosis. Functional assays revealed that DEPDC1B enhanced the migration, invasion, and proliferation of PCa cells in vitro and promoted tumor metastasis and growth in vivo. Mechanistic investigations clarified that DEPDC1B induced EMT and enhanced proliferation by binding to Rac1 and enhancing the Rac1-PAK1 pathway. This DEPDC1B-mediated oncogenic effect was reversed by a Rac1-GTP inhibitor or Rac1 knockdown. In conclusion, we discover that the DEPDC1B-Rac1-PAK1 signaling pathway may serve as a multipotent target for clinical intervention in mPCa.

Topoisomerase II-binding protein 1 promotes the progression of prostate cancer via ATR-CHK1 signaling pathway.

DNA damage response (DDR) plays an important role in the progression of cancers, including prostate cancer (PCa). Topoisomerase II-binding protein 1 (TopBP1) is an essential promotor of ATR-mediated DDR. Herein, we investigated the association between TopBP1 and PCa and determined its effect on the progression of PCa. The expression and clinical features of TopBP1 were analyzed using large-scale cohort of tissue microarray analyses and The Cancer Genome Atlas database, which indicated that TopBP1 was positively correlated with high Gleason Score, advanced clinical and pathological stages, the metastasis status. Multivariate analysis revealed that the upregulation of TopBP1 was an independent predictor for a worse biochemical recurrence-free survival (BCR-free survival). Furthermore, we discovered that downregulation of TopBP1 significantly suppressed the growth and migration ability of PCa lines by loss-of-function assays in vitro. Further mechanistic investigations clarified that TopBP1 promoted proliferation and migration by activating ATR-Chk1 signaling pathway.

HHLA2 and PD-L1 co-expression predicts poor prognosis in patients with clear cell renal cell carcinoma.

BACKGROUND: Although clear cell renal cell carcinoma (ccRCC) is well known as a highly immunogenic tumor, only a small subset of patients could benefit from current immunotherapy, which might be due to the heterogeneity of immune microenvironment in ccRCC. So, it is meaningful to explore novel immunotherapy or combination therapy for improving therapeutic efficacy. HHLA2, a newly discovered B7 family member, is prevalently expressed in numerous tumors, including ccRCC. This study aimed to investigate the prognostic impact of HHLA2/PD-L1 co-expression and its relationship with tumor-infiltrating lymphocytes (TILs). METHODS: The expression levels of HHLA2, PD-L1, CD8, and CD4 in cancer tissues from cases (206 in the training cohort and 197 in the validation cohort) with surgically resectable primary ccRCC were evaluated by immunohistochemistry. RESULTS: The positive rates of HHLA2 were much higher than those of PD-L1 in ccRCC tissues. HHLA2-positive expression was significantly associated with necrosis, microvascular invasion, advanced Fuhrman nuclear, and TNM stage and indicated a shorter progression-free survival (PFS) and overall survival (OS) in both cohorts. Moreover, patients with HHLA2/PD-L1 co-expression suffered the highest risk of disease progression and death by a significant margin. Besides, HHLA2/PD-L1 co-expression was significantly associated with a high density of CD8+ and CD4+ TILs. Notably, a new immune classification, based on HHLA2/PD-L1 co-expression and TILs, successfully stratified PFS and OS, especially in patients with TILs positivity. CONCLUSIONS: The expression of HHLA2 is more frequent than PD-L1 in ccRCC. HHLA2/PD-L1 co-expression had an adverse impact on the prognoses of patients with ccRCC; this finding provides a rationale for combination immunotherapy with anti-HHLA2 and PD-L1 blockage for patients with ccRCC in the future.

Discovering novel P38α inhibitors for the treatment of prostate cancer through virtual screening methods.

Aim: P38α plays a crucial role in the development of castration-resistant prostate cancer. Discovering novel inhibitors of P38α offers potential for the development of new anticancer drugs. Methods & results: Compounds from the Chemdiv and Enamine virtual libraries were filtered to construct the P38α inhibitor-like library. A total of 58 new P38α inhibitors were discovered via virtual screening; these included three compounds (compound 1, 5, 9) with kinase IC50 of below 10 µM. In vitro, these three compounds have the potential to suppress the viabilities of prostate cancer cell lines, however, only compound 9 can inhibit the proliferation and migration of prostate cancer cells. Conclusion: The potent compounds discovered in this study demonstrate anticancer functions by targeting the P38α mitogen-activated protein kinases signaling pathway and are worthy of further investigation.