SYT4 binds to SNAP25 to facilitate exosomal secretion and prostate cancer enzalutamide resistance.

Prostate carcinoma represents a predominant malignancy affecting the male population, with androgen deprivation therapy (ADT) serving as a critical therapeutic modality for advanced disease states, but it often leads to the development of resistance. Enzalutamide (Enz), a second-generation antiandrogen drug, initially offers substantial therapeutic benefit, but its efficacy wanes as drug resistance ensues. In this study, we found that synaptotagmin 4 (SYT4) is an upregulated gene in enzalutamide-resistant (EnzR) cell lines. The downregulation of SYT4, in combination with enzalutamide therapy, substantially enhances the antiproliferative effect on resistant prostate cancer cells beyond the capacity of enzalutamide monotherapy. SYT4 promotes vesicle efflux by binding to the synaptosome-associated protein 25 (SNAP25), thereby contributing to cell resistance against enzalutamide. The elevated expression of SYT4 is mediated by bromodomain-containing protein 4 (BRD4), and BRD4 inhibition effectively suppressed the expression of SYT4. Treatment with a therapeutic dose of enzalutamide combined with ASO-1, an antisense oligonucleotide drug targeting SYT4, shows promising results in reversing the resistance of prostate cancer to enzalutamide.

Transcriptomic insights into UTUC: role of inflammatory fibrosis and potential for personalized treatment.

BACKGROUND: Upper tract urothelial carcinoma (UTUC) is a rare disease, belonging to the same category of urothelial cancers as bladder cancer (BC). Despite sharing similar non-surgical treatment modalities, UTUC demonstrates a higher metastasis propensity than BC. Furthermore, although both cancers exhibit similar molecular disease emergence mechanisms, sequencing data reveals some differences. Our study investigates the transcriptomic distinctions between UTUC and BC, explores the causes behind UTUC's heightened metastatic tendency, constructs a model for UTUC metastasis and prognosis, and propose personalized treatment strategies for UTUC. METHODS: In our research, we utilized differential gene expression analysis, interaction networks, and Cox regression to explore the enhanced metastatic propensity of UTUC. We formulated and validated a prognostic risk model using diverse techniques, including cell co-culture, reverse transcription quantitative polymerase chain reaction (rt-qPCR), western blotting, and transwell experiments. Our methodological approach also involved survival analysis, risk model construction, and drug screening leveraging the databases of CTRPv2, PRISM and CMap. We used the Masson staining technique for histological assessments. All statistical evaluations were conducted using R software and GraphPad Prism 9, reinforcing the rigorous and comprehensive nature of our research approach. RESULTS: Screening through inflammatory fibrosis revealed a reduction of extracellular matrix and cell adhesion molecules regulated by proteoglycans in UTUC compared with BC, making UTUC more metastasis-prone. We demonstrated that SDC1, LUM, VEGFA, WNT7B, and TIMP3, are critical in promoting UTUC metastasis. A risk model based on these five molecules can effectively predict the risk of UTUC metastasis and disease-free survival time. Given UTUC's unique molecular mechanisms distinct from BC, we discovered that UTUC patients could better mitigate the issue of poor prognosis associated with UTUC's easy metastasis through tyrosine kinase inhibitors (TKIs) alongside the conventional gemcitabine and cisplatin chemotherapy regimen. CONCLUSIONS: The poor prognosis of UTUC because of its high metastatic propensity is intimately tied to inflammatory fibrosis induced by the accumulation of reactive oxygen species. The biological model constructed using the five molecules SDC1, LUM, VEGFA, WNT7B, and TIMP3 can effectively predict patient prognosis. UTUC patients require specialized treatments in addition to conventional regimens, with TKIs exhibiting significant potential.

FGF21 impedes peripheral myelin development by stimulating p38 MAPK/c-Jun axis.

Fibroblast growth factor 21 (FGF21) as a metabolic stress hormone, is mainly secreted by the liver. In addition to its well-defined roles in energy homeostasis, FGF21 has been shown to promote remyelination after injury in the central nervous system. In the current study, we sought to examine the potential roles of FGF21 in the peripheral nervous system (PNS) myelination. In the PNS myelin development, Fgf21 expression was reversely correlated with myelin gene expression. In cultured primary Schwann cells (SCs), the application of recombinant FGF21 greatly attenuates myelination-associated gene expression, including Oct6, Krox20, Mbp, Mpz, and Pmp22. Accordingly, the injection of FGF21 into neonatal rats markedly mitigates the myelination in sciatic nerves. On the contrary, the infusion of the anti-FGF21 antibody accelerates the myelination. Mechanistically, both extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) were stimulated by FGF21 in SCs and sciatic nerves. Following experiments including pharmaceutical intervention and gene manipulation revealed that the p38 MAPK/c-Jun axis, rather than ERK, is targeted by FGF21 for mediating its repression on myelination in SCs. Taken together, our data provide a new aspect of FGF21 by acting as a negative regulator for the myelin development process in the PNS via activation of p38 MAPK/c-Jun.

TrkA promotes MDM2-mediated AGPS ubiquitination and degradation to trigger prostate cancer progression.

BACKGROUND: As a novel necrosis manner, ferroptosis has been increasingly reported to play a role in tumor progression and treatment, however, the specific mechanisms underlying its development in prostate cancer remain unclear. Growing evidence showed that peroxisome plays a key role in ferroptosis. Herein, we identified a novel mechanism for the involvement of ferroptosis in prostate cancer progression, which may provide a new strategy for clinical treatment of prostate cancer. METHODS: Label-Free Mass spectrometry was used to screen and identify candidate proteins after ferroptosis inducer-ML210 treatment. Immunohistochemistry was undertaken to explore the protein expression of AGPS in prostate cancer tissues compared with normal tissues. Co-immunoprecipitation and GST pull-down were used to identify the directly binding of AGPS to MDM2 in vivo and in vitro. CCK8 assay and colony formation assay were used to illustrate the key role of AGPS in the progression of prostate cancer in vitro. The xenograft model was established to verify the key role of AGPS in the progression of prostate cancer in vivo. RESULTS: AGPS protein expression was downregulated in prostate cancer tissues compared with normal tissues from the first affiliated hospital of Zhengzhou University dataset. Lower expression was correlated with poorer overall survival of patients compared to those with high expression of AGPS. In addition, AGPS can promote ferroptosis by modulating the function of peroxisome-resulting in the lower survival of prostate cancer cells. Furthermore, it was shown that AGPS can be ubiquitinated and degraded by the E3 ligase-MDM2 through the proteasomal pathway. Meanwhile, kinase TrkA can promote the combination of AGPS and MDM2 by phosphorylating AGPS at Y451 site. It was verified that kinase TrkA inhibitor-Larotrectinib can increase the susceptibility of prostate cancer cells to ferroptosis, which leads to the inhibition of prostate cancer proliferation to a great extent in vitro and in vivo. CONCLUSION: Based on these findings, we proposed the combination of ferroptosis inducer and TrkA inhibitor to synergistically exert anti-tumor effects, which may provide a new strategy for the clinical treatment of prostate cancer.

8-Br-cGMP activates HSPB6 and increases the antineoplastic activity of quinidine in prostate cancer.

Heat shock protein family B [small] member 6 (HSPB6), widely found in various muscles, has been recently identified as a tumor suppressor gene. However, its role in prostate cancer remains unexplored. Herein, we investigated the expression of HSPB6 in prostate cancer and its association with prognosis. Our findings revealed that HSPB6 downregulation in prostate cancer correlated with a poor prognosis. Moreover, we discovered that HSPB6 can be phosphorylated and activated by 8-Br-cGMP, leading to apoptosis in prostate cancer cells by activating Cofilin. Additionally, we demonstrated that knocking down E2F1 by quinidine administration enhances the transcriptional level of HSPB6. Furthermore, we evaluated the combination of quinidine and 8-Br-cGMP as a potential therapeutic strategy for prostate cancer. Our results revealed that the combined treatment was more effective than either treatment alone in inhibiting the growth of prostate cancer through the HSPB6 pathway, both in vitro and in vivo. Overall, our study provides compelling evidence that HSPB6 suppresses malignant behavior in prostate cancer by inducing apoptosis. The combination of quinidine and 8-Br-cGMP emerges as a promising approach for the treatment of prostate cancer.

Antibody-drug conjugates in urinary tumors: clinical application, challenge, and perspectives.

Urinary tumors primarily consist of kidney, urothelial, and prostate malignancies, which pose significant treatment challenges, particularly in advanced stages. Antibody-drug conjugates (ADCs) have emerged as a promising therapeutic approach, combining monoclonal antibody specificity with cytotoxic chemotherapeutic payloads. This review highlights recent advancements, opportunities, and challenges in ADC application for urinary tumors. We discuss the FDA-approved ADCs and other novel ADCs under investigation, emphasizing their potential to improve patient outcomes. Furthermore, we explore strategies to address challenges, such as toxicity management, predictive biomarker identification, and resistance mechanisms. Additionally, we examine the integration of ADCs with other treatment modalities, including immune checkpoint inhibitors, targeted therapies, and radiation therapy. By addressing these challenges and exploring innovative approaches, the development of ADCs may significantly enhance therapeutic options and outcomes for patients with advanced urinary tumor.

Prediction for recurrent non-muscle invasive bladder cancer.

Non-muscle invasive bladder cancer (NMIBC) has a high recurrence rate, which places a significant burden on both patients and the healthcare system. Hence, it holds significant importance to predict the recurrence risk following treatment for individuals diagnosed with non-muscle invasive bladder cancer (NMIBC). As new generation technologies continue to emerge, an increasing number of recurrence risk prediction tools are being developed and discovered. This article provides an overview of the primary recurrence risk prediction tools currently available, including the liquid biopsy, tissue biopsy, and risk prediction tables. Each of these tools is described in detail and illustrated with relevant examples. Furthermore, we conduct an analysis of the advantages and disadvantages of these tools. This article aims to enhance the reader's understanding of the current progress in recurrence prediction tools and encourage their practical utilization in the fields of precision medicine and public health.

Dual-Functional MN-08 Attenuated Pulmonary Arterial Hypertension Through Vasodilation and Inhibition of Pulmonary Arterial Remodeling.

[Figure: see text].

[Clinical significance of expressions of tumor markers in peripheral blood in non-small cell lung cancer].

OBJECTIVE: To investigate the expressions of BJ-TSA-9, CK19 and Pre-proGRP mRNA in peripheral blood from the patients with non-small cell lung cancer and analyze their correlations with non-small cell lung cancer. METHODS: The expressions of BJ-TSA-9, CK19 and Pre-proGRP mRNA were detected by nested reverse transcription-PCR assay in peripheral blood from the patients with non-small cell lung cancer (n = 120), benign pulmonary disease (n = 106) and from healthy subjects (n = 80) so as to further investigate their relationship with clinicopathological features and prognosis. Meantime we also examined the sensitivity, specificity and accuracy of combination detection. RESULTS: The expressions of BJ-TSA-9, CK19 and Pre-proGRP mRNA in non-small cell lung cancer patients were 56.7%, 57.5%, 35.0%, higher than that of benign pulmonary disease (0.9%, 6.6%, 5.7%) and healthy groups (0, 3.8%, 0, all P < 0.05). The ROC curves indicated the sensitivity of combined detection was 84.3% and the specificity of combined detection was 94.6%. Univariate analysis revealed that the clinical stage, the ECOG score and the number of positive marker had significant association with overall survival (OS) (χ(2) = 67.928, 95.981, 60.285, all P = 0.000). Multivariate analysis indicated that the clinical stage, ECOG score and the number of positive marker was an independent prognostic factor each (HR = 2.866, 4.251, 1.845, all P = 0.000). CONCLUSION: BJ-TSA-9, CK19 and Pre-proGRP mRNA may be the specific and sensitive markers to detect circulating tumor cells in the peripheral blood of non-small cell lung cancer patients.

[Arthroscopic GraftLink technique reconstruction combined with suture anchor fixation for anterior cruciate ligament and medial collateral ligament injuries].

OBJECTIVE: To investigate the effectiveness of arthroscopic GraftLink technique reconstruction combined with suture anchor fixation in treatment of anterior cruciate ligament (ACL) rupture and medial collateral ligament (MCL) grade Ⅲ injury. METHODS: Between June 2015 and February 2018, 28 patients with ACL rupture and MCL grade Ⅲ injury were treated. Arthroscopic GraftLink technique was used to reconstruct ACL with autologous peroneus longus tendon (PLT), and suture anchor fixation was used to repair MCL. There were 22 males and 6 females, aged 21-47 years, with an average age of 30.4 years. The cause of injury included traffic accident in 18 cases, falling from height in 7 cases, and sports injury in 3 cases. The time from injury to admission was 1-2 weeks, with an average of 1.3 weeks. The preoperative Lysholm score of knee joint was 46.8±3.0 and the International Knee Documentation Commission (IKDC) score was 49.2±2.7. The American Orthopaedic Foot and Ankle Society (AOFAS) score of ankle joint was 98.29±0.72. Both Lachman test and valgus stress test were positive. There were 8 cases of meniscus injury and 2 cases of cartilage injury. RESULTS: The operation time ranged from 55 to 90 minutes, with an average of 72.5 minutes. All incisions healed by first intention after operation, and no complications related to operation occurred. All patients were followed up 6-38 months, with an average of 20.7 months. At 3 months after operation, the range of motion of the knee joint was 116- 132°, with an average of 122°. Lachman test showed that the anterior translation more than 5 mm in 2 cases, and the others were negative; while the valgus stress test showed that all patients were positive. At 6 months after operation, the Lysholm score and IKDC score of knee joint were 90.2±1.8 and 93.5±2.3, respectively, which were significantly higher than preoperative scores ( t=31.60, P=0.00; t=29.91, P=0.01); AOFAS score of ankle joint was 97.86±0.68, with no significant difference compared with preoperative score ( t=2.89, P=0.08). KT-1000 test showed that the difference of anterior relaxation between bilateral knee joints was less than 2 mm in 25 cases and 3 to 5 mm in 3 cases. CONCLUSION: The method of ACL reconstruction via arthroscopic GraftLink technique with PLT and MCL repair via suture anchor fixation has the advantages of less knee injury and faster recovery, and there is no significant impact on ankle function after tendon removal.

Telomerase-specific oncolytic virotherapy for human hepatocellular carcinoma.

AIM: To evaluate the therapeutic efficiency of replicative adenovirus CNHK300 targeted in telomerase-positive hepatocellular carcinoma. METHODS: CNHK300, ONYX-015 (55 kDa protein deleted adenovirus) and wtAd5 (wild type adenovirus 5) were compared, and virus proliferation assay, cell viability assay, Western blot and fluorescence microscopy were used to evaluate the proliferation and cytolysis selectivity of CNHK300. RESULTS: The replicative multiples in Hep3B and HepG II after 48 h of CNHK300 proliferation were 40625 and 65326 fold, respectively, similar to that of wtAd5. However, CNHK300 exhibited attenuated replicative ability in normal fibroblast cell line BJ. CNHK300 could lyse hepatocellular carcinoma cells at a low multiplicity of infection (MOI), but could not affect growth of normal cells even at a high MOI. CONCLUSION: CNHK300 is a cancer-selective replication-competent adenovirus which can cause oncolysis of liver cancer cells as well as wtAd5 (wild type adenovirus 5), but had severely attenuated replicative and cytolytic ability in normal cells. This novel strategy of cancer treatment offers a promising treatment platform.

[Comparison and analysis of clinical effects of total arthroscopic repair and arthroscopic-assisted small incision repair for the treatment of rotator cuff injury].

OBJECTIVE: To investigate the clinical effects of arthroscopic repair and arthroscopic-assisted small incision repair for the treatment of rotator cuff injury. METHODS: The clinical data of 86 patients with rotator cuff injury from January 2012 to January 2015 were analyzed retrospectively. All the patients were divided into two groups: arthroscopic assisted small incision repair group(group A) and arthroscopic repair group(group B). There were 46 patients in group A, including 25 males and 21 females, with an average age of (52.8±7.8) years old. And there were 40 patients in group B, including 23 males and 17 females, with an average age of (53.2±9.5) years old. Several indexes such as shoulder joint activity, muscle strength and ASES, UCLA and VAS scores were examined before and after operation to compare therapeutic effects between these two groups. RESULTS: All the patients were followed up, and the mean time was 20.8 months (ranged, 18 to 35 months). The results of patients in group A as follows: range of abduction motion of shoulder joint was (131.4±18.8)°, external rotation was (64.9±8.8)°, and internal rotation was(63.7±7.3)°. Results of patients in group B as follows: range of abduction motion of shoulder joint was(132.3±16.9), external rotation was(65.1±9.4)°, and internal rotation was(64.4±8.1)°. All the patients had better shoulder mobility than those before operation, but there were no significant differences between two groups after operation. Postoperative scores of patients in group A: ASES was 88.4±8.9, UCLA score was 29.6±3.6, VAS was 1.4±0.3; and in group B, the above scores were 89.5±9.6, 30.8±4.1 and 1.3±0.4 respectively. All the patients had better scores than those before operation, but there were no significant differences between two groups after operation. CONCLUSIONS: Arthroscopic repair and arthroscopic-assisted small incision for repair of rotator cuff injury has clinical curative effects to some extent, and these two methods could improve the safety and reliability of surgical treatment.

[Comparison of navelbine plus ifosfamide and cisplatin versus ifosfamide plus cisplatin in the treatment of advanced non small cell lung cancer].

BACKGROUND: To observe the efficacy and safety of navelbine (NVB) combined with ifosfamide (IFO) and cisplatin (DDP) (NIP regimen) and IFO plus DDP (IP regimen) for advanced non-small cell lung cancer (NSCLC). METHODS: One hundred and twenty patients with advanced NSCLC pathologically proved were randomly divided into group A (NIP regimen, n=60) and group B (IP regimen, n=60). RESULTS: In group A, 58 patients were evaluable. The response rates were 58.62%(34/58), 65.58%(17/26) and 53.12% (17/32) in whole group, untreated patients, and retreated patients, respectively. The median duration of survival was 11.3 months. One-year survival rate was 40.0%. In group B, 59 patients could be evaluated. The response rates were 40.68%(24/59), 63.33%(19/30) and 17.24%(5/29) in whole group, untreated patients, and retreated patients, respectively. The median duration of survival was 9 months and 1-year survival rate was 36.7%. There was no significant difference in objective response rate among all the patients and the patients with no prior treatment between the two groups ( P > 0.05, P > 0.05). However, among retreated patients, the response rate in group A was remarkably higher than that in group B ( P < 0.05). The main dose limiting toxicity was myelosuppression. Leukopenia at grade III+IV was significantly higher in the NIP arm than in the IP arm ( P < 0.05). CONCLUSIONS: NIP yields a higher response rate than IP does in retreated patients, with acceptable toxicity, which can be the first line regimen in the retreatment of advanced NSCLC. IP regimen showes a similar response rate and less toxicity in initial patients, compared with NIP regimen, so it might be considered a relevant regimen in initial patients with advanced NSCLC.

Rare pulmonary primitive neuroectodermal tumor metastasizing to the right atrium: a case report.

A 28-year-old man complained of intermittent irritable dry cough for 2 months with occasional bloody sputum. Positron emission tomography-computed tomography (PET-CT) suggested multiple heterogeneous soft tissue masses in the inferior lobes of both lungs, with heterogeneous increases in 18F-FDG uptake. No metabolic disorders were found in the rest of the body. CT-guided percutaneous lung puncture and biopsy and immunohistochemical study confirmed pulmonary primitive neuroectodermal tumor (PNET). PNET is characterized by small round blue cells and positive CD99 expression. After six cycles of chemotherapy with ifosfamide, dacarbazine and cisplatin, the lesions diminished substantially. At 2 months after the last cycle of chemotherapy, the patient complained of exertional dyspnea. PET-CT and echocardiogram suggested a space-occupying lesion in the right atrium. Autopsy revealed that this space-occupying lesion had the same pathomorphology and immunophenotype with pulmonary PNET, suggesting metastasis of pulmonary PNET to the right atrium. Here, we reported this rare case of pulmonary PNET metastasizing, instead of direct infiltrating or extending, into the heart.