Deciphering the immunological and prognostic features of bladder cancer through platinum-resistance-related genes analysis and identifying potential therapeutic target P4HB

ObjectivesTo identify the molecular subtypes and develop a scoring system for the tumor immune microenvironment (TIME) and prognostic features of bladder cancer (BLCA) based on the platinum-resistance-related (PRR) genes analysis while identifying P4HB as a potential therapeutic target.MethodsIn this study, we analyzed gene expression data and clinical information of 594 BLCA samples. We used unsupervised clustering to identify molecular subtypes based on the expression levels of PRR genes. Functional and pathway enrichment analyses were performed to understand the biological activities of these subtypes. We also assessed the TIME and developed a prognostic signature and scoring system. Moreover, we analyzed the efficacy of immune checkpoint inhibitors. Then we conducted real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) experiments to detect the expression level of prolyl 4-hydroxylase subunit beta (P4HB) in BLCA cell lines. Transfection of small interference ribonucleic acid (siRNA) was performed in 5637 and EJ cells to knock down P4HB, and the impact of P4HB on cellular functions was evaluated through wound-healing and transwell assays. Finally, siRNA transfection of P4HB was performed in the cisplatin-resistant T24 cell to assess its impact on the sensitivity of BLCA to platinum-based chemotherapy drugs.ResultsIn a cohort of 594 BLCA samples (TCGA-BLCA, n=406; GSE13507, n=188), 846 PRR-associated genes were identified by intersecting BLCA expression data from TCGA and GEO databases with the PRR genes from the HGSOC-Platinum database. Univariate Cox regression analysis revealed 264 PRR genes linked to BLCA prognosis. We identified three molecular subtypes (Cluster A-C) and the PRR scoring system based on PRR genes. Cluster C exhibited a better prognosis and lower immune cell infiltration compared to the other Clusters A and B. The high PRR score group was significantly associated with an immunosuppressive tumor microenvironment, poor clinical-pathological features, and a poor prognosis. Furthermore, the high PRR group showed higher expression of immune checkpoint molecules and a poorer response to immune checkpoint inhibitors than the low PRR group. The key PRR gene P4HB was highly expressed in BLCA cell lines, and cellular functional experiments in vitro indicate that P4HB may be an important factor influencing BLCA migration and invasion.ConclusionOur study demonstrates that the PRR signatures are significantly associated with clinical-pathological features, the TIME, and prognostic features. The key PRR gene, P4HB, s a biomarker for the individualized treatment of BLCA patients

Phyllopod Acts as an Adaptor Protein To Link the Sina Ubiquitin Ligase to the Substrate Protein Tramtrack

The RING domain protein Sina, together with Phyllopod and the F-box protein Ebi, forms a Ras-regulated E3 ubiquitin ligase complex that activates photoreceptor cell differentiation in the eye of Drosophila melanogaster. The expression of Phyllopod is induced upon Ras activation, allowing the complex to degrade the transcription repressor Tramtrack and removing its block of neuronal development in photoreceptor precursors. We show that Phyllopod functions as an adaptor in the complex, physically linking Sina with Tramtrack via separate binding domains. One 19-amino-acid domain in Phyllopod interacts with a region of Sina's SBD domain. Another domain in Phyllopod interacts with a C-terminal helix in the POZ domain of Tramtrack. This interaction is specific to the Tramtrack POZ domain and not to other POZ domain proteins present in photoreceptor precursors. Degradation of Tramtrack is dependent upon association of Sina with its cognate binding site in Phyllopod. These results illustrate how Ras signaling can modulate an E3 ligase activity not by the phosphorylation of substrate proteins but by regulating the expression of specific E3 adaptors

Hash-Based Signature for Flexibility Authentication of IoT Devices

5G provides a unified authentication architecture and access management for IoT (Internet of Things) devices. But existing authentication services cannot cover massive IoT devices with various computing capabilities. In addition, with the development of quantum computing, authentication schemes based on traditional digital signature technology may not be as secure as we expected. This paper studies the authentication mechanism from the user equipment to the external data network in 5G and proposed an authentication protocol prototype that conforms to the Third Generation Partnership Program (3GPP) standard. This prototype can accommodate various Hash-based signature technologies, applying their advantages in resource consumption to meet the authentication requirements of multiple types of IoT devices. The operation of the proposed authentication scheme is mainly based on the Hash function, which is more efficient than the traditional authentication scheme. It provides flexible and high-quality authentication services for IoT devices cluster in the 5G environment combining the advantages of Hash-based signature technology and 5G architecture

Additional file 2 of Activation of oxytocin receptors in mouse GABAergic amacrine cells modulates retinal dopaminergic signaling

Additional file 2. The images of the original, uncropped blots for the OxtR and GAPDH

CPT1A mediates chemoresistance in human hypopharyngeal squamous cell carcinoma via ATG16L1-dependent cellular autophagy

Hypopharyngeal squamous cell carcinoma (HSCC) is a highly aggressive malignancy that constitutes approximately 95% of all hypopharyngeal carcinomas, and it carries a poor prognosis. The primary factor influencing the efficacy of anti-cancer drugs for this type of carcinoma is chemoresistance. Carnitine palmitoyltransferase 1A (CPT1A) has been associated with tumor progression in various cancers, including breast, gastric, lung, and prostate cancer. The inhibition or depletion of CPT1A can lead to apoptosis, curbing cancer cell proliferation and chemoresistance. However, the role of CPT1A in HSCC is not yet fully understood. In this study, we discovered that CPT1A is highly expressed in HSCC and is associated with an advanced T-stage and a poor 5-year survival rate among patients. Furthermore, the overexpression of CPT1A contributes to HSCC chemoresistance. Mechanistically, CPT1A can interact with the autophagy-related protein ATG16L1 and stimulate the succinylation of ATG16L1, which in turn drives autophagosome formation and autophagy. We also found that treatment with 3-methyladenine (3-MA) can reduce cisplatin resistance in HSCC cells that overexpress CPT1A. Our findings also showed that a CPT1A inhibitor significantly enhances cisplatin sensitivity both in vitro and in vivo. This study is the first to suggest that CPT1A has a regulatory role in autophagy and is linked to poor prognosis in HSCC patients. It presents novel insights into the roles of CPT1A in tumorigenesis and proposes that CPT1A could be a potential therapeutic target for HSCC treatment

Additional file 1 of Activation of oxytocin receptors in mouse GABAergic amacrine cells modulates retinal dopaminergic signaling

Additional file 1: Fig. S1. The expression of OxtRs in mouse retina. Fig. S2. Example images showing OxtR-eYFP neurons are Brn3a (A) or melanopsin (B) positive in the GCL. Fig. S3. eYFP+ neurons in Oxtr-Cre; Ai3 mice are mainly GABAergic, but not glycinergic amacrine cells. Fig. S4. Distribution of OxtR-eYFP neurons in Oxtr-Cre; Ai3 mouse retina. Fig. S5. ChAT and CRH ACs are partially co-localized with OxtR-eYFP neurons, and oxytocin elevates DA level. Fig. S6. The effects of oxytocin and OxtR antagonist on the amplitude of ERG b-wave. Fig. S7. Effects of oxytocin on b-wave amplitude in the presence of V1AR or DA receptor antagonists