Joint time and frequency transfer through one International Telecommunication Union 100 GHz wavelength division multiplexing channel with commercial devices.

We proposed a joint time and frequency transfer scheme over a single International Telecommunication Union 100 GHz wavelength division multiplexing (WDM) channel using a normal commercial WDM device and commercial offset WDM device. A standard 100 GHz WDM channel is divided into three sub-channels with a frequency interval of more than 20 GHz for a time and frequency transfer, which could help to avoid the interference among time, frequency, and data signals in other WDM channels. A joint high-precision time and frequency transfer is, therefore, able to be performed with data transmission over WDM optical communication links without extra requirements on devices. A joint time and frequency transfer in a single 100 GHz WDM channel is experimentally demonstrated over a 60 km fiber link with the communication data transmission in the adjacent channels. The stability of the time transfer can be better than 15 ps at 1 s, and the stability of the frequency transfer can be better than 2.7×10-14 at 1 s, while the bit error rates of the adjacent channels are at the same level as the separate transmission.

Single-cell transcriptome analysis reveals the association between histone lactylation and cisplatin resistance in bladder cancer.

Patients with bladder cancer (BCa) frequently acquires resistance to platinum-based chemotherapy, particularly cisplatin. This study centered on the mechanism of cisplatin resistance in BCa and highlighted the pivotal role of lactylation in driving this phenomenon. Utilizing single-cell RNA sequencing, we delineated the single-cell landscape of Bca, pinpointing a distinctive subset of BCa cells that exhibit marked resistance to cisplatin with association with glycolysis metabolism. Notably, we observed that H3 lysine 18 lactylation (H3K18la) plays a crucial role in activating the transcription of target genes by enriching in their promoter regions. Targeted inhibition of H3K18la effectively restored cisplatin sensitivity in these cisplatin-resistant epithelial cells. Furthermore, H3K18la-driven key transcription factors YBX1 and YY1 promote cisplatin resistance in BCa. These findings enhance our understanding of the mechanisms underlying cisplatin resistance, offering valuable insights for identifying novel intervention targets to overcome drug resistance in Bca.

Synergistic ferroptosis-starvation therapy for bladder cancer based on hyaluronic acid modified metal-organic frameworks.

Bladder cancer (BCa) is one of the most common malignancies of the urinary tract. Metastasis and recurrence of BCa are the leading causes of poor prognosis, and only a few patients can benefit from current first-line treatments such as chemotherapy and immunotherapy. It is urgent to develop more effective therapeutic method with low side effects. Here, a cascade nanoreactor, ZIF-8/PdCuAu/GOx@HA (ZPG@H), is proposed for starvation therapy and ferroptosis of BCa. The ZPG@H nanoreactor was constructed by co-encapsulation of PdCuAu nanoparticles and glucose oxidase into zeolitic imidazolate framework-8 (ZIF-8) modified by hyaluronic acid. The vitro results indicated that ZPG@H enhanced intracellular reactive oxygen species levels and reduced mitochondrial depolarization in the tumor microenvironment. Therefore, the integrated advantages of starvation therapy and chemodynamic therapy endow ZPG@H with a perfect ferroptosis inducing ability. This effectiveness, combined with its excellent biocompatibility and biosafety, means that ZPG@H could make a critical contribution to the development of novel BCa treatments.

FGFBP1 as a potential biomarker predicting bacillus Calmette-Guérin response in bladder cancer.

Accurate prediction of Bacillus Calmette-Guérin (BCG) response is essential to identify bladder cancer (BCa) patients most likely to respond sustainably, but no molecular marker predicting BCG response is available in clinical routine. Therefore, we first identified that fibroblast growth factor binding protein 1 (FGFBP1) was upregulated in failures of BCG therapy, and the increased FGFBP1 had a poor outcome for BCa patients in the E-MTAB-4321 and GSE19423 datasets. These different expression genes associated with FGFBP1 expression are mainly involved in neutrophil activation, neutrophil-mediated immunity, and tumor necrosis factor-mediated signal pathways in biological processes. A significant positive correlation was observed between FGFBP1 expression and regulatory T-cell (Treg) infiltration by the Spearman correlation test in the BCG cohort (r = 0.177) and The Cancer Genome Atlas (TCGA) cohort (r = 0.176), suggesting that FGFBP1 may influence the response of BCa patients to BCG immunotherapy through immune escape. Though FGFBP1 expression was positively correlated with the expressions of PD-L1, CTLA4, and PDCD1 in TCGA cohort, a strong association between FGFBP1 and PD-L1 expression was only detected in the BCG cohort (r = 0.750). Furthermore, elevated FGFBP1 was observed in BCa cell lines and tissues in comparison to corresponding normal controls by RT-qPCR, Western blotting, and immunohistochemical staining. Increased FGFBP1 was further detected in the failures than in the responders by immunohistochemical staining. Notably, FGFBP1 is positively associated with PD-L1 expression in BCa patients with BCG treatment. To sum up, FGFBP1 in BCa tissue could be identified as a promising biomarker for the accurate prediction of BCG response in BCa.

Identification of tumor microenvironment-related signature for predicting prognosis and immunotherapy response in patients with bladder cancer.

The tumor microenvironment (TME) not only provides fertile soil for tumor growth and development but also widely involves immune evasion as well as the resistance towards therapeutic response. Accumulating interest has been attracted from the biological function of TME to its effects on patient outcomes and treatment efficacy. However, the relationship between the TME-related gene expression profiles and the prognosis of bladder cancer (BLCA) remains unclear. The TME-related genes expression data of BLCA were collected from The Cancer Genome Atlas (TCGA) database. NFM algorithm was used to identify the distinct molecular pattern based on the significantly different TME-related genes. LASSO regression and Cox regression analyses were conducted to identify TME-related gene markers related to the prognosis of BLCA and to establish a prognostic model. The predictive efficacy of the risk model was verified through integrated bioinformatics analyses. Herein, 10 TME-related genes (PFKFB4, P4HB, OR2B6, OCIAD2, OAS1, KCNJ15, AHNAK, RAC3, EMP1, and PRKY) were identified to construct the prognostic model. The established risk scores were able to predict outcomes at 1, 3, and 5 years with greater accuracy than previously known models. Moreover, the risk score was closely associated with immune cell infiltration and the immunoregulatory genes including T cell exhaustion markers. Notably, the predictive power of the model in immunotherapy sensitivity was verified when it was applied to patients with metastatic urothelial carcinoma (mUC) undergoing immunotherapy. In conclusion, TME risk score can function as an independent prognostic biomarker and a predictor for evaluating immunotherapy response in BLCA patients, which provides recommendations for improving patients' response to immunotherapy and promoting personalized tumor immunotherapy in the future.

Fiber-optic joint time and frequency transmission with enhanced time precision.

We propose a high-precision joint time and frequency transmission scheme based on bidirectional wavelength division multiplexing transmission over an optical fiber link. The time signal is generated based on the phase-stable frequency signal with employment of a dedicated designed low-jitter event generator. Time synchronization is realized by eliminating the time difference between the time signals of the master and slave stations, which is determined by accurate two-way time comparison. In this way, thanks to the high stability of the frequency transmission, low jitter of the dedicated designed event generator, and the high accuracy of the two-way time comparison, a high precision time signal with enhanced time stability and accuracy can be obtained at the slave station, which is synchronized to the master station. Experimentally, a joint time and frequency transmission system is demonstrated over a 62-km urban fiber link. The results show a time stability in terms of time deviation (TDEV) of 3.5 ps/s and 430 fs/10,000 s, and an accuracy of better than 20 ps can be realized.

The efficacy and safety of PD-1/PD-L1 immune checkpoint inhibitors in treating advanced urothelial cancer: a meta-analysis of clinical trials.

Survival outcomes in advanced urothelial cancer (UC) are dismal. Over the past years, immunotherapy remains an evolving treatment modality for these patients. This meta-analysis was performed to comprehensively evaluate the efficacy and safety of immune checkpoint inhibitors. For this purpose, 18 clinical trials comprising a total of 3,144 patients were identified from the PubMed database up to September 2020. Overall, the objective response rate (ORR) to PD-1/PD-L1 inhibitors was 0.20 [95% confidence intervals (CI) 0.17-0.23]. Furthermore, the pooled 1-year overall survival (OS) and 1-year progression-free survival (PFS) rates were 0.43 (95% CI 0.33-0.53) and 0.19 (95% CI 0.17-0.21), respectively. The summary rates of any-grade and grade ≥3 adverse events (AEs) were 0.66 (95% CI 0.58-0.74) and 0.13 (95% CI 0.09-0.18), respectively. Among the different subgroups, PD-1/PD-L1 inhibitors elicited a promising ORR in patients with lymph node-only metastasis compared to those with visceral metastasis (0.41 VS. 0.17). Additionally, patients with primary tumor in the lower tract had higher ORR compared to those with primary tumor in the upper tract (0.24 VS. 0.15). Briefly speaking, this immunotherapy protocol showed an encouraging efficacy and acceptable safety profile in the treatment of advanced UC. Moreover, our findings provided potential clinical significance for patients with lymph node-only metastasis or primary tumor in the lower tract. However, these exciting findings need further confirmation.

HnRNP-F promotes the proliferation of bladder cancer cells mediated by PI3K/AKT/FOXO1.

Our previous study showed that heterogeneous nuclear ribonucleoprotein F (hnRNP-F) could induce epithelial-mesenchymal transition and metastasis in bladder cancer (BC), however, the role and mechanism of hnRNP-F in mediating the proliferative ability of BC cells remain unclear. HnRNP-F promoted the proliferation of BC cells by using BC cell lines and cell counting kit-8 (CCK8), colony formation and flow cytometry assays in vitro. Furthermore, the association of hnRNP-F with the phosphoinositide 3­kinase (PI3K)/protein kinase B (AKT) signalling pathway was confirmed by western blotting after bioinformatic analysis. HnRNP-F expression was significantly decreased by treatment with the PI3K/AKT signalling pathway inhibitor LY294002, whereas hnRNP-F knockdown did not significantly affect PI3K or AKT expression, suggesting that hnRNP-F is likely a downstream target of the PI3K/AKT pathway. Forkhead box O1 (FOXO1) is a molecule downstream of PI3K/AKT and can be inhibited by phosphorylation. In addition, chromatin immunoprecipitation (ChIP) and luciferase reporter assays indicated that FOXO1 expression was negatively correlated with hnRNP-F expression as FOXO1 was found to bind to the promoter region of hnRNP-F mRNA and inhibit its transcription. To sum up, our findings suggest that hnRNP-F expression is regulated by the PI3K/AKT-mediated phosphorylation of FOXO1, with phosphorylation inhibiting FOXO1, which subsequently allows hnRNP-F to promote proliferation. This finding is a novel discovery in BC and could help reveal the mechanism of BC progression.

Hypoxia-induced elevated NDRG1 mediates apoptosis through reprograming mitochondrial fission in HCC.

Hypoxia, as a form of stress, plays a critical role in oncogenesis, including metabolic reprogramming. Mitochondrial, the centers of energy production, re-balance mitochondria dynamic to maintain cell survival during high levels of environmental stresses. NDRG1 is a hypoxia-inducible protein that is involved in various human cancers, including HCC. However, little is known about whether NDRG1 participants in the quality control of mitochondrial in times of stress. Here, we firstly showed that how NDRG1 exerted its role through mediating mitochondrial dynamic in HCC cells under hypoxia. Initially, we identified that NDRG1 expression varies with oxygen content. NDRG1 silencing notably induced cell apoptosis under hypoxia, while no obviously change of wildtype cells in hypoxia compared with that in normoxia. Further analysis revealed that NDRG1 silencing in HCC cells led to increase of pro apoptotic protein BAX and decrease in anti-apoptotic proteins Bcl-2 and Bclx, which meant mitochondrial damage were induced. In the analysis of mitochondria, we found that more released cytochrome c located in cytosolic with NDRG1 knockdown in hypoxia, which may be due to mitochondria division. And the following experiment proved that more fragmented mitochondria were presented in NDRG1 silencing cells, as well as destroyed mitochondrial membrane potential with evidence by JC-1 was verified. Moreover, these trends could be reversed by Mdivi1. Further research showed that NDRG1 silencing disrupt hypoxia-enhanced aerobic glycolysis through effectively decreased glucose uptake, lactate output and ECAR value. In sum, we provide the first direct evidence that NDRG1-driven change in mitochondrial dynamics and aerobic glycolysis maintain cells survival in HCC during hypoxia.

SMDT1-driven change in mitochondrial dynamics mediate cell apoptosis in PDAC.

Mitochondrial Ca2+ uptake, an important governing for Ca2+ homeostasis, is catalyzed by the mitochondrial calcium uniporter (MCU) complex. SMDT1, as a subunit of MCU complex, was essential for bridging the calcium-sensing role of MICU1 and MICU2 with the calcium-conducting role of MCU. However, the molecular mechanism and regulatory purpose of SMDT1 remain largely unexplored, especially no study was reported in cancer. Here, we firstly reported that how SMDT1 exerted its role through mediating mitochondrial dynamic in PDAC malignancy. In this study, by screening online of subunit of MCU complex, we confirmed that SMDT1 expression was significantly positive correlated with PDAC prognosis. The GEO datasets showed decreased SMDT1 expression in PDAC tumor compared with non-tumor tissues. SMDT1 overexpression could notably inhibit cell proliferation and induce cell apoptosis. Further analysis demonstrated that up-regulated SMDT1 in ASPC1 and Canpan1 cells led to increased accumulation of pro apoptotic protein BAX and decrease in anti-apoptotic proteins Bcl-2 and Bclx. And more releasing of cytochrome c located in cytosolic. Mechanistically, in the morphological analysis of mitochondria, more fragmented mitochondria were presented in SMDT1 overexpression cells by promting the phosphorylation of Drp1, increasing Fis and decreasing MFN1. Meanwhile, more Drp1 was translocated on the mitochondrial from the cytoplasm in up-regulated SMDT1 cells. On the basis of the evidence above we deduce that SMDT1-driven change in mitochondrial dynamics mediated cells apoptosis in PDAC. And, SMDT1 could serve as an important therapeutic target to normalize mitochondrial dynamic responsible for poor prognosis in PDAC.