NDR1 mediates PD-L1 deubiquitination to promote prostate cancer immune escape via USP10.

Prostate cancer (PCa) is one of the most common male genitourinary system malignancies. Despite the significant benefits of anti-PD-L1 immune checkpoint inhibitor therapy in other cancers, the reasons for its poor therapeutic efficacy in prostate cancer (PCa) remain unclear.NDR1 plays an important role in innate immunity, but its role in tumor immunity and immunotherapy has not been investigated. The role of NDR1 in the immune microenvironment of PCa and the related mechanisms are unknown. Here, we found a positive correlation between NDR1 and PD-L1 expression in PCa. NDR1 significantly inhibits CD8 + T cell infiltration and function, thereby promoting immune escape in prostate cancer.More importantly, NDR1 inhibition significantly enhanced CD8 + T cell activation, which enhanced the therapeutic effect of anti-PD-L1. Mechanistic studies revealed that NDR1 inhibits ubiquitination-mediated PD-L1 degradation via the deubiquitinase USP10, upregulates PD-L1, and promotes PCa immune escape. Thus, our study suggests a unique PD-L1 regulatory mechanism underlying PCa immunotherapy failure. The significance of NDR1 in PCa immune escape and its mechanism of action were clarified, and combined NDR1/PD-L1 inhibition was suggested as an approach to boost PCa immunotherapy effectiveness.

Wearable and implantable biosensors: mechanisms and applications in closed-loop therapeutic systems.

This review article examines the current state of wearable and implantable biosensors, offering an overview of their biosensing mechanisms and applications. We also delve into integrating these biosensors with therapeutic systems, discussing their operational principles and incorporation into closed-loop devices. Biosensing strategies are broadly categorized into chemical sensing for biomarker detection, physical sensing for monitoring physiological conditions such as pressure and temperature, and electrophysiological sensing for capturing bioelectrical activities. The discussion extends to recent developments in drug delivery and electrical stimulation devices to highlight their significant role in closed-loop therapy. By integrating with therapeutic devices, biosensors enable the modulation of treatment regimens based on real-time physiological data. This capability enhances the patient-specificity of medical interventions, an essential aspect of personalized healthcare. Recent innovations in integrating biosensors and therapeutic devices have led to the introduction of closed-loop wearable and implantable systems capable of achieving previously unattainable therapeutic outcomes. These technologies represent a significant leap towards dynamic, adaptive therapies that respond in real-time to patients' physiological states, offering a level of accuracy and effectiveness that is particularly beneficial for managing chronic conditions. This review also addresses the challenges associated with biosensor technologies. We also explore the prospects of these technologies to address their potential to transform disease management with more targeted and personalized treatment solutions.

Prevention and treatment strategies for kidney transplant recipients in the context of long-term existence of COVID-19.

The sudden outbreak of coronavirus disease 2019 (COVID-19) in early 2020 posed a massive threat to human life and caused an economic upheaval worldwide. Kidney transplant recipients (KTRs) became susceptible to infection during the COVID-19 pandemic owing to their use of immunosuppressants, resulting in increased hospitalization and mortality rates. Although the current epidemic situation is alleviated, the long-term existence of COVID-19 still seriously threatens the life and health of KTRs with low immunity. The Omicron variant, a highly infectious but less-pathogenic strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has raised concerns among transplant physicians regarding managing KTRs diagnosed with this variant. However, currently, there are no clear and unified guidelines for caring for KTRs infected with this variant. Therefore, we aimed to summarize the ongoing research on drugs that can treat Omicron variant infections in KTRs and explore the potential of adjusting immunotherapy strategies to enhance their responsiveness to vaccines. Herein, we discuss the situation of KTRs since the emergence of COVID-19 and focus on various prevention and treatment strategies for KTRs since the Omicron variant outbreak. We hope to assist physicians in managing KTRs in the presence of long-term COVID-19 variants.

A Pilot Study Using Machine Learning Algorithms and Wearable Technology for the Early Detection of Postoperative Complications After Cardiothoracic Surgery.

OBJECTIVE: To evaluate whether a machine learning algorithm (i.e. the "NightSignal" algorithm) can be used for the detection of postoperative complications prior to symptom onset after cardiothoracic surgery. SUMMARY BACKGROUND DATA: Methods that enable the early detection of postoperative complications after cardiothoracic surgery are needed. METHODS: This was a prospective observational cohort study conducted from July 2021 to February 2023 at a single academic tertiary care hospital. Patients aged 18 years or older scheduled to undergo cardiothoracic surgery were recruited. Study participants wore a Fitbit watch continuously for at least 1 week preoperatively and up to 90-days postoperatively. The ability of the NightSignal algorithm-which was previously developed for the early detection of Covid-19-to detect postoperative complications was evaluated. The primary outcomes were algorithm sensitivity and specificity for postoperative event detection. RESULTS: A total of 56 patients undergoing cardiothoracic surgery met inclusion criteria, of which 24 (42.9%) underwent thoracic operations and 32 (57.1%) underwent cardiac operations. The median age was 62 (IQR: 51-68) years and 30 (53.6%) patients were female. The NightSignal algorithm detected 17 of the 21 postoperative events a median of 2 (IQR: 1-3) days prior to symptom onset, representing a sensitivity of 81%. The specificity, negative predictive value, and positive predictive value of the algorithm for the detection of postoperative events were 75%, 97%, and 28%, respectively. CONCLUSIONS: Machine learning analysis of biometric data collected from wearable devices has the potential to detect postoperative complications-prior to symptom onset-after cardiothoracic surgery.

Liproxstatin-1 Alleviated Ischemia/Reperfusion-Induced Acute Kidney Injury via Inhibiting Ferroptosis.

Ferroptosis, as a novel regulable cell death, is characterized by iron overload, glutathione depletion, and an accumulation of lipid peroxides. Recently, it has been discovered that ferroptosis is involved in ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) and plays a crucial role in renal tubular cell death. In this study, we tried to investigate the effect and mechanism of liproxstatin-1 (Lip-1) in I/R-induced AKI and seek the key regulator of ferroptosis in I/R-induced AKI. Mice were administrated with clamping bilateral renal pedicles for 30 min. We found that early growth response 1 (EGR1) might be a key regulator of ferroptosis, and Lip-1 could suppress ferroptosis via EGR1. Meanwhile, Lip-1 could reduce macrophage recruitment and the release of inflammatory cytokines. These findings indicated that Lip-1 alleviated I/R-induced AKI via regulating EGR1, and it might pave the theoretical basis of a new therapeutic strategy for I/R-induced AKI.

Discovery of a small-molecule NDR1 agonist for prostate cancer therapy.

Prostatic cancer (PCa) is a common malignant neoplasm in men worldwide. Most patients develop castration-resistant prostate cancer (CRPC) after treatment with androgen deprivation therapy (ADT), usually resulting in death. Therefore, investigating new therapeutic targets and drugs for PCa patients is urgently needed. Nuclear Dbf2-related kinase 1 (NDR1), also known as STK38, is a serine/threonine kinase in the NDR/LATS kinase family that plays a critical role in cellular processes, including immunity, inflammation, metastasis, and tumorigenesis. It was reported that NDR1 inhibited the metastasis of prostate cancer cells by suppressing epithelial-mesenchymal transition (EMT), and decreased NDR1 expression might lead to a poorer prognosis, suggesting the enormous potential of NDR1 in antitumorigenesis. In this study, we characterized a small-molecule agonist named aNDR1, which specifically bound to NDR1 and potently promoted NDR1 expression, enzymatic activity and phosphorylation. aNDR1 exhibited drug-like properties, such as favorable stability, plasma protein binding capacity, cell membrane permeability, and PCa cell-specific inhibition, while having no obvious effect on normal prostate cells. Meanwhile, aNDR1 exhibited good antitumor activity both in vitro and in vivo. aNDR1 inhibited proliferation and migration of PCa cells and promoted apoptosis of PCa cells in vitro. We further found that aNDR1 inhibited subcutaneous tumors and lung metastatic nodules in vivo, with no obvious toxicity to the body. In summary, our study presents a potential small-molecule lead compound that targets NDR1 for clinical therapy of PCa patients.

Targeting the hedgehog pathway in MET mutation cancers and its effects on cells associated with cancer development.

The mutation of MET plays a crucial role in the initiation of cancer, while the Hedgehog (Hh) pathway also plays a significant role in cell differentiation and the maintenance of tumor stem cells. Conventional chemotherapy drugs are primarily designed to target the majority of cell populations within tumors rather than tumor stem cells. Consequently, after a brief period of remission, tumors often relapse. Moreover, the exclusive targeting of tumor stemness cell disregards the potential for other tumor cells to regain stemness and acquire drug resistance. As a result, current drugs that solely target the HGF/c-MET axis and the Hh pathway demonstrate only moderate efficacy in specific types of cancer. Mounting evidence indicates that these two pathways not only play important roles in cancer but also exert significant influence on the development of resistance to single-target therapies through the secretion of their own ligands. In this comprehensive review, we analyze and compare the potential impact of the Hh pathway on the tumor microenvironment (TME) in HGF/c-MET-driven tumor models, as well as the interplay between different cell types. Additionally, we further substantiate the potential and necessity of dual-pathway combination therapy as a critical target in MET addicted cancer treatment. Video Abstract.

Branched-chain keto-acid dehydrogenase kinase regulates vascular permeability and angiogenesis to facilitate tumor metastasis in renal cell carcinoma.

Branched-chain keto-acid dehydrogenase kinase (BCKDK) is the rate-limiting enzyme of branched-chain amino acid (BCAA) metabolism. In the last six years, BCKDK has been used as a kinase to promote tumor proliferation and metastasis. Renal cell carcinoma (RCC) is a highly vascularized tumor. A high degree of vascularization promotes tumor metastasis. Our objective is to explore the relationship between BCKDK and RCC metastasis and its specific mechanism. In our study, BCKDK is highly expressed in renal clear cell carcinoma and promotes the migration of clear cell renal cell carcinoma (ccRCC). Exosomes from ccRCC cells can promote vascular permeability and angiogenesis, especially when BCKDK is overexpressed in ccRCC cells. BCKDK can also augment the miR-125a-5p expression in ccRCC cells and derived exosomes, thereby decreasing the downstream target protein VE-cadherin level, weakening adhesion junction expression, increasing vascular permeability, and promoting angiogenesis in HUVECs. The novel BCKDK/Exosome-miR-125a-5p/VE-cadherin axis regulates intercellular communication between ccRCC cells and HUVECs. BCKDK plays a critical role in renal cancer metastasis, may be used as a molecular marker of metastatic ccRCC, and even may become a potential target of clinical anti-vascular therapy for ccRCC.

TOPK mediates immune evasion of renal cell carcinoma via upregulating the expression of PD-L1.

Although anti-PD-L1 therapy has been used in the clinical treatment of renal cell carcinoma (RCC), a proportion of patients are not sensitive to it, which may be attributed to the heterogeneity of PD-L1 expression. Here, we demonstrated that high TOPK (T-LAK cell-originated Protein Kinase) expression in RCC promoted PD-L1 expression by activating ERK2 and TGF-ß/Smad pathways. TOPK was positively correlated with PD-L1 expression levels in RCC. Meanwhile, TOPK significantly inhibited the infiltration and function of CD8+ T cells and promoted the immune escape of RCC. Moreover, inhibition of TOPK significantly enhanced CD8+ T cell infiltration, promoted CD8+ T cell activation, enhanced anti-PD-L1 therapeutic efficacy, and synergistically enhanced anti-RCC immune response. In conclusion, this study proposes a new PD-L1 regulatory mechanism that is expected to improve the effectiveness of immunotherapy for RCC.

BCKDK regulates breast cancer cell adhesion and tumor metastasis by inhibiting TRIM21 ubiquitinate talin1.

Breast cancer is the most common malignant cancer in women worldwide. Cancer metastasis is the major cause of cancer-related deaths. BCKDK is associated with various diseases, including proliferation, migration, and invasion in multiple types of human cancers. However, the relevance of BCKDK to the development and progression of breast cancers and its function is unclear. This study found that BCKDK was overexpressed in breast cancer, associated with poor prognosis, and implicated in tumor metastasis. The downregulation of BCKDK expression inhibited the migration of human breast cancer cells in vitro and diminished lung metastasis in vivo. BCKDK perturbed the cadherin-catenin complex at the adherens junctions (AJs) and assembled focal adhesions (FAs) onto the extracellular matrix, thereby promoting the directed migration of breast cancer cells. We observed that BCKDK acted as a conserved regulator of the ubiquitination of cytoskeletal protein talin1 and the activation of the FAK/MAPK pathway. Further studies revealed that BCKDK inhibited the binding of talin1 to E3 ubiquitin ligase-TRIM21, leading to the decreased ubiquitination/degradation of talin1. In conclusion, identifying BCKDK as a biomarker for breast cancer metastasis facilitated further research on diagnostic biomarkers. Elucidating the mechanism by which BCKDK exerted its biological effect could provide a new theoretical basis for developing new markers for breast cancer metastasis and contribute to developing new therapies for the clinical treatment of breast cancer patients.

Establishment and validation of a novel anoikis-related prognostic signature of clear cell renal cell carcinoma.

Background: Despite progression in its treatment, the clinical outcome of patients with clear cell renal cell carcinoma (ccRCC) remains not ideal. Anoikis is a unique form of programmed apoptosis, owing to insufficient cell-matrix interactions. Anoikis plays a crucial role in tumor migration and invasion, and tumor cells could protect themselves through the capacity of anoikis resistance. Methods: Anoikis-related genes (ARGs) were obtained from Genecards and Harmonizome portals. The ARGs related to ccRCC prognosis were identified through univariate Cox regression analysis, then we utilized these ARGs to construct a novel prognostic model for ccRCC patients. Moreover, we explored the expression profile of ARGs in ccRCC using the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) database. We also conducted Real-Time Polymerase Chain Reaction (RT-PCR) to probe ARGs expression of the risk score. Finally, we performed correlation analysis between ARGs and tumor immune microenvironment. Results: We identified 17 ARGs associated with ccRCC survival, from which 7 genes were chosen to construct a prognostic model. The prognostic model was verified as an independent prognostic indicator. The expression of most ARGs was higher in ccRCC samples. These ARGs were closely correlated with immune cell infiltration and immune checkpoint members, and had independent prognostic value respectively. Functional enrichment analysis demonstrated that these ARGs were significantly associated with multiple types of malignances. Conclusion: The prognostic signature was identified to be highly efficient in predicting ccRCC prognosis, and these ARGs were closely related to tumor microenvironment.

Prognostic and Immunological Role of STK38 across Cancers: Friend or Foe?

Although STK38 (serine-threonine kinase 38) has been proven to play an important role in cancer initiation and progression based on a series of cell and animal experiments, no systemic assessment of STK38 across human cancers is available. We firstly performed a pan-cancer analysis of STK38 in this study. The expression level of STK38 was significantly different between tumor and normal tissues in 15 types of cancers. Meanwhile, a prognosis analysis showed that a distinct relationship existed between STK38 expression and the clinical prognosis of cancer patients. Furthermore, the expression of STK38 was related to the infiltration of immune cells, such as NK cells, memory CD4+ T cells, mast cells and cancer-associated fibroblasts in a few cancers. There were three immune-associated signaling pathways involved in KEGG analysis of STK38. In general, STK38 shows a significant prognostic value in different cancers and is closely associated with cancer immunity.

The Crucial Role of AR-V7 in Enzalutamide-Resistance of Castration-Resistant Prostate Cancer.

Prostate cancer (PCa) has the second highest incidence of malignancies occurring in men worldwide. The first-line therapy of PCa is androgen deprivation therapy (ADT). Nonetheless, most patients progress to castration-resistant prostate cancer (CRPC) after being treated by ADT. As a second-generation androgen receptor (AR) antagonist, enzalutamide (ENZ) is the current mainstay of new endocrine therapies for CRPC in clinical use. However, almost all patients develop resistance during AR antagonist therapy due to various mechanisms. At present, ENZ resistance (ENZR) has become challenging in the clinical treatment of CRPC. AR splice variant 7 (AR-V7) refers to a ligand-independent and constitutively active variant of the AR and is considered a key driver of ENZR in CRPC. In this review, we summarize the mechanisms and biological behaviors of AR-V7 in ENZR of CRPC to contribute novel insights for CRPC therapy.

Discrimination of adulterated milk using temperature-perturbed two-dimensional infrared correlation spectroscopy and multivariate analysis.

The discrimination method for adulterated milk is proposed based on temperature-perturbed two-dimensional (2D) infrared correlation spectroscopy and N-way partial least squares discriminant analysis (NPLS-DA). Two brands of pure and adulterated milk samples were prepared. The mid-infrared spectra of all samples were obtained from 30 â„ƒ to 55 â„ƒ with an interval of 5 â„ƒ. Under the perturbation of temperature, synchronous 2D correlation spectra were calculated to build discrimination models of pure milk and adulterated milk. In comparison, the NPLS-DA models were built based on three-dimensional (3D) stacked map (sample × temperature × wavenumber variable). For the NPLS-DA models of two brands of milk, the discrimination accuracy of unknown samples in the prediction set is 100% using temperature-perturbed 2D infrared correlation spectra, versus 77.8% using conventional 3D stacked map. The proposed method can be used as an alternative way for classifying pure and adulterated milk.

[A real-world study of low molecular weight heparin sodium in the treatment of severe and critical bite by Trimeresurus stejnegeri].

OBJECTIVE: To investigate the clinical effect of low molecular weight heparin sodium combined with antivenin in the treatment of severe and critical bite by Trimeresurus stejnegeri. METHODS: The clinical data of 48 patients with severe or critical bite by Trimeresurus stejnegeri admitted to emergency department of Southeast Hospital Affiliated to Xiamen University from March 2017 to May 2019 were retrospectively analyzed. On the basis of early treatment of antivenom serum, internal administration and external application of Jidesheng snake tablet, and wound incision and detoxification, the patients were divided into heparin treatment group and non-heparin treatment group according to whether the low molecular heparin sodium was used or not. The patients in the two groups were compared in terms of gender, age, clinical classification, swelling degree of injured limbs, change of coagulation function index, bleeding of skin, mucous membrane or digestive tract, blood transfusion, local symptoms of bite, length of hospital stay and prognosis. RESULTS: There was no significant difference in terms of gender, age, clinical classification or swelling degree of injured limbs between the two groups. On the 3rd day of treatment, the platelet count (PLT) in the heparin treatment group was significantly higher than that in the non-heparin treatment group [×109/L: 210.0 (160.0, 252.0) vs. 136.0 (104.0, 198.5), P < 0.05]. However, there was no significant difference in the four coagulation test results between the two groups. On the 6th day of treatment, the plasma thrombin time (TT) in the heparin treatment group was significantly shorter than that on the 3rd day of treatment [s: 30.3 (20.4, 37.0) vs. 34.7 (24.0, 73.4), P < 0.05], and the fibrinogen (FIB) in the heparin treatment group was significantly higher than that in the non-heparin treatment group [g/L: 0.60 (0.31, 1.07) vs. 0.20 (0.14, 0.60), P < 0.01]. The incidence of bleeding in the heparin treatment group was significantly lower than that in the non-heparin treatment group [21.7% (5/23) vs. 64.0% (16/25), P < 0.01]; 11 patients in the heparin treatment group and 18 patients in the non-heparin treatment group received blood transfusion and prothrombin complex supplement respectively. There was no significant difference in the length of hospital stay between the heparin group and non-heparin treatment group (days: 6.91±1.92 vs. 7.48±2.27, P > 0.05). The patients in both groups were followed up for 1 week to 1 month after treatment, and no death or local necrosis of skin and soft tissue was found. CONCLUSIONS: For the patients with severe and critical bite by Trimeresurus stejnegeri, on the basis of injection of antivenom serum, internal administration and external application of Jidesheng snake tablet, and wound incision and detoxification, early application of low molecular weight heparin sodium anticoagulation and other comprehensive treatment is helpful to improve limb swelling and inflammation, reduce blood transfusion, promote the recovery of coagulation function, and shorten the length of hospitalization.