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Intratumoral genomic heterogeneity in glioblastoma (GBM) is a barrier to overcoming therapy resistance. Treatments that are effective independent of genotype are urgently needed. By correlating intracellular metabolite levels with radiation resistance across dozens of genomically-distinct models of GBM, we find that purine metabolites, especially guanylates, strongly correlate with radiation resistance. Inhibiting GTP synthesis radiosensitizes GBM cells and patient-derived neurospheres by impairing DNA repair. Likewise, administration of exogenous purine nucleosides protects sensitive GBM models from radiation by promoting DNA repair. Neither modulating pyrimidine metabolism nor purine salvage has similar effects. An FDA-approved inhibitor of GTP synthesis potentiates the effects of radiation in flank and orthotopic patient-derived xenograft models of GBM. High expression of the rate-limiting enzyme of de novo GTP synthesis is associated with shorter survival in GBM patients. These findings indicate that inhibiting purine synthesis may be a promising strategy to overcome therapy resistance in this genomically heterogeneous disease. Targeting genotype-independent abnormalities may overcome therapy resistance in glioblastoma despite intratumoral genomic heterogeneity. Here, the authors show that glioblastoma radiation resistance is promoted by purine metabolism and can be overcome by inhibitors of purine synthesis.

The hepatocyte growth factor (HGF) along with its receptor (c-MET) are crucial in preserving standard cellular physiological activities, and imbalances in the c-MET signaling pathway can lead to the development and advancement of tumors. It has been extensively demonstrated that immune checkpoint inhibitors (ICIs) can result in prolonged remission in certain patients. Nevertheless, numerous preclinical studies have shown that MET imbalance hinders the effectiveness of anti-PD-1/PD-L1 treatments through various mechanisms. Consequently, clarifying the link between the c-MET signaling pathway and the tumor microenvironment (TME), as well as uncovering the effects of anti-MET treatment on ICI therapy, is crucial for enhancing the outlook for tumor patients. In this review, we examine the impact of abnormal activation of the HGF/c-MET signaling pathway on the control of the TME and the processes governing PD-L1 expression in cancer cells. The review thoroughly examines both clinical and practical evidence regarding the use of c-MET inhibitors alongside PD-1/PD-L1 inhibitors, emphasizing that focusing on c-MET with immunotherapy enhances the effectiveness of treating MET tumors exhibiting elevated PD-L1 expression.

The importance of the Hippo-Yes-associated protein 1 (YAP1) pathway in gastric carcinogenesis and metastasis has attracted considerable research attention; however, the regulatory network of YAP1 in gastric cancer (GC) is not completely understood. In this study, ubiquitin-specific peptidase 49 (USP49) was identified as a novel deubiquitinase of YAP1, knockdown of USP49 inhibited the proliferation, metastasis, chemoresistance, and peritoneal metastasis of GC cells. Overexpression of USP49 showed opposing biological effects. Moreover, USP49 was transcriptionally activated by the YAP1/TEAD4 complex, which formed a positive feedback loop with YAP1 to promote the malignant progression of GC cells. Finally, we collected tissue samples and clinical follow-up information from 482 GC patients. The results showed that USP49 expression was high in GC cells and positively correlated with the expression of YAP1 and its target genes, connective tissue growth factor ( CTGF ) and cysteine-rich angiogenic inducer 61 ( CYR61 ). Survival and Cox regression analysis showed that high USP49 expression was associated with poor prognosis and was an independent prognostic factor. Moreover, patients with high USP49 and YAP1 expression had extremely short overall survival. The findings of this study reveal that the aberrant activation of the USP49/YAP1 positive feedback loop plays a critical role in the malignant progression of GC, thus providing potential novel prognostic factors and therapeutic targets for GC.

Background Parkinson’s disease (PD) is associated with enteric nervous system dysfunction and gut microbiota dysbiosis. Short-chain fatty acids (SCFAs), derived from gut microbiota, are supposed to anticipate PD pathogenesis via the pathway of spinal cord and vagal nerve or the circulatory system. However, the serum concentration of SCFAs in PD patients is poorly known. This study aims to investigate the exact level of SCFAs in PD patients and its correlation with Parkinson’s symptoms. Methods 50 PD patients and 50 healthy controls were recruited, and their demographic and clinical characteristics were collected. The serum concentration of SCFAs was detected using a gas chromatography-mass spectrometer. SCFAs were compared between PD and control groups. The correlation between serum SCFAs and Parkinson’s symptoms and the potential effects of medications on the serum SCFAs was analyzed. Results Serum propionic acid, butyric acid and caproic acid were lower, while heptanoic acid was higher in PD patients than in control subjects. However, only the serum level of propionic acid was correlated with Unified Parkinson’s Disease Rating Scale (UPDRs) part III score (R = -0.365, P  = 0.009), Mini-mental State Examination (MMSE) score (R = -0.416, P  = 0.003), and Hamilton Depression Scale (HAMD) score (R = 0.306, P  = 0.03). There was no correlation between other serum SCFAs and motor complications. The use of trihexyphenidyl or tizanidine increased the serum concentration of propionic acid. Conclusions Serum SCFAs are altered in PD patients, and the decrease of serum propionic acid level is correlated with motor symptoms, cognitive ability and non-depressed state. Thus, the gut microbial-derived SCFAs potentially affect Parkinson’s symptoms through the blood circulation. Propionic acid supplementation might ameliorate motor and non-motor symptoms of PD patients, although clinical trials are needed to test this hypothesis.

F-box and WD repeat domain-containing 5 (FBXW5), with WD40 repeats, can bind to the PPxY sequence of the large tumor suppressor kinases 1/2 (LATS1/2) kinase domain, resulting in ubiquitination. Ubiquitination and the subsequent degradation of LATS1/2 abrogate the Hippo pathway and worsen gastric cancer (GC). However, the effects and molecular mechanisms of FBXW5 in GC remain unexplored. To elucidate the clinical significance of FBXW5, immunohistochemistry was conducted to reveal the positive correlation between FBXW5 expression and lymph node metastasis ( p  < 0.001) and TNM stage (training cohort: p  = 0.018; validation cohort: p  = 0.001). Further, patients with high FBXW5 expression were found to have poor prognosis (training cohort: log-rank p  = 0.020; validation cohort: log-rank p  = 0.025). Cell experiments revealed the promoting effects of FBXW5 on the proliferation, invasion, metastasis, and chemoresistance of GC cells. Blocking LATS1-YAP1 leads to the loss of FBXW5-mediated regulation of the Hippo pathway and partial functions. Further, co-immunoprecipitation and in vivo ubiquitination assays revealed the interaction between FBXW5 and LATS1, which promoted the ubiquitination and degradation of LATS1. Based on mouse xenograft assays, FBXW5 silencing attenuated the growth of subcutaneous tumor xenografts. Altogether, FBXW5 was found to inactivate the Hippo signaling pathway by enhancing LATS1 ubiquitination and degradation, which promoted the invasion, metastasis, and drug resistance of GC cells.

Chemoresistance is the most significant challenge affecting the clinical efficacy of the treatment of patients with gastric cancer (GC). Here we reported that transmembrane protein 160 (TMEM160) suppressed ferroptosis and induced chemoresistance in GC cells. Mechanistically, TMEM160 recruited the E3 ligase TRIM37 to promote K48-linked ubiquitination and degradation of KEAP1, thereby activating NRF2 and transcriptionally upregulating the target genes GPX4 and SLC7A11 to inhibit ferroptosis. Further in vitro and in vivo experiments demonstrated that the combination of TMEM160 targeting and chemotherapy had a synergistic inhibitory effect on the growth of GC cells, which was partially NRF2-dependent. Moreover, TMEM160 and NRF2 protein levels were markedly overexpressed in GC tissues, and their co-overexpression was an independent factor for poor prognosis. Collectively, these findings indicate that TMEM160, as a pivotal negative regulator of ferroptosis, exerts a crucial influence on the chemoresistance of GC through the TRIM37-KEAP1/NRF2 axis, providing a potential new prognostic factor and combination therapy strategy for patients with GC.

Background The effectiveness of anti-programmed cell death protein 1(PD-1)/programmed cell death 1 ligand 1(PD-L1) therapy in treating certain types of cancer is associated with the level of PD-L1. However, this relationship has not been observed in colorectal cancer (CRC), and the underlying regulatory mechanism of PD-L1 in CRC remains unclear. Methods Binding of TMEM160 to PD-L1 was determined by co-immunoprecipitation (Co-IP) and GST pull-down assay.The ubiquitination levels of PD-L1 were verified using the ubiquitination assay. Phenotypic experiments were conducted to assess the role of TMEM160 in CRC cells. Animal models were employed to investigate how TMEM160 contributes to tumor growth.The expression and clinical significance of TMEM160 and PD-L1 in CRC tissues were evaluated by immunohistochemistry(IHC). Results In our study, we made a discovery that TMEM160 interacts with PD-L1 and plays a role in stabilizing its expression within a CRC model. Furthermore, we demonstrated that TMEM160 hinders the ubiquitination-dependent degradation of PD-L1 by competing with SPOP for binding to PD-L1 in CRC cells. Regarding functionality, the absence of TMEM160 significantly inhibited the proliferation, invasion, metastasis, clonogenicity, and radioresistance of CRC cells, while simultaneously enhancing the cytotoxic effect of CD8 + T cells on tumor cells. Conversely, the upregulation of TMEM160 substantially increased these capabilities. In severely immunodeficient mice, tumor growth derived from lentiviral vector shTMEM160 cells was lower compared with that derived from shNC control cells. Furthermore, the downregulation of TMEM160 significantly restricted tumor growth in immune-competent BALB/c mice. In clinical samples from patients with CRC, we observed a strong positive correlation between TMEM160 expression and PD-L1 expression, as well as a negative correlation with CD8A expression. Importantly, patients with high TMEM160 expression exhibited a worse prognosis compared with those with low or no TMEM160 expression. Conclusions Our study reveals that TMEM160 inhibits the ubiquitination-dependent degradation of PD-L1 that is mediated by SPOP, thereby stabilizing PD-L1 expression to foster the malignant progress, radioresistance, and immune evasion of CRC cells. These findings suggest that TMEM160 holds potential as a target for the treatment of patients with CRC.

Interferon regulatory factor 2 binding protein 2 (IRF2BP2) is a transcriptional repressor involved in regulating gene expression and other biological processes, including tumorigenesis. However, the clinical significance and roles of IRF2BP2 in human gastric cancer (GC) remain uncertain. Clinical GC tissues were obtained from GC patients at the First Affiliated Hospital of Nanchang University. Immunohistochemistry (IHC) was conducted to detect the IRF2BP2 protein in clinical paraffin specimens. Cell proliferation, migration and invasion were evaluated by MTT, colony formation assays and transwell assays. Co‐immunoprecipitation was conducted to detect the interaction between TEA domain family members 4 (TEAD4) and vestigial‐like family member 4 (VGLL4) or Yes‐associated protein 1 (YAP1). Dual‐luciferase reporter assay was used to confirm the binding of miR‐101‐3p to the 3′‐UTR. The expression of IRF2BP2 was significantly higher in GC tissues than in normal tissues. Patients with higher IRF2BP2 protein expression had lower survival. IRF2BP2 knockdown inhibited proliferation, migration, invasion and epithelial‐mesenchymal transition in GC cells. IRF2BP2 knockdown decreased the mRNA and protein levels of connective tissue growth factor (CTGF). The interaction between IRF2BP2 and VGLL4 increased the binding of TEAD4 to YAP1, resulting in the transcriptional coactivation of CTGF. In addition, miR‐101‐3p suppressed the expression of CTGF by directly targeting the 3′‐UTR of IRF2BP2. Taken together, these findings provide a model for the role of miR‐101‐3p‐IRF2BP2‐CTGF signalling axis in GC and a novel insight into the mechanism of GC progression and metastasis.

Background Most genetic skeletal disorders (GSD) were complex, disabling and life-threatening without effective diagnostic and treatment methods. However, its impacts on health system have not been well studied. The study aimed to systematically evaluate the health-care utilization and economic burden in GSD patients. Methods The patients were derived from 2018 Nationwide Inpatient Sample and Nationwide Readmissions Database. GSD patients were extracted based on International Classification of Diseases-10th revision codes. Results A total of 25,945 (0.12%) records regarding GSD were extracted from all 21,400,282 records in NIS database. GSD patients were likely to have significantly longer length of stay (6.50 ± 0.08 vs. 4.63 ± 0.002, P  < 0.001), higher total charges ($85,180.97 ± 1,239.47 vs. $49,884.26 ± 20.99, P  < 0.001), suffering more procedure, diagnosis and transferring records in comparison to patients with common conditions. GSD patients had a significantly higher 30-day all-cause readmission rate based on Nationwide Readmissions Database. Conclusions The heavy health-care utilization and economic burden emphasized the urgency for policy leaders, scientific and pharmaceutical researchers, health care providers and employers to identify innovative ways and take effective measurements immediately, and eventually to help improve the care, management, and treatment of these devastating diseases.

Background Follistatin-like 1 (FSTL1) plays a central role in the progression of tumor and tumor immunity. However, the effect of FSTL1 on the prognosis and immune infiltration of gastric cancer (GC) remains to be elucidated. Methods The expression of FSTL1 data was analyzed in Oncomine and TIMER databases. Analyses of clinical parameters and survival data were conducted by Kaplan-Meier plotter and immunohistochemistry. Western blot assay and real-time quantitative PCR (RT-qPCR) were used to analyze protein and mRNA expression, respectively. The correlations between FSTL1 and cancer immune infiltrates were analyzed by Tumor Immune Estimation Resource (TIME), Gene Expression Profiling Interactive Analysis (GEPIA), and LinkedOmics database. Results The expression of FSTL1 was significantly higher in GC tissues than in normal tissues, and bioinformatic analysis and immunohistochemistry (IHC) indicated that high FSTL1 expression significantly correlated with poor prognosis in GC. Moreover, FSTL1 was predicted as an independent prognostic factor in GC patients. Bioinformatics analysis results suggested that FSTL1 mainly involved in tumor progression and tumor immunity. And significant correlations were found between FSTL1 expression and immune cell infiltration in GC. Conclusions The study effectively revealed useful information about FSTL1 expression, prognostic values, potential functional networks, and impact of tumor immune infiltration in GC. In summary, FSTL1 can be used as a biomarker for prognosis and evaluating immune cell infiltration in GC.