TPP1 is associated with risk of advanced precursors and cervical cancer survival.

It is unclear how telomere-binding protein TPP1 interacts with human telomerase reverse transcriptase (hTERT) and influences cervical cancer development and progression. This study included all eligible 156 cervical cancers diagnosed during 2003-2008 and followed up through 2014, 102 cervical intraepithelial neoplasia (CIN) patients, and 16 participants with normal cervix identified at the same period. Correlation of expression of TPP1 and hTERT in these lesions was assessed using Kappa statistics. TPP1 was knocked down by siRNA in three cervical cancer cell lines. We assessed mRNA expression using quantitative real-time polymerase chain reaction and protein expression using tissue microarray-based immunohistochemical staining. We further analyzed the impact of TPP1 expression on the overall survival of cervical cancer patients by calculating the hazard ratio (HR) with 95% confidence intervals (CIs) using the multivariable-adjusted Cox regression model. Compared to the normal cervix, high TPP1expression was significantly associated with CIN 3 and cervical cancers (P<0.001 for both). Expressions of TPP1 and hTERT were highly correlated in CIN 3 (Kappa statistics = 0.50, P = 0.005), squamous cell carcinoma (Kappa statistics = 0.22, P = 0.011), and adenocarcinoma/adenosquamous carcinoma (Kappa statistics = 0.77, P = 0.001). Mechanistically, knockdown of TPP1 inhibited the expression of hTERT in both mRNA and protein levels. High expression of TPP1 (HR = 2.61, 95% CI 1.23-5.51) and co-high expression of TPP1 and hTERT (HR = 2.38, 95% CI 1.28-4.43) were independently associated with worse survival in cervical cancer patients. TPP1 and hTERT expression was correlated and high expression of TPP1 was associated with high risk of CIN 3 and cervical cancer and could predict a worse survival in cervical cancer.

Nanotheranostics in cancer lymph node metastasis: The long road ahead.

Lymph node metastasis (LNM) significantly impacts the prognosis of cancer patients. Despite significant advancements in diagnostic techniques and treatment modalities, clinical challenges continue to persist in the realm of LNM. These include difficulties in early diagnosis, limited treatment efficacy, and potential side effects and injuries associated with treatment. Nanotheranostics, a field within nanotechnology, seamlessly integrates diagnostic and therapeutic functionalities. Its primary goal is to provide precise and effective disease diagnosis and treatment simultaneously. The development of nanotheranostics for LNM offers a promising solution for the stratified management of patients with LNM and promotes the advancement of personalized medicine. This review introduces the mechanisms of LNM and challenges in its diagnosis and treatment. Furthermore, it demonstrates the advantages and development potential of nanotheranostics, focuses on the challenges nanotheranostics face in its application, and provides an outlook on future trends. We consider nanotheranostics a promising strategy to improve clinical effectiveness and efficiency as well as the prognosis of cancer patients with LNM.

Recent advances in targeting myeloid-derived suppressor cells and their applications to radiotherapy.

Myeloid-derived suppressor cells (MDSCs) are a group of heterogenous immature myeloid cells with potent immune suppressive properties that not only constrain anti-tumor immune activation and functions, promote tumor progression, but also contribute to treatment resistance and tumor relapse. Targeting MDSCs may be a promising new cancer treatment method, but there is still a problem of low treatment efficiency. Combined application with radiotherapy may be a potential method to solve this problem. Drug delivery systems (DDSs) provide more efficient targeted drug delivery capability and can reduce the toxicity and side effects of drugs. Recent advance in DDSs targeting development, recruitment, differentiation, and elimination of MDSCs have shown promising effect in reversing immune inhibition and in overcoming radiotherapy resistance. In this review, we systematically summarized DDSs applied to target MDSCs for the first time, and classified and discussed it according to its different mechanisms of action. In addition, this paper also reviewed the biological characteristics of MDSCs and their role in the initiation, progression, and metastasis of cancer. Moreover, this review also summarizes the role of DDSs targeting MDSCs in radiosensitization. Finally, the future development of DDSs targeting MDSCs is also prospected.

Research trends of targeted therapy for cholangiocarcinoma from 2003 to 2022: a bibliometric and visual analysis.

In the past 20 years, targeted therapy for cholangiocarcinoma has attracted certain attention. There is a significant upward in papers focusing on this field. In this study, we used bibliometric and visual methods to explore the current status and future directions in cholangiocarcinoma-targeted therapy research. A total of 1057 papers published in English from 2003 to 2022 were extracted from the Web of Science Core Collection SCI-expanded database. Furthermore, Citespace, Vosviewer, and Excel 2016 were utilized to conduct bibliometric and visual analysis. The volume of annual publications has steadily increased over the past two decades. The USA has published the largest number of publications, and the Mayo Clinic acted as the dominant institution. Cancers, Frontiers in Oncology, and Hepatology were the prolific resources in this research field. Moreover, the co-cited reference analysis uncovered the landmark paper in this field. With regard to research hotspots and frontiers, the burst keywords analysis showed that growth factor receptors and pathogenesis might become the hot topics of future research. To sum up, our study displays the current research status and future directions in the targeted therapy for cholangiocarcinoma. More comprehensive and in-depth investigations should focus on critical genetic mutations and their molecular mechanisms to prompt the molecular-targeted therapy.

Comparison of Definitive Radiotherapy-Based Treatment and Surgical-Based Treatment for Locally Advanced Head and Neck Soft Tissue Sarcoma.

Background: Head and neck soft-tissue sarcomas are rare but aggressive malignancies. Definitive radiotherapy might be an alternative treatment choice in patients unfit for surgery with preservation of organ function and facial morphology. Whether definitive radiotherapy is comparable with surgery has not been fully demonstrated. In this study, we compared the prognosis of patients with radiotherapy-based treatment and with surgery-based treatment. Methods: From May 2014 to February 2021, patients with locally advanced head and neck soft-tissue sarcoma treated with either definitive radiotherapy-based treatment or radical surgery-based treatment were retrospectively enrolled. Clinical outcomes including tumor response, patients' survival and acute treatment-related toxicities were evaluated. Kaplan-Meier curves with log-rank test were used to compare survival data. Cox regression analysis was used to explore prognostic factors. Results: A total of 24 patients (12 males and 12 females, 3 to 61 years old) were eligible for analysis. The median follow-up time was 49 (range: 6-96) months. In 16 patients receiving definitive radiotherapy-based treatment, 6 reached complete response. The survival curve showed that there was no statistically significant difference in overall survival (OS), distant metastasis-free survival (DMFS), loco-regional relapse-free survival (LRRFS) and progression-free survival (PFS) between the two groups of patients (p = 0.35, p = 0.24, p = 0.48, p = 0.1, respectively). COX regression analysis showed that older age was associated with poor DMFS. There was no significant difference in grade 3-4 toxicities between the two groups. Conclusions: In cases of contradictions to surgery, refusal to surgery or failure to complete resection, chemoradiotherapy might be an alternative treatment option.

Histone acetylation-related IncRNA: Potential biomarkers for predicting prognosis and immune response in lung adenocarcinoma, and distinguishing hot and cold tumours.

Background: Histone acetylation-related lncRNAs (HARlncRNAs) play significant roles in various cancers, but their impact on lung adenocarcinoma (LUAD) remains unclear. This study aimed to develop a new HARlncRNA-based prognostic model for LUAD and to explore its potential biological mechanisms. Methods: We identified 77 histone acetylation genes based on previous studies. HARlncRNAs related to prognosis were screened by co-expression, univariate and multivariate analyses, and least absolute shrinkage selection operator regression (LASSO). Afterward, a prognostic model was established based on the screened HARlncRNAs. We analysed the relationship between the model and immune cell infiltration characteristics, immune checkpoint molecule expression, drug sensitivity, and tumour mutational burden (TMB). Finally, the entire sample was divided into three clusters to further distinguish between hot and cold tumours. Results: A seven-HARlncRNA-based prognostic model was established for LUAD. The area under the curve (AUC) of the risk score was the highest among all the analysed prognostic factors, indicating the accuracy and robustness of the model. The patients in the high-risk group were predicted to be more sensitive to chemotherapeutic, targeted, and immunotherapeutic drugs. It was worth noting that clusters could effectively identify hot and cold tumours. In our study, clusters 1 and 3 were considered hot tumours that were more sensitive to immunotherapy drugs. Conclusion: We developed a risk-scoring model based on seven prognostic HARlncRNAs that promises to be a new tool for evaluating the prognosis and efficacy of immunotherapy in patients with LUAD.

Prospects and feasibility of synergistic therapy with radiotherapy, immunotherapy, and DNA methyltransferase inhibitors in non-small cell lung cancer.

The morbidity and mortality of lung cancer are increasing, seriously threatening human health and life. Non-small cell lung cancer (NSCLC) has an insidious onset and is not easy to be diagnosed in its early stage. Distant metastasis often occurs and the prognosis is poor. Radiotherapy (RT) combined with immunotherapy, especially with immune checkpoint inhibitors (ICIs), has become the focus of research in NSCLC. The efficacy of immunoradiotherapy (iRT) is promising, but further optimization is necessary. DNA methylation has been involved in immune escape and radioresistance, and becomes a game changer in iRT. In this review, we focused on the regulation of DNA methylation on ICIs treatment resistance and radioresistance in NSCLC and elucidated the potential synergistic effects of DNA methyltransferases inhibitors (DNMTis) with iRT. Taken together, we outlined evidence suggesting that a combination of DNMTis, RT, and immunotherapy could be a promising treatment strategy to improve NSCLC outcomes.

Integrated analysis reveals common DNA methylation patterns of alcohol-associated cancers: A pan-cancer analysis.

Background: The role of alcohol in carcinogenesis has received increasing attention in recent years. Evidence shows its impacts on various aspects, including epigenetics alteration. The DNA methylation patterns underlying alcohol-associated cancers are not fully understood. Methods: We investigated the aberrant DNA methylation patterns in four alcohol-associated cancers based on the Illumina HumanMethylation450 BeadChip. Pearson coefficient correlations were identified between differential methylated CpG probes and annotated genes. Transcriptional factor motifs were enriched and clustered using MEME Suite, and a regulatory network was constructed. Results: In each cancer, differential methylated probes (DMPs) were identified, and 172 hypermethylated and 21 hypomethylated pan-cancer DMPs (PDMPs) were examined further. Annotated genes significantly regulated by PDMPs were investigated and enriched in transcriptional misregulation in cancers. The CpG island chr19:58220189-58220517 was hypermethylated in all four cancers and silenced in the transcription factor ZNF154. Various biological effects were exerted by 33 hypermethylated and seven hypomethylated transcriptional factor motifs grouped into five clusters. Eleven pan-cancer DMPs were identified to be associated with clinical outcomes in the four alcohol-associated cancers, which might provide a potential point of view for clinical outcome prediction. Conclusion: This study provides an integrated insight into DNA methylation patterns in alcohol-associated cancers and reveals the corresponding features, influences, and potential mechanisms.

Non-inferior efficacy of non-surgical treatment to surgical treatment in patients with nonmetastatic head and neck rhabdomyosarcoma: a SEER-based study.

PURPOSE: Head and neck rhabdomyosarcoma (HNRMS) is a rare but aggressive malignant neoplasm. Given the young patient age and critical anatomy of the head and neck, performing surgery on the primary tumor still remains debatable. This study aimed to evaluate the impact of the non-surgery-based treatment versus surgery-based treatment on patients with nonmetastatic HNRMS. METHODS: Patients diagnosed with nonmetastatic HNRMS between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database were enrolled in our study. Inverse probability treatment weighting (IPTW) method was employed to balance confounding factors between surgery and non-surgery groups. Kaplan-Meier methods and COX regression analyses were used to analyze survival outcomes of overall survival (OS) and cancer-specific survival (CSS). Prognostic nomogram was established to predict survival. RESULTS: A total of 260 eligible patients were extracted from the SEER database. Kaplan-Meier survival curves revealed that there was no significant difference in OS and CSS between the surgery and non-surgery groups both before and after IPTW (p > 0.05). Cox regression analyses and IPTW-adjusted Cox regression analyses for both OS and CSS showed similar survival between the two groups. Prognostic factors were explored and a nomogram for patients in the surgery group was constructed. Risk stratification based on the nomogram indicated that patients in surgery-high-risk group did not benefit from primary surgery. While those in surgery-low-risk group had an equal survival outcome to those in non-surgery group. CONCLUSIONS: Our study revealed that compared to patients receiving surgery, those not receiving surgery had similar survival outcomes for nonmetastatic HNRMS. Our established nomogram may serve as a practical tool for individual prognostic evaluations.

Determination of optimum number of cycles of induction chemotherapy for locoregionally advanced nasopharyngeal carcinoma: a single-center retrospective study.

BACKGROUND: Induction chemotherapy (IC) followed by concurrent chemo-radiotherapy (CCRT) is the current standard of care for locoregionally advanced nasopharyngeal carcinoma (LA-NPC) patients. However, there is still no consensus on the optimum number of IC cycles. In this study, we aimed to assess the efficacy and toxicities of two or more cycles of IC for LA-NPC patients. METHODS: Data of LA-NPC patients consecutively treated with IC followed by concurrent chemo-radiotherapy (CCRT) in our institute from 2017 to 2022 were retrospectively retrieved and analyzed. Survival outcomes of patients who received two IC cycles were compared with those who received more than two IC cycles. Univariate and multivariate Cox regression analysis were then performed to determine factors that could be independent predictors of survival. Chi-square test and Fisher's exact test were used to compare treatment associated acute toxicities between the two groups. RESULTS: A total of 125 patients were recruited in this study. There were 89 patients who received 2 cycles (IC = 2) of IC and 36 received more than 2 cycles (IC > 2) of IC. The median follow-up time was 26 months [IQR 16-38]. The 3-year overall survival rate was not statistically significant between the two groups (95.50% vs. 86.11%, P = 0.501). Similarly, loco-regional recurrence free survival and progression free survival were not significant (97.75% vs. 97.22%, P = 0.694; and 88.76% vs. 83.33%, P = 0.129), but distant metastasis free survival was significant (88.76% vs. 86.11%, P = 0.049). Multivariate Cox regression analysis showed that IC regimen was an independent prognostic factor. CONCLUSIONS: Two cycles of IC is effective and more than two does not add any additional benefit to the survival outcomes of LA-NPC patients.

A shear-thinning, ROS-scavenging hydrogel combined with dental pulp stem cells promotes spinal cord repair by inhibiting ferroptosis.

Spinal cord injury (SCI) is a serious clinical disease. Due to the deformability and fragility of the spinal cord, overly rigid hydrogels cannot be used to treat SCI. Hence, we used TPA and Laponite to develop a hydrogel with shear-thinning ability. This hydrogel exhibits good deformation, allowing it to match the physical properties of the spinal cord; additionally, this hydrogel scavenges ROS well, allowing it to inhibit the lipid peroxidation caused by ferroptosis. According to the in vivo studies, the TPA@Laponite hydrogel could synergistically inhibit ferroptosis by improving vascular function and regulating iron metabolism. In addition, dental pulp stem cells (DPSCs) were introduced into the TPA@Laponite hydrogel to regulate the ratios of excitatory and inhibitory synapses. It was shown that this combination biomaterial effectively reduced muscle spasms and promoted recovery from SCI.

Ataxia telangiectasia mutated kinase inhibition promotes irradiation-induced PD-L1 expression in tumour-associated macrophages through IFN-I/JAK signalling pathway.

Tumour-associated macrophages (TAMs) are one of the primary sources of PD-L1 expression in the tumour microenvironment (TME). Ionizing radiation (IR) promotes PD-L1 expression in tumour cells. However, the effect of IR on macrophage PD-L1 expression and the underlying mechanisms remain unclear. ATM kinase, as the key kinase for initiating DNA damage repair (DDR) process, is associated with innate immune STING axis activation. Here, we explored the molecular mechanism implicated in macrophage PD-L1 expression regulated by IR as well as the role of ATM kinase in this process. IR-regulated PD-L1 expression in macrophages and associated signalling pathways were explored by in vitro studies using murine and human macrophage cell lines. A colorectal xenograft murine model was employed to demonstrate the impact of targeting ATM and PD-L1 expression in TAMs following IR on growth of tumour in vivo. IR up-regulated PD-L1 expression in macrophages, which was further augmented by ATM kinase inhibition. ATM inhibition increased IR-induced DNA damage, which activated STING/interferon regulatory factor 3 (IRF3) signalling pathway and up-regulated type I interferon (IFN-I) expression in macrophages. IFN-I bound to the IFN α receptor 1 on macrophages, activated the downstream JAK1 and STAT1/3 signalling and eventually led to PD-L1 up-expression. ATM inhibition augmented IR-induced PD-L1 expression in macrophages and CD8+ T cell infiltration, and promoted anti-tumour efficacy in vivo. These results suggested that ATM inhibition promoted IR-induced PD-L1 expression through the activation of innate immunity in TAMs, which provided a novel approach to enhance the anti-tumour efficacy of RT.

Study on the prognosis, immune and drug resistance of m6A-related genes in lung cancer.

BACKGROUND: Few studies have demonstrated that the relationship between m6A-related genes and the prognosis, tumor microenvironment and drug resistance of LC. METHODS: The main results were analyzed with bioinformatics methods. RESULTS: Hence, we found 10 m6A-related genes expressed less in tumor samples in comparison with normal ones. Using consensus clustering, all LC patients were grouped into 2 subgroups according to the overall expression of 10 differential expressed m6A-related genes. In two clusters, the OS and immune characteristics were different. We analyzed the predictive potential of 10 m6A-related genes in the prognosis of LC, and obtained a risk prognosis model on the strength of ZC3H13, CBLL1, ELAVL1 and YTHDF1 as the hub candidate genes through LASSO cox. The expression of 4 hub m6A-related genes was validated by IHC in the HPA database. The infiltration level of dendritic cell, CD4+ T cell and neutrophil that were affected by CNV level of m6A-related genes in LUAD and LUSC patients. Moreover, based on GSCALite database, we found that LUSC patients with hypermethylation tended to have a better overall survival. In terms of drug sensitivity, etoposide correlated negatively with ELAVL1, HNRNPC, RBM15B, YTHDF2 and CBLL1. ZC3H13 had positively association with afatinib, while HNRNPC was positively associated with dasatinib, erlotinib, lapatinib and TGX221. Crizotinib had a negative correlation with ELAVL1, CBLL1, HNRNPC and RBM15B. CONCLUSION: In conclusion, m6A-related genes are important participants in LC and the expression levels of ZC3H13, CBLL1, ELAVL1 and YTHDF1 are significant for prediction and treatment of LC. Researches of drug resistance based on m6A-related genes need to pay more attention for producing new therapeutic strategies of LC and CBLL1 may contribute to target treatment for further research.

Corrigendum: Hypoxia response element-directed expression of aFGF in neural stem cells promotes the recovery of spinal cord injury and attenuates SCI-induced apoptosis.

[This corrects the article DOI: 10.3389/fcell.2021.693694.].

Atezolizumab with chemotherapy in first-line treatment for metastatic urothelial cancer: a cost-effectiveness analysis.

Purpose: To evaluate the cost-effectiveness of atezolizumab plus chemotherapy as first-line treatment for metastatic urothelial cancer (mUC). Materials & methods: A Markov model was established for the analysis. Parametric survival models were used to fit to progression-free survival and overall survival data in the IMvigor130 study. A series of one-way and probabilistic sensitivity analyses were performed to test the robustness of the model. Results: The incremental cost-effectiveness ratios for atezolizumab plus chemotherapy versus chemotherapy alone were US$475,633.17 and $207,488.17 per quality-adjusted life year in the USA and China, respectively. Utility for the progression-free survival and progressive disease states, the cost of atezolizumab had the most significant impact on the incremental cost-effectiveness ratio. Conclusion: Atezolizumab plus chemotherapy is not a cost-effective treatment option as a first-line treatment for metastatic urothelial cancer.

PARP inhibitor plus radiotherapy reshapes an inflamed tumor microenvironment that sensitizes small cell lung cancer to the anti-PD-1 immunotherapy.

Small cell lung cancer (SCLC) is a highly malignant tumor with extremely poor prognosis. The treatment strategy is very limited, and patient outcomes remain dismal with the 5-year survival rate being mere 3-6%. Thus, novel therapeutic strategies for SCLC patients are urgently needed. In this study, we found that the triple-therapy of poly (ADP-ribose) polymerase (PARP) inhibitor, radiotherapy (RT) and anti-PD-1 treatment significantly inhibited tumor growth and prolonged survival in the syngeneic SCLC models in immunocompetent C57BL/6 mice. Mechanistically, we demonstrated that the combination of PARP inhibitor niraparib and RT reshaped an inflamed tumor microenvironment, including activation of the cGAS/STING immune response pathway, induction of immunogenic cell death, and upregulation of PD-L1 on tumor cells. Furthermore, this triple-therapy substantially augmented CD8+ T cell infiltration and activation, and enhanced anti-tumor effects as revealed by increased median survival time and reduced tumor volume without additional myelosuppression or hepatic injury. Together, our studies demonstrated that PARP inhibitor combined with RT potentiated anti-tumor immunity and enhanced the efficacy of anti-PD-1 immunotherapy in preclinical study, which provided a promising therapeutic strategy for SCLC patients in clinic.

Catalpol as a Component of Rehmannia glutinosa Protects Spinal Cord Injury by Inhibiting Endoplasmic Reticulum Stress-Mediated Neuronal Apoptosis.

Disturbance of the internal environment in the spinal cord after spinal cord injury (SCI) is an important cause of the massive death of neurons in the injury area and one of the major problems that lead to the difficult recovery of motor function in patients. Rehmannia glutinosa, a famous traditional Chinese medicine, is commonly used in neurodegenerative diseases, whereas an iridoid glycoside extract of catalpol (CAT), with antioxidant, antiapoptotic, and neuroprotective pharmacological effects. However, the neuroprotective and anti-apoptosis mechanism of CAT in SCI remains unclear. In our study, we found that CAT has a restorative effect on the lower limb motor function of rats with SCI by establishing a rat model of SCI and treating CAT gavage for 30 days. Our study further found that CAT has the effect of inhibiting apoptosis and protecting neurons, and the action pathway may reduce endoplasmic reticulum (ER) stress by inhibiting CHOP and GRP78 expression and then reduce apoptosis and protect neurons through the Caspase3/Bax/Bcl-2 pathway. In conclusion, we demonstrated that CAT can treat SCI by inhibiting ER stress-mediated neuronal apoptosis and has the potential to be a clinical drug for the treatment of SCI.