Study of the significance of the combination of the fibrinogen-albumin ratio and sarcopenia in predicting the prognosis of laryngeal cancer patients undergoing radical surgery.

OBJECTIVE: This study aims to investigate how the impact of preoperative sarcopenia and inflammatory markers for laryngeal cancer patients and develop a new scoring system to predict their prognosis. MATERIALS AND METHODS: Patients who underwent laryngectomy for laryngeal cancer (LC) from December 2015 to December 2020 at the Second Affiliated Hospital of Fujian Medical University were included. Independent prognostic factors were determined using univariate and multivariate analyses. A new scoring system (SFAR) was established based on FAR and preoperative sarcopenia, and statistically analyzed. RESULTS: 198 cases included in this study that met the admission criteria. Multivariate analysis shown that preoperative sarcopenia, pTNM stage, and FAR were independent prognostic factors for laryngeal cancer. Based on these three indicators, we developed the SFAR scoring system. Multivariate analysis showed that SFAR was an independent predictor of laryngeal cancer (p < 0.001). SFAR was then incorporated into a prognostic model that included T-stage and N-stage, and a column-line graph was generated to accurately predict its survival. CONCLUSION: Systemic inflammation and sarcopenia are significantly associated with postoperative prognosis in laryngeal cancer. A new scoring system (SFAR) had implications for improving the prognosis of patients undergoing surgery for laryngeal cancer.

cNEK6 induces gemcitabine resistance by promoting glycolysis in pancreatic ductal adenocarcinoma via the SNRPA/PPA2c/mTORC1 axis.

Resistance to gemcitabine in pancreatic ductal adenocarcinoma (PDAC) leads to ineffective chemotherapy and, consequently, delayed treatment, thereby contributing to poor prognosis. Glycolysis is an important intrinsic reason for gemcitabine resistance as it competitively inhibits gemcitabine activity by promoting deoxycytidine triphosphate accumulation in PDAC. However, biomarkers are lacking to determine which patients can benefit significantly from glycolysis inhibition under the treatment of gemcitabine activity, and a comprehensive understanding of the molecular mechanisms that promote glycolysis in PDAC will contribute to the development of a strategy to sensitize gemcitabine chemotherapy. In this study, we aimed to identify a biomarker that can robustly indicate the intrinsic resistance of PDAC to gemcitabine and guide chemotherapy sensitization strategies. After establishing gemcitabine-resistant cell lines in our laboratory and collecting pancreatic cancer and adjacent normal tissues from gemcitabine-treated patients, we observed that circRNA hsa_circ_0008383 (namely cNEK6) was highly expressed in the peripheral blood and tumor tissues of patients and xenografts with gemcitabine-resistant PDAC. cNEK6 enhanced resistance to gemcitabine by promoting glycolysis in PDAC. Specifically, cNEK6 prevented K48 ubiquitination of small ribonucleoprotein peptide A from the BTRC, a ubiquitin E3 ligase; thus, the accumulated SNRPA stopped PP2Ac translation by binding to its G-quadruplexes in 5' UTR of mRNA. mTORC1 pathway was aberrantly phosphorylated and activated owing to the absence of PP2Ac. The expression level of cNEK6 in the peripheral blood and tumor tissues correlated significantly and positively with the activation of the mTORC1 pathway and degree of glycolysis. Hence, the therapeutic effect of gemcitabine is limited in patients with high cNEK6 levels, and in combination with the mTORC1 inhibitor, rapamycin, can enhance sensitivity to gemcitabine chemotherapy.

Sulindac (K-80003) with nab-paclitaxel and gemcitabine overcomes drug-resistant pancreatic cancer.

The Nab-paclitaxel combined with gemcitabine (AG) regimen is the main chemotherapy regimen for pancreatic cancer, but drug resistance often occurs. Currently, the ability to promote sensitization in drug-resistant cases is an important clinical issue, and the strategy of repurposing conventional drugs is a promising strategy. This study aimed to identify a classic drug that targets chemotherapy resistance's core signaling pathways and combine it with the AG regimen to enhance chemosensitivity. We also aimed to find reliable predictive biomarkers of drug combination sensitivity. Using RNA sequencing, we found that abnormal PI3K/Akt pathway activation plays a central role in mediating resistance to the AG regimen. Subsequently, through internal and external verification of randomly selected AG-resistant patient-derived organoid (PDO) and PDO xenograft models, we discovered for the first time that the classic anti-inflammatory drug sulindac K-80003, an inhibitor of the PI3K/Akt pathway that we focused on, promoted sensitization in half (14/28) of AG-resistant pancreatic ductal adenocarcinoma cases. Through RNA-sequencing, multiplex immunofluorescent staining, and immunohistochemistry experiments, we identified cFAM124A as a novel biomarker through which sulindac K-80003 promotes AG sensitization. Its role as a sensitization marker is explained via the following mechanism: cFAM124A enhances both the mRNA expression of cathepsin L and the activity of the cathepsin L enzyme. This dual effect stimulates the cleavage of RXRα, leading to large amounts of truncated RXRα, which serves as a direct target of K-80003. Consequently, this process results in the pathological activation of the PI3K/Akt pathway. In summary, our study provides a new treatment strategy and novel biological target for patients with drug-resistant pancreatic cancer.

Necroptosis enhances 'don't eat me' signal and induces macrophage extracellular traps to promote pancreatic cancer liver metastasis.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with dismal prognosis due to distant metastasis, even in the early stage. Using RNA sequencing and multiplex immunofluorescence, here we find elevated expression of mixed lineage kinase domain-like pseudo-kinase (MLKL) and enhanced necroptosis pathway in PDAC from early liver metastasis T-stage (T1M1) patients comparing with non-metastatic (T1M0) patients. Mechanistically, MLKL-driven necroptosis recruits macrophages, enhances the tumor CD47 'don't eat me' signal, and induces macrophage extracellular traps (MET) formation for CXCL8 activation. CXCL8 further initiates epithelial-mesenchymal transition (EMT) and upregulates ICAM-1 expression to promote endothelial adhesion. METs also degrades extracellular matrix, that eventually supports PDAC liver metastasis. Meanwhile, targeting necroptosis and CD47 reduces liver metastasis in vivo. Our study thus reveals that necroptosis facilitates PDAC metastasis by evading immune surveillance, and also suggest that CD47 blockade, combined with MLKL inhibitor GW806742X, may be a promising neoadjuvant immunotherapy for overcoming the T1M1 dilemma and reviving the opportunity for radical surgery.

Escherichia coli-Induced cGLIS3-Mediated Stress Granules Activate the NF-κB Pathway to Promote Intrahepatic Cholangiocarcinoma Progression.

Patients with concurrent intrahepatic cholangiocarcinoma (ICC) and hepatolithiasis generally have poor prognoses. Hepatolithiasis is once considered the primary cause of ICC, although recent insights indicate that bacteria in the occurrence of hepatolithiasis can promote the progression of ICC. By constructing in vitro and in vivo ICC models and patient-derived organoids (PDOs), it is shown that Escherichia coli induces the production of a novel RNA, circGLIS3 (cGLIS3), which promotes tumor growth. cGLIS3 binds to hnRNPA1 and G3BP1, resulting in the assembly of stress granules (SGs) and suppression of hnRNPA1 and G3BP1 ubiquitination. Consequently, the IKKα mRNA is blocked in SGs, decreasing the production of IKKα and activating the NF-κB pathway, which finally results in chemoresistance and produces metastatic phenotypes of ICC. This study shows that a combination of Icaritin (ICA) and gemcitabine plus cisplatin (GP) chemotherapy can be a promising treatment strategy for ICC.

A Novel Trojan Horse Nanotherapy Strategy Targeting the cPKM-STMN1/TGFB1 Axis for Effective Treatment of Intrahepatic Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is characterized by its dense fibrotic microenvironment and highly malignant nature, which are associated with chemotherapy resistance and very poor prognosis. Although circRNAs have emerged as important regulators in cancer biology, their role in ICC remains largely unclear. Herein, a circular RNA, cPKM is identified, which is upregulated in ICC and associated with poor prognosis. Silencing cPKM in ICC cells reduces TGFB1 release and stromal fibrosis, inhibits STMN1 expression, and suppresses ICC growth and metastasis, moreover, it also leads to overcoming paclitaxel resistance. This is regulated by the interactions of cPKM with miR-199a-5p or IGF2BP2 and by the ability of cPKM to stabilize STMN1/TGFB1 mRNA. Based on these findings, a Trojan horse nanotherapy strategy with co-loading of siRNA against cPKM (si-cPKM) and paclitaxel (PTX) is developed. The siRNA/PTX co-loaded nanosystem (Trojan horse) efficiently penetrates tumor tissues, releases si-cPKM and paclitaxel (soldiers), promotes paclitaxel sensitization, and suppresses ICC proliferation and metastasis in vivo. Furthermore, it alleviates the fibrosis of ICC tumor stroma and reopens collapsed tumor vessels (opening the gates), thus enhancing the efficacy of the standard chemotherapy regimen (main force). This novel nanotherapy provides a promising new strategy for ICC treatment.

Prognostic impact of lymphovascular and perineural invasion in squamous cell carcinoma of the tongue.

This study aimed to investigate the prognostic impact of lymphovascular and perineural invasions in patients with squamous cell carcinoma of the tongue who received surgery-based treatment at our institution between January 2013 and December 2020. Patients were divided into four groups based on the presence of perineural (P-/P +) and lymphovascular invasions (V-/V +): P-V-, P-V + , P + V-, and P + V + . Log-rank and Cox proportional hazard models were used to evaluate the association between perineural /lymphovascular invasion and overall survival (OS). Altogether, 127 patients were included, and 95 (74.8%), 8 (6.3%), 18 (14.2%), and 6 (4.7%) cases were classified as P-V-, P-V + , P + V-, and P + V + , respectively. Pathologic N stage (pN stage), tumor stage, histological grade, lymphovascular invasion, perineural invasion, and postoperative radiotherapy were significantly associated with OS (p < 0.05). OS was significantly different among the four groups (p < 0.05). Significant between-group differences in OS were detected for node-positive (p < 0.05) and stage III-IV (p < 0.05) cases. OS was the worst in the P + V + group. Lymphovascular and perineural invasions are independent negative prognostic factors for squamous cell carcinoma of the tongue. Patients with lymphovascular and/or perineural invasion may have significantly poorer overall survival than those without neurovascular involvement.

lncRNA-LET Regulates Glycolysis and Glutamine Decomposition of Esophageal Squamous Cell Carcinoma Through miR-93-5p/miR-106b-5p/SOCS4.

Background: Dysregulated non-coding RNAs exhibit critical functions in various cancers. Nonetheless, the levels and corresponding functions of cirCSNX14 in esophageal squamous cell carcinoma (ESCC) yet remain to be elucidated. Methods: Initially, the aberrant low levels of lncRNA-LET within ESCC tissues are validated via qRT-PCR observations. Moreover, the effects of lncRNA-LET upregulation on cell proliferation in vitro are determined. In addition, a series of assays determining the mechanistic views related to metabolism is conducted. Furthermore, the effects of lncRNA-LET in affecting tumor growth are investigated in vivo in a mouse model. Moreover, the interactions between lncRNA-LET and its networks are predicted and determined by RNA immunoprecipitation-assisted qRT-PCR as well as luciferase reporter assays. Results: The downregulation of lncRNA-LET is correlated to the poor prognosis of ESCC patients. Moreover, the upregulated expression of lncRNA-LET could have reduced the cell viability. In vivo tumor inhibition efficacy assays showed that an increase of lncRNA-LET presented excellent inhibitory effects on cancer proliferation as reflected by tumor weight and volume in mice. Finally, the mechanistic views regarding the effects of miR-106b-5p or miR-93-5p and SOCS4 on ESCC are related to the feedback of lncRNA-LET. Conclusion: Collectively, this study suggested that lncRNA-LET miR-93-5p or the miR-106b-5p-SOCS4 axis may provide great potential in establishing ESCC therapy.

Influence of Lymphangio vascular (V) and perineural (N) invasion on survival of patients with resected esophageal squamous cell carcinoma (ESCC): a single-center retrospective study.

Background: Lymphangio vascular invasion (LVI) and perineural invasion (PNI) are associated with survival following resection for gastrointestinal cancer. But the relationship between LVI/PNI and survival of esophageal squamous cell carcinoma (ESCC) is still unclear. We aim to demonstrate the prognostic significance of LVI/PNI in ESCC. Methods: A total of 195 ESCC patients underwent curative surgery from 2012 to 2018 was collected in the 2nd Affiliated Hospital of Fujian Medical University. All the patients were divided into four groups based on the status of the neurovascular invasion: (1) neither LVI nor PNI (V0N0); (2) LVI alone (V1N0); (3) PNI alone (V0N1); (4) combined LVI and PNI (V1N1). First, the analysis included the Kaplan-Meier survival estimates with the Log rank test were performed to determine median overall survival (OS) in different groups divided according to the clinical factor, respectively. And the association between OS with multi clinical factors was examined using Cox regression analysis. Next, the risk factors for recurrence in patients with V1N1 were analyzed with univariate and multivariate logistic regression analyses, respectively. Results: The cases in V0N0, V1N0, V0N1, and V1N1 groups were 91 (46.7%), 62 (31.8%), 9 (4.6%) and 33 (16.9%), respectively. The OS in the four groups was different (P < 0.001). The 1-, 3- and 5-year OS in V0N0 group was higher than that in V1N1 group, respectively (1-year OS: 93.4% vs 75.8%, 3-year OS: 53.8 % vs 24.2%, 5-year OS: 48.1% vs 10.5%). The OS in stage I-II for patients with V1N1 was significantly lower than that in the other groups (V0N0, V1N0, V0N1) (P < 0.001). The postoperative adjuvant chemotherapy was a significant impact factor of OS for ESCC patients with V1N1 (P = 0.004). Lymphatic invasion and LVI were significantly prognosis factors associated (P = 0.036, P = 0.030, respectively). The ulcerative type is a risk factor for V1N1 occurance (P = 0.040). Conclusions: The LVI and PNI are important prognosis factors for ESCC patients. ESCC patients with simultaneous lymphangio vascular and perineural invasion (V1N1) showed worse OS than patients with either lymphangio vascular or perineural invasion alone (V1N0 or V0N1) or none (V0N0). In addition, adjuvant chemotherapy may prolong the OS for ESCC patients with V1N1.

Survival outcomes for patients with four treatments in stages I-III esophageal squamous cell carcinoma: a SEER analysis.

BACKGROUND: Esophageal cancer (EC) is globally acknowledged as one of the most common malignancies among all gastrointestinal cancers. Furthermore, in Eastern Asia, squamous cell carcinoma is the main pathological type of EC. There are different treatments for esophageal squamous cell carcinoma (ESCC), but there is still a lack of large-sample analysis of prognosis among different treatments, especially for different tumor stages. The analysis of the prognosis of ESCC patients with different treatments may be helpful to choose the treatment methods for different stages ESCC. METHODS: A total of 3,346 patients with pathological ESCC between 1976 and 2016 were derived from the Surveillance, Epidemiology, and End Results (SEER) database. All clinical factors associated with prognosis were collected and analyzed to achieve the difference of prognosis among different treatments in ESCC patients, such as ages, sex, race, tumor grade, anatomic location and so on. Kaplan-Meier and Cox proportional hazard analysis were used to compare survival of different treatments in ESCC patients with stage I-III. RESULTS: The overall survival (OS) in all ESCC patients who had received surgery and surgery plus radiation therapy or/and chemotherapy are superior than that had not received any treatments and radiation therapy or/and chemotherapy. The OS in ESCC patients with stage I who had received surgery and surgery plus radiation therapy or/and chemotherapy are superior than that had not received any treatments and radiation therapy or/and chemotherapy. The OS in ESCC patients with stage II/III who had received surgery and surgery plus radiation therapy or/and chemotherapy are superior than that in other groups. Age, race and grade as an independent predictive factor for survival (P<0.05). A nomogram model was constructed to show surgery group had better 1-, 3- and 5-year OS than radiation therapy or/and chemotherapy group (OS: 78.5% vs. 59.2%, 37.9% vs. 18.4%, 16.9% vs. 6.1%). CONCLUSIONS: Surgery is still the first choice for all ESCC patients with stage I-III. Radiotherapy and chemotherapy could improve the survival rate in ESCC patients with stage II-III who have received surgery.

Multiplexed bead-based mesofluidic system for gene diagnosis and genotyping.

We have developed a novel multiplexed bead-based mesofluidic system (MBMS) based on the specific recognition events on the surface of a series of microbeads (diameter 250 µm) arranged in polydimethylsiloxane (PDMS) microchannels (diameter 300 µm) with the predetermined order and assembled an apparatus implementing automatically the high-throughput bead-based assay and further demonstrated its feasibility and flexibility of gene diagnosis and genotyping, such as ß-thalassemia mutation detection and HLA-DQA genotyping. The apparatus, consisting of bead-based mesofluidic PDMS chip, liquid-processing module, and fluorescence detection module, can integrate the procedure of automated-sampling, hybridization reactions, washing, and in situ fluorescence detection. The results revealed that MBMS is fast, has high sensitivity, and can be automated to carry out parallel and multiplexed genotyping and has the potential to open up new routes to flexible, high-throughput approaches for bioanalysis.

Development of an up-converting phosphor technology-based 10-channel lateral flow assay for profiling antibodies against Yersinia pestis.

In this study, a 10-channel up-converting phosphor technology-based lateral flow (TC-UPT-LF) assay was developed to profile antibodies against Yersinia pestis. Ten expressed Y. pestis proteins were covalently conjugated with an up-converting phosphor particle to develop double-antigen sandwich immunochromatographic strips to detect corresponding antibodies. After optimization one by one, each strip was integrated into a TC-UPT-LF disc for simultaneously detection of different antibodies. A scanning biosensor was also developed to acquire the results. The performance of the TC-UPT-LF assay was evaluated by using standard samples and plague monkey serum samples. Fifty-one patient serum samples were detected by the TC-UPT-LF assay. The TC-UPT-LF disc could be stable for 10 days at 37°C with an average CV of 10.3%. Its sensitivity and qualitative results are comparable to those of ELISA. Its linearity fitting coefficient of determination (R2) for different antibody detection is between 0.93 and 0.99. Besides F1 antibody, the LcrV and YopD antibodies also showed higher positive ratio than the other seven antibodies, as 100% (13/13) and 92% (12/13) in monkey sera and 86.3% (44/51) and 66.7% (34/51) in patient sera, respectively. It is suggested that the TC-UPT-LF assay has been successfully developed for multi-detection and LcrV and YopD can be the potential diagnostic markers of the plague.