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The crucial role of CD4 + and CD8 + T cells in shaping and controlling immune responses during immune disease and cancer development has been well established and used to achieve marked clinical benefits. CD3 + CD4 - CD8 - double-negative (DN) T cells, although constituting a rare subset of peripheral T cells, are gaining interest for their roles in inflammation, immune disease and cancer. Herein, we comprehensively review the origin, distribution and functions of this unique T cell subgroup. First, we focused on characterizing multifunctional DN T cells in various immune responses. DN regulatory T cells have the capacity to prevent graft-versus-host disease and have therapeutic value for autoimmune disease. T helper-like DN T cells protect against or promote inflammation and virus infection depending on the specific settings and promote certain autoimmune disease. Notably, we clarified the role of DN tumor-infiltrating lymphocytes and outlined the potential for malignant proliferation of DN T cells. Finally, we reviewed the recent advances in the applications of DN T cell-based therapy for cancer. In conclusion, a better understanding of the heterogeneity and functions of DN T cells may help to develop DN T cells as a potential therapeutic tool for inflammation, immune disorders and cancer.

The understanding of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFK-2/FBPase 3, PFKFB3) has advanced considerably since its initial identification in human macrophages in the mid-1990s. As a vital regulator of glycolysis, accumulating studies have suggested that PFKFB3 is associated with many aspects of cancer, including carcinogenesis, cancer cell proliferation, vessel aggressiveness, drug resistance and tumor microenvironment. In this review, we summarize current knowledge of PFKFB3 regulation by several signal pathways and its function in cancer development in different cell types in cancer tissues. Ubiquitous PFKFB3 has emerged as a potential target for anti-neoplastic therapy. Cancer: A drug strategy to impede tumor metabolism Targeting an enzyme called 6-phosphofructo-2-kinase 3 (PFKFB3), a key regulator of cellular glycolytic metabolism, could help shrink tumors. In a review article, Weidong Han and colleagues from Zhejiang University in Hangzhou, China, summarize the function of PFKFB3 in tumor metabolism in normal cancer cells, cancer stem cells, endothelial cells and immune cells. The enzyme plays a critical role in controlling glycolysis, the process by which cells break down sugars to make energy. Additionally, PFKFB3 can promote cell growth independent of its effects on glycolysis. To date, one drug company has tested a PFKFB3 inhibitor and observed anti-cancer activity in some patients in early human trials. The authors suggest that anti-PFKFB3 agents may need to be combined with immunotherapy and/or chemotherapy to maximize anti-tumor effects.

Objective To evaluate the predictive value of long non-coding RNA (lncRNA) X-inactive specific transcript (XIST) for survival, and determine the involvement of miRNA(miR)-200b-3p and zinc finger E-box-binding homeobox (ZEB) 1/2 in the pro-tumor effect of lncRNA XIST in liver cancer. Methods We evaluated lncRNA XIST expression in liver cancer tissues and cell lines by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and analyzed the correlation between its expression and overall survival of liver cancer patients by Kaplan–Meier analysis. Its effects on cell proliferation, migration, and invasion were analyzed by Cell-Counting Kit-8 and Transwell assays. The association between lncRNA XIST and miR-200b-3p, and the effects of lncRNA XIST on ZEB1/2 expression were explored using luciferase reporter assays, real-time PCR, and western blotting. Results The lncRNA XIST was significantly upregulated in liver cancer, and increased lncRNA XIST expression was associated with a poor prognosis. The lncRNA XIST promoted liver cancer cell proliferation, migration, and invasion in vitro, and acted as a molecular sponge for miR-200b-3p, and also regulated the expression of ZEB1/2 via miR-200b-3p. Conclusion The lncRNA XIST is an oncogenic lncRNA that promotes liver cancer metastasis, and its pro-metastatic phenotype can be partially attributed to the lncRNA XIST/miR-200b-3p/ZEB1/2 signaling axis.

Previous studies have shown the correlation between p-STAT3 overexpression and prognosis in a variety of human tumors. However, their correlation in lung cancer remains controversial. We performed a systematic review and meta-analysis to explore the correlation between p-STAT3 overexpression and prognosis in lung cancer patients. We searched PubMed, Embase, Web of Science, CNKI, VIP, and WanFang Data to identify relevant studies. Two reviewers independently screened the literature search results, extracted data, and assessed the methodological quality of the included studies. Then, meta-analysis was performed by using Review Manager 5.3 and STATA 14 software. A random-effect model was employed to evaluate all related pooled results. Statistical heterogeneity of each study was assessed by I2. Publication bias was determined by funnel plot and the Begg's or Egger's tests. Eventually, 13 studies were included in present meta-analysis. Among these 13 studies, 8 studies were associated with the overall survival of lung cancer and 10 studies with other clinicopathological characteristics. The results of this meta-analysis suggested that p-STAT3 overexpression may be a poor prognosis biomarker in lung cancer (HR: 1.23; 95% CI: 1.04-1.46; P = 0.02). In terms of other clinicopathological characteristics, p-STAT3 overexpression was more frequent to advanced TNM stages ranging from III to IV (OR: 1.92; 95% CI: 1.13-3.27; P = 0.02) and lymphatic node metastasis (OR: 1.81; 95% CI: 1.20-2.72; P = 0.004). But, it was not associated with tumor differentiation (OR: 0.82; 95% CI: 0.44-1.53; P = 0.54). p-STAT3 overexpression has significant correlation with poorer overall survival of lung cancer patients, as well as with more advanced TNM stages and lymph node metastasis. Thus, it may serve a biomarker for poor prognosis in lung cancer. Nevertheless, our findings should be confirmed by large prospective studies.

Primary MET amplification is an infrequent tumorigenic driver gene alteration identified in pulmonary neoplasms. Data on the effectiveness of MET-tyrosine kinase inhibitor (TKI) therapy in de novo MET amplification are relatively scarce, and there remains a dearth of empirical evidence supporting the use of precision therapy as first-line treatment for advanced non-small cell lung cancer (NSCLC) with primary MET amplification. We present a case of advanced lung adenocarcinoma in an elderly patient with primary MET amplification. The patient had an initial ECOG Performance Status (PS) 2. DNA-NGS analysis of tissue samples revealed a MET gene copy number (GCN) of 8, indicating MET amplification, without other oncogenic mutations associated with available drugs being detected. This finding was validated by MET fluorescence in situ hybridization (FISH), which showed cluster amplification. Initial treatment with savolitinib resulted in a sustained partial response lasting more than sixteen months. Our results suggest that savolitinib is effective and safe for the treatment of elderly patients with de novo amplified MET metastatic NSCLC and may therefore be considered a potential treatment option worthy of prospective study confirmation.

Cancer survivors are vulnerable to frailty. While few studies have focused on the association of frailty with mortality risk among cancer survivors, the current study aimed to reveal this association. In this cohort study, 4723 cancer survivors were enrolled from the National Health and Nutrition Examination Surveys (NHANES, 1999–2018). Frailty status was quantified using the 53-item frailty index. Death outcomes were linked to National Death Index mortality data (as of December 31, 2019). Cox proportional hazard models were used to estimate HRs (95% CIs). The median (IQR) frailty score was 0.190 (0.132, 0.277). During the median follow-up of 6.7 years, 1775 all-cause deaths (including 581 cancer deaths and 385 cardiac deaths) were documented. Compared to the lowest tertile of frailty scores, the adjusted HRs (95% CIs) for the highest tertile were 2.698 (2.224, 3.272) for all-cause mortality ( P trend < 0.001), 2.145 (1.547, 2.973) for cancer mortality ( P trend < 0.001), and 3.735 (2.231, 6.251) for cardiac mortality ( P trend < 0.001). Moreover, a positive dose‒response association between the frailty score and mortality risk was determined. Each per-unit increase in the frailty score (natural logarithm transformed) was found to increase all-cause mortality by 159% ( P  < 0.001), cancer mortality by 103% ( P  < 0.001), and cardiac mortality by 256% ( P  < 0.001). A consistent result was shown when stratifying by age, sex, race, body mass index, and type of cancer. This study suggested that the frailty index was positively associated with all-cause mortality and cause-specific mortality (including cancer and cardiac deaths) among cancer survivors.

In the international randomised phase 3 CORRECT trial (NCT01103323), regorafenib significantly improved overall survival versus placebo in patients with treatment-refractory metastatic colorectal cancer. Of the 760 patients in CORRECT, 111 were Asian (mostly Japanese). This phase 3 trial was done to assess regorafenib in a broader population of Asian patients with refractory metastatic colorectal cancer than was studied in CORRECT. In this randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial done in 25 hospitals in mainland China, Hong Kong, South Korea, Taiwan, and Vietnam, we recruited Asian patients aged 18 years or older with progressive metastatic colorectal cancer who had received at least two previous treatment lines or were unable to tolerate standard treatments. Patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and adequate bone marrow, liver, and renal function, without other uncontrolled medical disorders. We randomly allocated patients (2:1; with a computer-generated unicentric randomisation list [prepared by the study funder] and interactive voice response system; block size of six; stratified by metastatic site [single vs multiple organs] and time from diagnosis of metastatic disease [<18 months vs ≥18 months]) to receive oral regorafenib 160 mg once daily or placebo on days 1–21 of each 28 day cycle; patients in both groups were also to receive best supportive care. Participants, investigators, and the study funder were masked to treatment assignment. The primary endpoint was overall survival, and we analysed data on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01584830. Between April 29, 2012, and Feb 6, 2013, we screened 243 patients and randomly assigned 204 patients to receive either regorafenib (136 [67%]) or placebo (68 [33%]). After a median follow-up of 7·4 months (IQR 4·3–12·2), overall survival was significantly better with regorafenib than it was with placebo (hazard ratio 0·55, 95% CI 0·40–0·77, one-sided p=0·00016; median overall survival 8·8 months [95% CI 7·3–9·8] in the regorafenib group vs 6·3 months [4·8–7·6] in the placebo group). Drug-related adverse events occurred in 132 (97%) of 136 regorafenib recipients and 31 (46%) of 68 placebo recipients. The most frequent grade 3 or higher regorafenib-related adverse events were hand–foot skin reaction (22 [16%] of 136 patients in the regorafenib group vs none in the placebo group), hypertension (15 [11%] vs two [3%] of 68 patients in the placebo group), hyperbilirubinaemia (nine [7%] vs one [1%]), hypophosphataemia (nine [7%] vs none), alanine aminotransferase concentration increases (nine [7%] vs none), aspartate aminotransferase concentration increases (eight [6%] vs none), lipase concentration increases (six [4%] vs one [1%]), and maculopapular rash (six [4%] vs none). Drug-related serious adverse events occurred in 12 (9%) patients in the regorafenib group and three (4%) in the placebo group. This phase 3 trial is the second to show an overall survival benefit with regorafenib compared with placebo in patients with treatment-refractory metastatic colorectal cancer, substantiating the role of regorafenib as an important treatment option for patients whose disease has progressed after standard treatments. In this trial, preceding standard treatments did not necessarily include targeted treatments. Adverse events were generally consistent with the known safety profile of regorafenib in this setting. Bayer HealthCare Pharmaceuticals.

In the 8th edition of the American Joint Committee on Cancer (AJCC) staging system for Non-Small Cell Lung Cancer (NSCLC), tumors exhibiting main bronchial infiltration (MBI) near the carina and those presenting with complete lung obstructive pneumonia/atelectasis (P/ATL) have been reclassified from T3 to T2. Our investigation into the Surveillance, Epidemiology, and End Results (SEER) database, spanning from 2007 to 2015 and adjusted via Propensity Score Matching (PSM) for additional variables, disclosed a notably inferior overall survival (OS) for patients afflicted with these conditions. Specifically, individuals with P/ATL experienced a median OS of 12 months compared to 15 months (p < 0.001). In contrast, MBI patients demonstrated a slightly worse prognosis with a median OS of 22 months versus 23 months (p = 0.037), with both conditions significantly correlated with lymph node metastasis (All p < 0.001). Upon evaluating different treatment approaches for these particular T2 NSCLC variants, while adjusting for other factors, surgery emerged as the optimal therapeutic strategy. We counted those who underwent surgery and found that compared to surgery alone, the MBI/(P/ATL) group experienced a much higher proportion of preoperative induction therapy or postoperative adjuvant therapy than the non-MBI/(P/ATL) group (41.3%/54.7% vs. 36.6%). However, for MBI patients, initial surgery followed by adjuvant treatment or induction therapy succeeded in significantly enhancing prognosis, a benefit that was not replicated for P/ATL patients. Leveraging the XGBoost model for a 5-year survival forecast and treatment determination for P/ATL and MBI patients yielded Area Under the Curve (AUC) scores of 0.853 for P/ATL and 0.814 for MBI, affirming the model's efficacy in prognostication and treatment allocation for these distinct T2 NSCLC categories.

Cancer cells adopt various modes of migration during metastasis. How the ubiquitination machinery contributes to cancer cell motility remains underexplored. Here, we report that tripartite motif (TRIM) 59 is frequently up-regulated in metastatic breast cancer, which is correlated with advanced clinical stages and reduced survival among breast cancer patients. TRIM59 knockdown (KD) promoted apoptosis and inhibited tumor growth, while TRIM59 overexpression led to the opposite effects. Importantly, we uncovered TRIM59 as a key regulator of cell contractility and adhesion to control the plasticity of metastatic tumor cells. At the molecular level, we identified programmed cell death protein 10 (PDCD10) as a target of TRIM59. TRIM59 stabilized PDCD10 by suppressing RING finger and transmembrane domain-containing protein 1 (RNFT1)-induced lysine 63 (K63) ubiquitination and subsequent phosphotyrosine-independent ligand for the Lck SH2 domain of 62 kDa (p62)-selective autophagic degradation. TRIM59 promoted PDCD10-mediated suppression of Ras homolog family member A (RhoA)-Rho-associated coiled-coil kinase (ROCK) 1 signaling to control the transition between amoeboid and mesenchymal invasiveness. PDCD10 overexpression or administration of a ROCK inhibitor reversed TRIM59 loss-induced contractile phenotypes, thereby accelerating cell migration, invasion, and tumor formation. These findings establish the rationale for targeting deregulated TRIM59/PDCD10 to treat breast cancer.

Patients with epidermal growth factor receptor (EGFR) exon 21 L858R substitution benefit less from standard EGFR tyrosine kinase inhibitor (TKI) treatment, and whether anti-angiogenic therapy was beneficial to the EGFR L858R subpopulation was inconclusive. A retrospective study was conducted to investigate the survival benefit and the target characteristics of the anti-angiogenic agent in the EGFR L858R patients in our center, comparing those treated with or without anti-angiogenic therapy (cohort A and cohort B). At the median follow-up time of 31.0 months vs 32.7 months (cohort A vs. B) respectively, Cohort A (n = 58) had a significantly prolonged median OS compared to Cohort B (n = 101) (60.0 months vs.37.0 months, HR 0.51, p  = 0.016). Anti-angiogenic therapy significantly prolonged the OS in patients with liver metastases (NA vs.26.0 months, HR 0.17, p  = 0.023) comparing to patients without liver metastases (60.0 months vs.37.0 months, HR 0.63, p = 0.129). For brain metastatic patients, anti-angiogenic treatment tended to improve median OS with (65.0 months vs.35.0 months, HR 0.29, p  = 0.068) or without brain radiotherapy (73.0 months vs.29.0 months, HR 0.24, p  = 0.171). The grade 3 or more adverse events were manageable and consistent with previous studies. Patients with EGFR L858R mutation treated with anti-angiogenic therapy in their course of treatment had a significantly prolonged OS compared to those who had never received an anti-angiogenic agent. Patients with liver metastases might benefit more from anti-angiogenic therapy than those without.