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Abstract Background Breast cancer metastasis to the bone can be exacerbated by osteoporosis, is associated with poor long-term survival, and has limited therapeutic options. Sclerostin (SOST) is an endogenous inhibitor of bone formation, and an attractive target for treatment of osteoporosis. However, it is unclear whether SOST can be used as a therapeutic target for bone metastases of breast cancer, and whether small molecule compounds that target SOST in breast cancer cells can inhibit breast cancer bone metastasis. Methods SOST expression in 442 breast cancer tissues was characterized by immunohistochemistry and statistically analyzed for the association with breast cancer bone metastases. Bone metastatic breast cancer SCP2 cells were induced for SOST silencing or overexpression and their bone metastatic behaviors were tested in vitro and in vivo. To identify potential therapeutics, we screened inhibitors of the interaction of SOST with STAT3 from a small chemical molecule library and tested the inhibitory effects of one inhibitor on breast cancer growth and bone metastasis in vitro and in vivo. Results We found that up-regulated SOST expression was associated with breast cancer bone metastases and worse survival of breast cancer patients. SOST silencing significantly reduced the bone metastatic capacity of SCP2 cells. SOST interacted with STAT3 to enhance the TGF-β/KRAS signaling, increasing both tumor growth and bone metastasis. Treatment with one lead candidate, S6, significantly inhibited the growth of breast-cancer organoids and bone metastasis in mice. Conclusions Our findings highlight a new class of potential therapeutics for treatment of bone metastasis in breast cancer.

Objective: The function of euchromatic histone-lysine N-methyltransferase 2 (EHMT2) has been studied in several cancers; however, little is known about its role in mantle cell lymphoma (MCL). Thus, this study aimed to characterize the significance and function of EHMT2 in MCL. Methods: EHMT2 expression in MCL and reactive hyperplasia (RH) were investigated by immunohistochemistry. Genome-wide analysis of DNA methylation was performed on EHMT2 + MCL samples. The function of EHMT2 was determined by CCK8, flow cytometry, and western blot assays. Gene expression profile analysis was performed before and after EHMT2 knockdown to search for EHMT2-regulated genes. Co-immunoprecipitation (Co-IP) experiments were conducted to identify the proteins interacting with EHMT2. Results: EHMT2 was expressed in 68.57% (24/35) of MCLs but not in any RHs. Genome-wide analysis of DNA methylation on EHMT2 + MCLs revealed that multiple members of the HOX, FOX, PAX, SOX, and CDX families were hypermethylated or hypomethylated in EHMT2 + MCLs. BIX01294, a EHMT2 inhibitor, inhibited MCL cell growth and stalled cells in the G1 phase. Additionally, BIX01294 downregulated the expressions of cell cycle proteins, cyclin D1, CDK4, and P21, but upregulated the expressions of apoptosis-related proteins, Bax and caspase-3. Co-IP experiments revealed that EHMT2 interacted with UHRF1, HDAC1, and HDAC2 but not with HDCA3. After EHMT2 knockdown, multiple genes were regulated, including CD5 and CCND1, mostly enriched in the Tec kinase signaling pathway. In addition, several genes (e.g., MARCH1, CCDC50, HIP1, and WNT3) were aberrantly methylated in EHMT2 + MCLs. Conclusions: For the first time, we determined the significance of EHMT2 in MCL and identified potential EHMT2-regulated genes.

Abstract Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are clonal hematopoietic stem cell diseases arising from the bone marrow (BM), and approximately 30% of MDS eventually progress to AML, associated with increasingly aggressive neoplastic hematopoietic clones and poor survival. Dysregulated immune microenvironment has been recognized as a key pathogenic driver of MDS and AML, causing high rate of intramedullary apoptosis in lower-risk MDS to immunosuppression in higher-risk MDS and AML. Immune checkpoint molecules, including programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1), play important roles in oncogenesis by maintaining an immunosuppressive tumor microenvironment. Recently, both molecules have been examined in MDS and AML. Abnormal inflammatory signaling, genetic and/or epigenetic alterations, interactions between cells, and treatment of patients all have been involved in dysregulating PD-1/PD-L1 signaling in these two diseases. Furthermore, with the PD-1/PD-L1 pathway activated in immune microenvironment, the milieu of BM shift to immunosuppressive, contributing to a clonal evolution of blasts. Nevertheless, numerous preclinical studies have suggested a potential response of patients to PD-1/PD-L1 blocker. Current clinical trials employing these drugs in MDS and AML have reported mixed clinical responses. In this paper, we focus on the recent preclinical advances of the PD-1/PD-L1 signaling in MDS and AML, and available and ongoing outcomes of PD-1/PD-L1 inhibitor in patients. We also discuss the novel PD-1/PD-L1 blocker-based immunotherapeutic strategies and challenges, including identifying reliable biomarkers, determining settings, and exploring optimal combination therapies.

Abstract Background The optimal treatment for elderly patients with esophageal cancer (EC) remains controversial. In the present study, we aimed to investigate whether elderly patients with stage II–III EC could benefit from trimodal therapy. Methods The selected elderly patients with stage II–III EC between 2004 and 2015 were included in a retrospective cohort study from the Surveillance, Epidemiology, and End Results database. The patients were divided into two groups based on whether or not they underwent surgery. The inverse probability of treatment weighting (IPTW) analysis was used to balance the confounding factors between the two groups. The Cox regression analysis, the log‐rank test, and the Kaplan–Meier curves were conducted to identify the survival benefits of different treatment regimes. Results A total of 1596 patients were included in this cohort study, in which 278 patients underwent surgery. In the combination of chemoradiotherapy and surgery group, there were more male patients, more patients aged between 75 and 79 years, and more married patients in the surgery group. Moreover, there were more patients with adenomatous carcinoma, more patients with a tumor size of less than 5 cm, and more patients with a T3 stage in the combination group. In the survival analysis, patients in the combination group had a longer overall survival (OS) and EC‐specific survival (ECSS). After IPTW analysis, the survival analysis generated similar results. The competitive risk model found that our results were stable. There was still a significant difference in OS and ECSS between the combination group and chemoradiotherapy alone group for esophageal adenocarcinoma (p

ATP synthase inhibitory factor 1 (ATPIF1) is a mitochondrial protein with an activity in inhibition of F1Fo-ATP synthase. ATPIF1 activity remains unknown in the control of immune activity of T cells. In this study, we identified ATPIF1 activity in the induction of CD8+ T cell function in tumor models through genetic approaches. ATPIF1 gene inactivation impaired the immune activities of CD8+ T cells leading to quick tumor growth (B16 melanoma and Lewis lung cancer) in ATPIF1-KO mice. The KO T cells exhibited a reduced activity in proliferation and IFN-γ secretion with metabolic reprogramming of increased glycolysis and decreased oxidative phosphorylation (OXPHOS) after activation. T cell exhaustion was increased in the tumor infiltrating leukocytes (TILs) of KO mice as revealed by the single-cell RNA sequencing (scRNA-seq) and confirmed by flow cytometry. In contrast, ATPIF1 overexpression in T cells increased expression of IFN-γ and Granzyme B, subset of central memory T cells in CAR-T cells, and survival rate of NALM-6 tumor-bearing mice. These data demonstrate that ATPIF1 deficiency led to tumor immune deficiency through induction of T cell exhaustion. ATPIF1 overexpression enhanced the T cell tumor immunity. Therefore, ATPIF1 is a potential molecular target in the modulation of antitumor immunity of CD8+ T cells in cancer immunotherapy. Induction of ATPIF1 activity may promote CAR-T activity in cancer therapy.

Abstract Background Few studies have been conducted on the relationship between chronic periodontitis and postoperative pneumonia (POP) in patients with lung and esophageal cancer. Furthermore, it remains controversial as to whether improving the periodontal condition of patients with lung and esophageal cancer before surgery reduces the incidence of POP. This retrospective study was conducted to assess the effects of periodontal therapy in patients with lung and esophageal cancer to prevent POP. Methods A total of 265 patients with lung or esophageal cancer complicated with chronic periodontitis who underwent open thoracotomy between July 2015 and June 2019 were selected and given the choice of being in the experimental or control group. A total of 141 participants in the experimental group received periodontal therapy, and 124 participants in the control group did not receive periodontal therapy. All clinical data of participants in both groups were retrospectively studied to determine the incidence of POP on the 30th day after discharge from hospital. Results Eight patients in the experimental and six in the control group, respectively, were excluded from the study. It was found that four of the 133 patients suffered from POP in the experimental group (incidence: 3.01%). A total of 18 of 118 patients in the control group had a pulmonary infection (incidence: 15.25%). POP incidence in the experimental group was significantly lower than that in the control group, and in the level analysis of different types of periodontitis, surgical methods, and diseases (p

Abstract Background There have been few studies on the relationship between oral status and postoperative pneumonia (POP) in patients with lung cancer, and whether improving their oral condition assists with a lower incidence of POP before lung cancer surgery remains controversial. This retrospective study was conducted by a stomatologist to assess the effect of controlling oral pathogenic bacteria of patients with lung cancer to prevent POP. Methods A total of 235 patients with lung cancer who underwent lobectomy by open thoracotomy between July 2015 and December 2018 were selected and given the choice of being in the experimental or control group. A total of 122 participants in the experimental group received professional oral plaque control, and 113 participants in the control group did not receive plaque control. All clinical data of participants in both groups were retrospectively studied to determine the incidence of POP at the thirtieth day of discharge from hospital. Results Eight in the experimental group and six in the control group were excluded from the study. It was found that four of 114 patients suffered from POP in the experimental group (incidence = 3.51%). A total of 17 of 107 patients in the control group had pulmonary infection (incidence = 15.89%). Odds ratio was 0.19. The incidence of POP in the experimental group was significantly lower than that of the control group (P

Abstract Background The necessity of the inferior pulmonary ligament (IPL) dissection after an upper lobectomy remains controversial. This meta-analysis aimed to evaluate whether this accessional procedure could reduce the postoperative complications and improve outcomes. Methods PubMed, Embase, Ovid, Cochrane Library, CBM, and CNKI databases were searched for the relevant studies which compared the dissection with preservation of IPL during the upper lobectomy. The Review Manager 5.3 software was used for this meta-analysis. Results Three RCTs and five CCTs were included in this meta-analysis. These studies contained a total of 610 patients, in which 315 patients received a pulmonary ligament dissection (group D) after the upper lobectomy, while the other 295 patients preserved the pulmonary ligament (group P). No significant difference was demonstrated between the group D and group P in terms of drainage time after surgery (MD 0.14, 95%CI − 0.05 to 0.33, P = 0.15), rate of postoperative dead space (OR 1.33, 95%CI 0.72 to 2.46, P = 0.36), rate of postoperative complications (OR 1.20, 95%CI 0.66 to 2.19, P = 0.56). However, the pooled comparison revealed a greater change of the right main bronchial angle (MD 5.00, 95%CI 1.68 to 8.33, P = 0.003) in group D compared with group P, indicated that the dissection of IPL may lead to a greater distortion of bronchus. Conclusions This meta-analysis confirmed that the dissection of IPL do not effectively reduce the postoperative complications and improve the prognosis. Therefore, it is not necessary to dissect the IPL after an upper lobectomy.

Aims: This study aimed to (a) assess the effectiveness and safety of apatinib as a subsequent treatment for patients with sorafenib-resistant hepatocellular carcinoma (HCC), and (b) identify the clinical factors influencing their treatment outcomes. Methods: The electronic medical records of consecutive patients with newly diagnosed advanced HCC treated with first-line sorafenib from 2015 to 2017 were retrospectively reviewed. Patients who were confirmed to have primary resistance to sorafenib were enrolled in this study. The outcomes of patients treated with apatinib were compared with those of patients who received supportive care. The primary endpoint was overall survival (OS). Results: A total of 92 patients with sorafenib-resistant advanced HCC (84 men and 8 women; mean age, 51.9 years) were included. All patients had an etiology of hepatitis B. The median OS in the overall cohort was 5.0 months [95% confidence interval (CI): 3.9, 6.0]. Of 92 patients, 58 (63.0%) were treated with apatinib, and 34 (37.0%) received supportive care. Apatinib treatment was associated with longer survival times than supportive care for patients with sorafenib-resistant advanced HCC (median OS: 7.0 versus 4.0 months, p

AC0010 is a pyrrolopyrimidine-based irreversible inhibitor of epidermal growth factor receptor (EGFR), structurally distinct from previously reported pyrimidine-based irreversible EGFR inhibitors such as osimertinib and rociletinib. AC0010 selectively inhibits EGFR T790M mutation in both preclinical and clinical studies. However, AC0010 treatment eventually triggers drug resistance with unknown mechanism. To this end, we established two H1975 NSCLC-derived lines resistant to AC0010 after a series of drug exposure and selection in either nude-mice xenograft tumor (H1975-P) or cell culture (H1975-AVR) settings. Both lines obtained 100-fold resistance to AC0010 as compared to the parental lines. To elucidate underlying mechanism, we performed unbiased RNAseq-based profiling analysis and found that H1975-P cells had c-MET overexpression, whereas H1975-AVR cells had BCL-2 overexpression. AC0010 resistance was partially abrogated by targeting c-MET or BCL-2 using either pharmacological (small molecule inhibitors) and/or genetic (siRNA-based knockdown) approach, respectively. Our study shows that drug resistance to AC0010 can be developed via the different mechanism in a cell context–dependent manner and provides the proof-of-concept evidence for rational drug combinations to overcome resistance for maximal therapeutic efficacy.

Abstract Although low‐dose radiation (LDR) possesses the two distinct functions of inducing hormesis and adaptive responses, which result in immune enhancement and tumor inhibition, its clinical applications have not yet been elucidated. The major obstacle that hinders the application of LDR in the clinical setting is that the mechanisms underlying induction of tumor inhibition are unclear, and the risks associated with LDR are still unknown. Thus, to overcome this obstacle and elucidate the mechanisms mediating the antitumor effects of LDR, in this study, we established an in vivo lung cancer model to investigate the participation of the immune system in LDR‐induced tumor inhibition and validated the pivotal role of the immune system by impairing immunity with high‐dose radiation (HDR) of 1 Gy. Additionally, the LDR‐induced adaptive response of the immune system was also observed by sequential HDR treatment in this mouse model. We found that LDR‐activated T cells and natural killer cells and increased the cytotoxicity of splenocytes and the infiltration of T cells in the tumor tissues. In contrast, when immune function was impaired by HDR pretreatment, LDR could not induce tumor inhibition. However, when LDR was administered before HDR, the immunity could be protected from impairment, and tumor growth could be inhibited to some extent, indicating the induction of the immune adaptive response by LDR. Therefore, we demonstrated that immune enhancement played a key role in LDR‐induced tumor inhibition. These findings emphasized the importance of the immune response in tumor radiotherapy and may help promote the application of LDR as a novel approach in clinical practice.

Abstract Background We aimed to compare mediastinoscopy-assisted esophagectomy (MAE) with the Ivor Lewis procedure in T2 middle and lower thoracic esophageal carcinoma patients in fields of perioperative complications and overall survival (OS). Methods The clinical data of 112 T2 esophageal cancer patients who received MAE (n = 31) or Ivor Lewis procedure (n = 81) from January 2010 to December 2015 were retrospectively analyzed in propensity score analysis. Thirty-eight T2 esophageal cancer patients who underwent MAE (n = 19) and Ivor Lewis procedure (n = 19) were included in this study. The perioperative conditions and OS were analyzed. Results The MAE group showed shorter operation time (143.2 ± 20.6 vs 176.8 ± 31.1 min, P = 0.001), less drainage in 24 h (119.2 ± 235.1 vs 626.3 ± 396.3 mL, P

Gastric cancer (GC) is the TOP3 leading cause of human mortality in malignant tumors. Notwithstanding, the association between GC and circRNAs is not clear. The purpose of this research was to determine the association between GC progression and circRNAs. The data of circRNAs was obtained from the Gene Expression Omnibus (GEO) database to identify gene, which differentially expressed circRNAs in GC tissues and paired normal tissues. The expression of circRNAs in cancer tissues and normal tissues were tested, and the target circRNA was verified before and after surgery in the plasma. A circRNA-micro(mi)RNA-mRNA competing endogenous RNAs (ceRNAs) network was established, and GO and KEGG analysis are performed. Five candidate circRNAs were identified through bioinformatics analysis. Hsa_circ_0021087 and hsa_circ_0005051 were both downregulated in GC tissues, cells and plasma by RTq-PCR. Additionally, there was a significant difference in the expression of plasma hsa_circ_0021087 in patients with GC at the preoperative and postoperative stages (P < 0.001). Hsa_circ_0021087 also promoted the proliferation of GC cells in vitro. Next, the circRNA-miRNA-mRNA network of hsa_circ_0021087 was predicted, which may be associated with the development of GC by bioinformatics analysis. In summary, the aforementioned dual-circular RNAs may have important implications on the potential, novel and non-invasive diagnostic method for patients with GC.