Hypoxia-induced HMGB1 expression of HCC promotes tumor invasiveness and metastasis via regulating macrophage-derived IL-6.

Hypoxia is associated with the progression of hepatocellular carcinoma through promotion of spontaneous metastasis but the mechanism remains unclear. Here, we hypothesis that tumor cell-derived HMGB1 orchestrates macrophages infiltration and promotes metastasis of HCC via enhancing macrophage-secreted IL-6 under hypoxia. HMGB1 expression was robustly exacerbated in tumors of HCC patients with PVTT. Meanwhile, hypoxia exposure gave rise to HMGB1 expression in hepatoma cells of human and mouse in a HIF-1α-dependent manner and subsequently induced the infiltration and reprogramming of macrophages to augment the expression of Il-6. Further study demonstrated macrophage-derived IL-6 enhanced the invasiveness and metastasis of murine HCC cells. Therefore, our study provides a novel understanding of the relationship between tumor cells and tumor associated macrophages (TAMs) in the context of hypoxia.

Exploration of the impact of multimode thermal therapy versus radiofrequency ablation on CD8+ T effector cells of liver malignancies based on single cell transcriptomics.

Introduction: Multimode thermal therapy (MTT) is an innovative interventional therapy developed for the treatment of liver malignancies. When compared to the conventional radiofrequency ablation (RFA), MTT typically offers improved prognosis for patients. However, the effect of MTT on the peripheral immune environment and the mechanisms underlying the enhanced prognosis have yet to be explored. The aim of this study was to further investigate the mechanisms responsible for the difference in prognosis between the two therapies. Methods: In this study, peripheral blood samples were collected from four patients treated with MTT and two patients treated with RFA for liver malignancies at different time points before and after the treatment. Single cell sequencing was performed on the blood samples to compare and analyze the activation pathways of peripheral immune cells following the MTT and RFA treatment. Results: There was no significant effect of either therapy on the composition of immune cells in peripheral blood. However, the differential gene expression and pathway enrichment analysis demonstrated enhanced activation of T cells in the MTT group compared to the RFA group. In particular, there was a remarkable increase in TNF-α signaling via NF-κB, as well as the expression of IFN-α and IFN-γ in the CD8+ effector T (CD8+ Teff) cells subpopulation, when compared to the RFA group. This may be related to the upregulation of PI3KR1 expression after MTT, which promotes the activation of PI3K-AKT-mTOR pathway. Conclusion: This study confirmed that MTT could more effectively activate peripheral CD8+ Teff cells in patients compared with RFA and promote the effector function, thus resulting in a better prognosis. These results provide a theoretical basis for the clinical application of MTT therapy.

E3 Ubiquitin Ligase MARCH8 Promotes Pancreatic Cancer Growth and Metastasis by Activating STAT3 via Degradation of PTPN4.

OBJECTIVE: The role E3 ubiquitin ligase membrane-associated RING-CH 8 (MARCH8) has not been studied in pancreatic cancer. METHOD: Pancreatic cancer cell lines and the normal pancreatic cells were tested in vitro studies and male athymic nude mice were tested in vivo studies. Measuring cell viability by Cell Counting Kit-8 assay (CCK8), 5-ethynyl-2'- deoxyuridine (Edu) staining, and colony formation assay. Wound healing assay was implemented for cell migration and Transwell assay was performed for cell invasion to evaluate the histological status by hematoxylin and eosin staining and to detect the protein ubiquitination by ubiquitination assay. The protein expression was determined by immunohistochemistry staining and western blotting, and mRNA expression was measured by quantitative reverse transcription polymerase chain reaction. RESULT: The expression of MARCH8 was increased whereas PTPN4 was decreased in pancreatic cancer cells. Overexpression of MARCH8 promoted the growth, migration, and invasion of cells, and knockdown of PTPN4 had the similar effects both in vitro and in vivo. MARCH8 promoted PTPN4 protein degradation through ubiquitination. Moreover, PTPN4 suppressed the transcription activities of STAT3 by impairing the level of pSTAT3 (705), while inhibition of PTPN4 activated phosphorylation of STAT3. CONCLUSIONS: MARCH8 promoted pancreatic cancer growth and invasion through mediating the degradation of PTPN4 and activated the phosphorylation of STAT3.

Heterogeneous Information Network-Based Patient Similarity Search.

Patient similarity search is a fundamental and important task in artificial intelligence-assisted medicine service, which is beneficial to medical diagnosis, such as making accurate predictions for similar diseases and recommending personalized treatment plans. Existing patient similarity search methods retrieve medical events associated with patients from Electronic Health Record (EHR) data and map them to vectors. The similarity between patients is expressed by calculating the similarity or dissimilarity between the corresponding vectors of medical events, thereby completing the patient similarity measurement. However, the obtained vectors tend to be high dimensional and sparse, which makes it hard to calculate patient similarity accurately. In addition, most of existing methods cannot capture the time information in the EHR, which is not conducive to analyzing the influence of time factors on patient similarity search. To solve these problems, we propose a patient similarity search method based on a heterogeneous information network. On the one hand, the proposed method uses a heterogeneous information network to connect patients, diseases, and drugs, which solves the problem of vector representation of mixed information related to patients, diseases, and drugs. Meanwhile, our method measures the similarity between patients by calculating the similarity between nodes in the heterogeneous information network. In this way, the challenges caused by high-dimensional and sparse vectors can be addressed. On the other hand, the proposed method solves the problem of inaccurate patient similarity search caused by the lack of use of time information in the patient similarity measurement process by encoding time information into an annotated heterogeneous information network. Experiments show that our method is better than the compared baseline methods.

Clinical Outcomes and Predictors in Patients With Unresectable Colorectal Cancer Liver Metastases Following Salvage Percutaneous Radiofrequency Ablation: A Single Center Preliminary Experience.

PURPOSE: The purpose of this study was to investigate the clinical efficacy of salvage percutaneous radiofrequency ablation in patients with unresectable colorectal cancer liver metastases. METHODS: The cohort consisted of 81 patients with 126 colorectal cancer liver metastases who underwent radiofrequency ablation between January 2012 and September 2016. The clinical data and ablation data were retrospectively analyzed. The local tumor progression-free survival, overall survival, and prognostic factors were analyzed using the log-rank test and Cox regression model. RESULTS: The technique success rate was 99.21%. The primary efficacy rate was 100% at the 1-month follow-up. Minor complications were observed in 2 patients, which recovered within 1 week. The median local tumor progression-free survival time of all patients was 29.8 months. The absence of subsequent chemotherapy was an independent predictor of a shorter local tumor progression-free survival time (P < 0.001, hazard ratio: 2.823, 95% confidence interval: 1.603, 4.972). The median overall survival time was 26.8 months. A lesion size greater than 3 cm (P = 0.011, hazard ratio: 2.112, 95% confidence interval: 1.188, 3.754) and the presence of early local tumor progression (P = 0.011, hazard ratio: 2.352, 95% confidence interval: 1.217, 4.545) were related to a shorter survival time. CONCLUSIONS: Percutaneous radiofrequency ablation is safe in patients with colorectal cancer liver metastases refractory from chemotherapy. Subsequent chemotherapy is important to enhance local control. Small lesions and favorable early responses are related to prolonged overall survival.

CT-guided cryoablation for unresectable pelvic recurrent colorectal cancer: a retrospective study.

OBJECTIVE: The study aimed to investigate the efficacy of computed tomography (CT)-guided cryoablation debulking of unresectable pelvic recurrent colorectal cancer (CRC). PATIENTS AND METHODS: From January 2013 to April 2016, 30 patients (18 males and 12 females; aged 57.8±10.5 years) with unresectable pelvic recurrent CRC who had previously received radiotherapy or chemotherapy were included. A total of 35 tumors ranging from 1.2 to 6.3 cm underwent cryoablation. Tumor response was evaluated 1 month after cryoablation according to the Modified Response Evaluation Criteria in Solid Tumors. Logistic regression was used to analyze the risk factors for tumor response. Degree of pain palliation was also determined using the Numerical Rating Scale. Cox proportional hazard models were used to identify predictors of outcomes. RESULTS: Cryoablation was successfully performed in all patients. Complete response (CR) was achieved for 27 tumors in 23 patients and partial response was achieved for eight tumors in seven patients 1 month after cryoablation. The rate of CR was 77.14%, and tumor size was an independent risk factor for CR. Pain relief was satisfactory in 21 symptomatic patients (P<0.001), and the median duration of pain relief was 6.0 months (95% CI: 2.67-9.33). Serum carcinoembryonic antigen (CEA) was significantly decreased after cryoablation in 15 patients with elevated CEA (P=0.005). The median progression-free survival (PFS) was 10.0 months (95% CI: 4.43-15.67). Multivariate analysis revealed that tumor size (HR =3.089, P<0.001), sex (HR =0.089, P=0.002), and elevated CEA (HR =7.015, P=0.002) were independent predictors of PFS. CONCLUSION: CT-guided cryoablation is a safe and effective therapeutic option for pelvic recurrent CRC. Tumor size is an important predictor of poor outcomes.

Image-guidedcryoablation in unresectable or recurrent advanced colorectal cancer: a retrospective study.

Purpose: The present study retrospectively analyzed thesafety and efficacy of computed tomography (CT)-guided cryoablationin the treatment ofunresectable or recurrent advanced colorectal cancer, which did not respond well to or experienced progression with radiotherapy or chemotherapy. Materials and Methods: From January 2013 to April 2015, 31 lesions in 27 patients (16 males, 11 females; mean age of 57.2 years) with pelvic unresectableadvanced or recurrent colorectal cancer were included in the study. The tumor diameter was approximately 3.37 ±1.41 cm. The primary tumor included 25 rectal cancers, 1 sigmoid colon adenocarcinoma, and 1 ileocecal mucinous adenocarcinoma. Cryoablation was performed with 17-gauge cryoprobes and monitored by 64-slice spiral CT. Follow-up was carried out by contrast-enhanced magnetic resonance imaging (MRI). The treatment efficacy was evaluated by symptom palliation, decreased carcinoembryonic antigen (CEA) serum level, and tumor response. Results: The cryoablation procedure was well-tolerated in all patients without major complications or procedure-related mortality. Long-term complications included abscess formation (1 patient), skin frostbite and post-sacrum antrum formation (1 patient). Pain relief was satisfactory in patients with perineal pain (P<0.001), and the median time of pain relief was 3.0 months. Complete ablations were obtained in 22 lesions of 18 patients, while 9 lesions in 9 patients underwent incomplete ablation. The median time to local recurrence for lesions with complete ablations was 15.0 months, and that to the progression of tumors with incomplete ablation was 4.0 months. Conclusion: CT-guided cryoablation is a minimally invasive, safe, and effective therapeutic option for unresectableadvanced or recurrent colorectal cancer. The treatment is well-tolerated by patients, and pain relief is achieved rapidly.

CT-guided Hookwire localization before video-assisted thoracoscopic surgery for solitary ground-glass opacity dominant pulmonary nodules: radiologic-pathologic analysis.

The optimal screening or treatment strategies of solitary pulmonary nodules especially ground-glass opacities (GGOs) remain controversial. With CT-guided Hookwire localization, it is accurate to find the small lesions during video-assisted thoracoscopic surgery (VATS). In this study, we evaluate the efficiency and safety of CT-guided Hookwire localization of GGO-dominant (GGO component > 50%) pulmonary nodules before VATS and investigate the correlation between the radiologic features and pathology. From April 2008 to April 2014, a total of 273 patients with solitary GGO-dominant pulmonary nodules were included. Tumor size was 12.4 ± 5.7 mm in diameter, including 208 pulmonary adenocarcinomas and 65 benign nodules. Dislodgement occurred in six patients (2.20%) during surgery. Postoperative complications included asymptomatic needle track hemorrhage (27.1%), minimal pneumothorax (5.9%) and hemoptysis (0.4%). In 208 (76.2%) pulmonary adenocarcinomas, 82 nodules showed ≥90% GGO and 126 showed 50%≤GGO<90%, while 84 nodules staged as T1aN0M0, 96 staged as T1bN0M0, and 28 staged as T1cN0M0. The multivariable analysis demonstrated that 50%≤GGO<90% (HR=2.459, 95% CI: 1.246-4.853, P=0.010), speculation (HR=3.911, 95% CI: 1.966-7.663, P<0.001), lobulation (HR=4.582, 95% CI: 2.149-9.767, P<0.001) and vascular convergence (HR=4.096, 95% CI: 1.132-14.824, P=0.032) were the independent risk factors to identification of the malignant GGO-dominant pulmonary nodules. In conclusions,CT-guided Hookwire localizati for GGO-dominant pulmonary nodules before VATS is a safe and effective procedure for accurate diagnosis and resection of indeterminate solitary pulmonary nodules.

Hybrids of the Benzofuran Core from Natural Products and the 2,4-Dihydroxy-5-isopropylbenzene Fragment as Potent Hsp90 Inhibitors: Design, Synthesis and Bioevaluation.

Several chemical fragments have been confirmed as highly efficient cores for the design of Hsp90 inhibitors. Molecular hybridization of potent fragments has been widely used as a rational drug discovery strategy. In this study, a novel class of hybrids of benzofuran, a privileged core from natural products, and 2,4-dihydroxy-5-isopropyl phenyl, an efficient fragment in Hsp90 inhibitors, were designed and synthesized. Subsequent evaluation confirmed they inhibited cell proliferation and regulated the level of client proteins through Hsp90 inhibition. Some of the hybrids can serve as leads to obtain novel chemotypes of Hsp90 inhibitors. The methods reported here may expand the range of known structural types accommodated by the ATP binding site of Hsp90.