ABSTRACT
The low abundance of circulating tumour DNA (ctDNA) in plasma samples makes the analysis of ctDNA biomarkers for the detection or monitoring of early-stage cancers challenging. Here we show that deep methylation sequencing aided by a machine-learning classifier of methylation patterns enables the detection of tumour-derived signals at dilution factors as low as 1 in 10,000. For a total of 308 patients with surgery-resectable lung cancer and 261 age- and sex-matched non-cancer control individuals recruited from two hospitals, the assay detected 52-81% of the patients at disease stages IA to III with a specificity of 96% (95% confidence interval (CI) 93-98%). In a subgroup of 115 individuals, the assay identified, at 100% specificity (95% CI 91-100%), nearly twice as many patients with cancer as those identified by ultradeep mutation sequencing analysis. The low amounts of ctDNA permitted by machine-learning-aided deep methylation sequencing could provide advantages in cancer screening and the assessment of treatment efficacy.
Subject(s)
Biomarkers, Tumor/genetics , Circulating Tumor DNA/genetics , Lung Neoplasms/diagnosis , Lung Neoplasms/genetics , Machine Learning/statistics & numerical data , Adult , Biomarkers, Tumor/blood , Case-Control Studies , Circulating Tumor DNA/blood , DNA Methylation , Early Detection of Cancer/methods , Female , High-Throughput Nucleotide Sequencing , Humans , Lung Neoplasms/blood , Lung Neoplasms/pathology , Male , Middle Aged , Sequence Analysis, DNA/methodsSubject(s)
Fusion Proteins, bcr-abl/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , RNA, Messenger/analysis , Real-Time Polymerase Chain Reaction , Child , Fusion Proteins, bcr-abl/analysis , Humans , K562 Cells , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Real-Time Polymerase Chain Reaction/methods , Real-Time Polymerase Chain Reaction/standards , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
Chemoresistance is common in patients with biliary tract cancer (BTC) including gallbladder cancer (GBC) and cholangiocarcinoma (CC). Therefore, it is necessary to identify effective chemotherapeutic agents for BTC. In the present study, we for the first time tested the effect of farnesoid X receptor (FXR) agonists GW4064 and CDCA (chenodeoxycholic acid) in combination with cisplatin (CDDP) on increasing the chemosensitivity in BTC. Our results show that co-treatment of CDDP with FXR agonists remarkably enhance chemosensitivity of BTC cells. Mechanistically, we found that activation of FXR induced expression of small heterodimer partner (SHP), which in turn inhibited signal transducer and activator of transcription 3 (STAT3) phosphorylation and resulted in down-regulation of Bcl-xL expression in BTC cells, leading to increased susceptibility to CDDP. Moreover, the experiments on tumor-bearing mice showed that GW4064/CDDP co-treatment inhibited the tumor growth in vivo by up-regulating SHP expression and down-regulating STAT3 phosphorylation. These results suggest CDDP in combination with FXR agonists could be a potential new therapeutic strategy for BTC.
Subject(s)
Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cholangiocarcinoma/drug therapy , Cisplatin/pharmacology , Gallbladder Neoplasms/drug therapy , Iron-Binding Proteins/agonists , Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism , bcl-X Protein/biosynthesis , Animals , Biliary Tract/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Chenodeoxycholic Acid/pharmacology , Down-Regulation/drug effects , Drug Synergism , Humans , Isoxazoles/pharmacology , Mice , Mice, Inbred BALB C , Mice, Nude , Phosphorylation/drug effects , STAT3 Transcription Factor/metabolism , FrataxinABSTRACT
OBJECTIVE: To compare the efficacy difference between triple acupuncture method at cervical Jiaji (EX-B 2) and conventional acupuncture for cervicogenic headache. METHODS: A total of 66 patients were randomly divided into a triple acupuncture group and a conventional acupuncture group, 33 cases in each one. The acupoints selected in the two groups were identical, including C1 to C7 of cervical Jiaji (EX-B 2) as well as Baihui (GV 20), Qiangjian (GV 18), Naokong (GB 19), Fengchi (GB 20), Fengfu (GV 16), Tianzhu (BL 10), etc. The conven- tional acupuncture was performed at acupoints on the head in the two groups; triple acupuncture was performed at cervical Jiaji (EX-B 2) in the triple acupuncture group while perpendicular acupuncture was performed with a depth of 25 to 40 mm in the conventional acupuncture group. The treatment was given once a day. Five treatments were considered as one session and totally two sessions were required. The changes of simplified McGill scale before and after acupuncture were observed in the two groups, and the efficacy of the two groups was compared. RESULTS: After acupuncture, the simplified McGill scale was both reduced in the two groups (both P < 0.01), and there was no significant difference between the two groups after treatment (all P > 0.05). The cured and markedly effective rate was 75.8% (25/33) and the total effective rate was 93.9% (31/33) in the triple acupuncture group, which were superior to 57.6% (19/33, P < 0.01) and 84.8% (28/33, P < 0.05) in the conventional acupuncture group respectively. CONCLUSION: The efficacy of triple acupuncture method at cervical Jiaji (EX-B 2) is superior to that of conventional acupuncture for cervicogenic headache.