Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide and the fourth most lethal cancer in China. However, although genomic studies have identified some mutations associated with ESCC, we know little of the mutational processes responsible. To identify genome-wide mutational signatures, we performed either whole-genome sequencing (WGS) or whole-exome sequencing (WES) on 104 ESCC individuals and combined our data with those of 88 previously reported samples. An APOBEC-mediated mutational signature in 47% of 192 tumors suggests that APOBEC-catalyzed deamination provides a source of DNA damage in ESCC. Moreover, PIK3CA hotspot mutations (c.1624G>A [p.Glu542Lys] and c.1633G>A [p.Glu545Lys]) were enriched in APOBEC-signature tumors, and no smoking-associated signature was observed in ESCC. In the samples analyzed by WGS, we identified focal (<100 kb) amplifications of CBX4 and CBX8. In our combined cohort, we identified frequent inactivating mutations in AJUBA, ZNF750, and PTCH1 and the chromatin-remodeling genes CREBBP and BAP1, in addition to known mutations. Functional analyses suggest roles for several genes (CBX4, CBX8, AJUBA, and ZNF750) in ESCC. Notably, high activity of hedgehog signaling and the PI3K pathway in approximately 60% of 104 ESCC tumors indicates that therapies targeting these pathways might be particularly promising strategies for ESCC. Collectively, our data provide comprehensive insights into the mutational signatures of ESCC and identify markers for early diagnosis and potential therapeutic targets.

Follicular helper T (Tfh) cells are recognized as a distinct CD4+ helper T-cell subset, which provides for B-cell activation and production of specific antibody responses, and play a critical role in the development of autoimmune disease. So far, only one study investigated the circulating Tfh cells increased in a subset of SLE patients. Since relatively little is known about the Tfh cells in rheumatoid arthritis (RA) patients, in this study, Tfh-cell frequency, related cytokine IL-21, and transcription factor Bcl-6 were investigated in 53 patients with RA and 31 health controls. Firstly, we found that the frequency of CD4+CXCR5+ICOShigh Tfh cells was increased significantly in the peripheral blood of RA patients, compared with that in healthy controls. It is known that Tfh cells are critical for directing the development of an antibody response by germinal centers B cells; secondly, we observed that the Tfh-cell frequency is accompanied by the level of anti-CCP antibody in RA patients. Furthermore, expression of Bcl-6 mRNA and plasma IL-21 concentrations in RA patients was increased. Taken together, these findings have shown that the increased frequency of circulating Tfh cells is correlated with elevated levels of anti-CCP antibody, indicating the possible involvement of Tfh cells in the disease progression of RA.

The current study discovered an increased frequency of Tfh cells in AITD patients, which implies that this cell subset might play an important role in the pathogenesis of AITD.

Cancer stem cells play a critical role in colorectal cancer (CRC) progression. Myeloid‐derived suppressor cells (MDSCs) promote tumor progression through multiple mechanisms in CRC. The roles of MDSCs in CRC cell stemness are unclear. MDSC‐derived exosomes are proposed to act as intercellular messengers. Herein, it is reported that granulocytic MDSCs (G‐MDSCs) promote CRC cell stemness and progression in mice through exosomes. It is found that S100A9, is highly expressed in G‐MDSC‐derived exosomes, and its blockade suppresses CRC cell stemness and the susceptibility of mice to AOM/DSS‐induced colitis‐associated colon cancer. Hypoxia induces G‐MDSCs to secrete more exosomes in a hypoxia‐inducible factor 1α (HIF‐1α)‐dependent manner, and respiratory hyperoxia can reduce CRC cells stemness through the inhibition of GM‐Exo production. Study‐based CRC patients also show that human MDSCs enhance CRC cell stemness and growth via exosomal S100A9, and plasma exosomal S100A9 level in CRC patients is markedly higher than that in healthy subjects. Thus, this study suggests that G‐MDSCs promote CRC cell stemness and growth through exosomal S100A9. Moreover, respiratory hyperoxia may be a beneficial strategy to reduce CRC cells stemness through the inhibition of GM‐Exo production. MDSCs exosomal S100A9 may be a marker for predicting the development of CRC.

Analysis of plasma microRNAs (miRNAs) by quantitative polymerase chain reaction (qPCR) provides a potential approach for cancer diagnosis. However, absolutely quantifying low abundant plasma miRNAs is challenging with qPCR. Digital PCR offers a unique means for assessment of nucleic acids presenting at low levels in plasma. This study aimed to evaluate the efficacy of digital PCR for quantification of plasma miRNAs and the potential utility of this technique for cancer diagnosis. We used digital PCR to quantify the copy number of plasma microRNA-21-5p (miR-21–5p) and microRNA-335–3p (miR-335–3p) in 36 lung cancer patients and 38 controls. Digital PCR showed a high degree of linearity and quantitative correlation with miRNAs in a dynamic range from 1 to 10,000 copies/μL of input, with high reproducibility. qPCR exhibited a dynamic range from 100 to 1×107 copies/μL of input. Digital PCR had a higher sensitivity to detect copy number of the miRNAs compared with qPCR. In plasma, digital PCR could detect copy number of both miR-21–5p and miR-335–3p, whereas qPCR was only able to assess miR-21–5p. Quantification of the plasma miRNAs by digital PCR provided 71.8% sensitivity and 80.6% specificity in distinguishing lung cancer patients from cancer-free subjects.