Background: Prostate cancer (PCa) is the second most prevalent cancer in males worldwide, yet detecting PCa and its metastases remains a major challenging task in clinical research setups. The present study aimed to characterize the metabolic changes underlying the PCa progression and investigate the efficacy of related metabolic panels for an accurate PCa assessment.Methods: In the present study, 75 PCa subjects, 62 PCa patients with bone metastasis (PCaB), and 50 benign prostatic hyperplasia (BPH) patients were enrolled, and we performed a cross-sectional metabolomics analysis of serum samples collected from these subjects using a¹H nuclear magnetic resonance (NMR)-based metabolomics approach.Results: Multivariate analysis revealed that BPH, PCa, and PCaB groups showed distinct metabolic divisions, while univariate statistics integrated with variable importance in the projection (VIP) scores identified a differential metabolite series, which included energy, amino acid, and ketone body metabolism. Herein, we identified a series of characteristic serum metabolic changes, including decreased trends of 3-HB and acetone as well as elevated trends of alanine in PCa patients compared with BPH subjects, while increased levels of 3-HB and acetone as well as decreased levels of alanine in PCaB patients compared with PCa. Additionally, our results also revealed the metabolic panels of discriminant metabolites coupled with the clinical parameters (age and body mass index) for discrimination between PCa and BPH, PCaB and BPH, PCaB and PCa achieved the AUC values of 0.828, 0.917, and 0.872, respectively.Conclusions: Overall, our study gave successful discrimination of BPH, PCa and PCaB, and we characterized the potential metabolic alterations involved in the PCa progression and its metastases, including 3-HB, acetone and alanine. The defined biomarker panels could be employed to aid in the diagnosis and classification of PCa in clinical practice.

Background: Doxorubicin is a widely used chemotherapy drug for the treatment of a variety of cancers, however it also has serious side effects such as anaphylaxis and heart damage. Therefore, it’s very important to understand the downstream molecular pathways that are essential for Doxorubicin function in cancer treatment. Methods: HeLa S3 cells were treated with different concentrations of Doxorubicin for 24 hours. Then, the mRNA levels of Notch pathway components in the Doxorubicin treated cells were determined by Real-Time qRT-PCR. Lentiviral transfection was used to up-regulate and down-regulate HES1 expression. Cell proliferation and apoptosis were measured with MTT assay and flow cytometry. Finally, immunofluorescence was used to detect protein subcellular location. Result: Doxorubicin treatment strongly increases the expression of multiple Notch pathway components in cancer cells. The Notch target HES1 is activated by Doxorubicin and is required for the Doxorubicin driven apoptosis. In addition, over-expression of HES1 can further enhances Doxorubicin’s role in promoting apoptosis. Mechanistically, HES1 activates PARP1 and regulates the subcellular location of AIF to mediate the apoptosis response under Doxorubicin treatment. Conclusion: Our results provided novel insights into the downstream molecular pathways underlying Doxorubicin treatment and suggested that manipulation of Notch signaling pathway could have synergistic effect with Doxorubicin for cancer treatment.

Background and aims: AlthoughHelicobacter pyloriis recognized as an extracellular infection bacterium, it can lead to an increase in the number of CD8⁺T cells after infection. At present, the characteristics ofH. pyloriantigen‐specific CD8⁺T cells and the epitope response have not been elucidated. This study was focused on putative protective antigen UreB to detect specific CD8⁺T‐cell responses in vitro and screen for predominant response epitopes.Methods: The PBMCs collected fromH. pylori‐infected individuals were stimulated by UreB peptide pools in vitro to identify the immunodominant CD8⁺T‐cell epitopes. Furthermore, their HLA restriction characteristics were detected accordingly by NGS. Finally, the relationship between immunodominant responses and appearance of gastric symptoms afterH. pyloriinfection was conducted.Results: UreB‐specific CD8⁺T‐cell responses were detected inH. pylori‐infected individuals. Three of UreB dominant epitopes (A‐2 (UreB_443–451: GVKPNMIIK), B‐4 (UreB_420–428: SEYVGSVEV), and C‐1 (UreB_5–13: SRKEYVSMY)) were firstly identified and mainly presented by HLA‐A*1101, HLA‐B*4001 and HLA‐C*0702 alleles, respectively. C‐1 responses were mostly occurred inH. pylori‐infected subjects without gastric symptoms and may alleviate the degree of gastric inflammation.Conclusions: The UreB dominant epitope‐specific CD8⁺T‐cell response was closely related to the gastric symptoms afterH. pyloriinfection, and the C‐1 (UreB_5‐13) dominant peptides may be protective epitopes.

Safety profiles and humoral responses to inactivated severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccines have been previously assessed, but cellular immune responses to inactivated SARS‐CoV‐2 vaccines remain understudied. Here, we report the comprehensive characteristics of SARS‐CoV‐2‐specific CD4⁺ and CD8⁺ T‐cell responses elicited by the BBIBP‐CorV vaccine. A total of 295 healthy adults were recruited, and SARS‐CoV‐2‐specific T‐cell responses were detected after stimulation with overlapping peptide pools spanning the entire length of the envelope (E), membrane (M), nucleocapsid (N), and spike (S) proteins. Robust and durable CD4⁺ (p < 0.0001) and CD8⁺ (p < 0.0001) T‐cell responses specific to SARS‐CoV‐2 were detected following the third vaccination, with an increase in specific CD8⁺ T‐cells, compared to CD4⁺ T‐cells. Cytokine profiles showed that interferon gamma and tumor necrosis factor‐α were predominantly expressed with the negligible expression of interleukin (IL)‐4 and IL‐10, indicating a Th1‐ or Tc1‐biased response. Compared to E and M proteins, N and S activated a higher proportion of specific T‐cells with broader functions. The predominant frequency of the N antigen (49/89) was highest for CD4⁺ T‐cell immunity. Furthermore, N_19–36 and N_391–408 were identified to contain dominant CD8⁺ and CD4⁺ T‐cell epitopes, respectively. In addition, N_19–36‐specific CD8⁺ T‐cells were mainly effector memory CD45RA cells, whereas N_391–408‐specific CD4⁺ T‐cells were mainly effector memory cells. Therefore, this study reports comprehensive features of T‐cell immunity induced by the inactivated SARS‐CoV‐2 vaccine BBIBP‐CorV and proposes highly conserved candidate peptides which may be beneficial in vaccine optimization.

Nat. Genet. 48, 827–837 (2016); published online 13 June 2016; corrected after print 20 March 2017 In the version of this article initially published, residue R384 was incorrectly highlighted in the protein model depicted in Figure 7e. The correct residue is R394. The error has been corrected in theHTML and PDF versions of the article.