Immunotherapy has provided new approaches for tumor treatment.The immune status within the tumor microenvironment of cancer patients,characterized as"cold"or"hot",determines whether they will respond to immunotherapy.This article innovatively proposes the concept of"cell batteries(or Tesla Cell)"to promote the"cold-hot switch"of the tumor microenvironment.It reviews the current research status and progress in tumor immunotherapy,focusing on the concepts of"cold tumors"and"hot tumors,"the conversion strategies between them,as well as the types and applications of"Tesla cell",aiming to provide a theoretical foundation for the development of new immunotherapeutic strategies for tumors.

Objective:To investigate the mechanism of 6-sialyllactose (6-SL) in interfering the immune checkpoint inhibitor-induced colitis (ICIC) through the bacterial 16S rDNA sequencing.Methods:BALB/c mice were randomly divided into the normal control (NC) group ( n = 7), dextran sulfate sodium (DSS) group ( n = 6), ICIC group ( n = 6), and ICIC+6-SL group ( n = 6). The DSS group was continuously fed with 3.5% DSS drinking water for 7 days to induce colonic inflammation; the ICIC group was administered cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4, 150 μg) intraperitoneally on days 0 and 4 in addition to 3.5% DSS drinking water to establish the ICIC mouse model; the ICIC+6-SL group was given 6-SL [150 mg/ (kg·d) ] by gavage simultaneously with the establishment of the ICIC model. Changes in mouse body weight and disease activity index (DAI) were statistically analyzed, and all mice were sacrificed on day 7 to observe gross and histopathological morphological changes in the colon and to tally histopathological scores; the fresh colonic feces were collected for 16S rDNA sequencing to statistically analyze the diversity and species differences in the microbiota of mice of each group. Results:The success rate of the ICIC model was 100%, with all mice surviving. At the endpoint of the study (day 7), compared with the NC and DSS groups, the ICIC group had lower mouse body weight ( P < 0.05), higher DAI ( P < 0.05), damaged integrity of colonic mucosal tissue, and typical ulcerative lesions; the ICIC+6-SL group showed significant alleviation of body weight loss, significantly lower DAI scores, and lower pathological scores compared to the ICIC group, with all differences being statistically significant (all P < 0.05). 16S rDNA sequencing of mouse intestinal feces indicated that the alpha diversity of colonic microbiota in the ICIC group was lower than that in the NC and DSS groups (both P < 0.05), while the ICIC+6-SL group had higher alpha diversity than the ICIC group ( P < 0.05). In beta diversity analysis, the ANOSIM statistical value R = 0.376, P = 0.001 for the PCoA analysis of colonic microbiota and a Stress value of 0.125, P = 0.001 for the NMDS analysis indicated differences in the composition of colonic microbiota among the groups, with the greatest difference between the NC and ICIC groups, and the ICIC+6-SL group's microbiota composition was closer to that of the NC group compared to the ICIC group. Lefse analysis and Kruskal-Wallis test-based differential microbiota analysis showed that at the phylum level, compared to the NC group, the abundance of Bacteroidetes was significantly reduced in the ICIC group, while Campilobacterota was increased, and 6-SL administration could increase the abundance of Bacteroidetes and Campilobacterota in the ICIC group. At the genus level, compared to other groups, the abundance of unclassified_f_Lachnospiraceae and norank_f_Muribaculaceae was the lowest in the ICIC group, while Helicobacter, Akkermansia, and Escherichia-Shigella were enriched. Compared to the ICIC group, the abundance of unclassified_f_Lachnospiraceae and norank_f_ Muribaculaceae was increased in the ICIC+6-SL group, while the abundance of Helicobacter and Escherichia-Shigella was significantly suppressed. Conclusions:6-SL, an oligosaccharide derived from human milk, alleviates intestinal inflammatory injury in ICIC mice, reducing disease activity. This beneficial effect may be related to its regulation of gut microbiota profiling, an increased diversity of microbiota, a restoration of Bacteroidetes, and an inhibition of the growth advantage of pathogenic bacteria such as Helicobacter and Escherichia-Shigella.

The gut microbiota of infants is crucial for the establishment and development of immune system tolerance and responsiveness, as well as long-term health.Breast milk, as the only recommended source of nutrition for infants under 6 months old, possesses all the necessary nutrients and functional components for their growth, development, and health promotion.Human milk oligosaccharides (HMOs), as distinctive functional components that distinguish human milk from other mammalian milk, possess natural targeting properties to reach the colorectum in its intact form and are essential for the maturation of the gut microbiota, development of the digestive system and maintenance of the immune system function in infants, providing natural protection for the digestive and immune systems of newborns.This article reviews the latest research on how HMOs affect the development of the immune system and homeostasis in infants, and focuses on the mechanism by which HMOs control the gut microbiota and influence the immune system′s response through the gut microbiota-immune axis.

Objective To establish a method of LC-MS/MS for determining cordycepin(Cor)and 3′-deoxyinosine(3′-Deo)concentration in rat plasma,and to study their pharmacokinetics in rats.Methods Protein was precipitated with methanol using 2-chloadenosine(2-Chl)as an internal standard.The chromatography was performed on Kinetex C18(3 mm×100 mm,2.6 μm,Phenomenex,USA)with gradient elution in aqueous(5 mmol·L-1 ammonium acetate)-methanol solution as mobile phase.ESI ion source was used for mass spectrometry,and positive ion multiple reaction monitoring(MRM)was used for scanning detection.The pharmacokinetics of Cor and 3′-Deo after oral administration of Cor(10 mg·kg-1)were studied in rats.Results Cor at 0.5-100 ng·mL-1 and 3′-Deo at 1-200 ng·mL-1 had good linearity,and the lower limits of quantification were 0.5 and 1 ng·mL-1,respectively.After oral administration of Cor in rats,the plasma concentration of Cor was low,which was mainly converted into the metabolite 3′-Deo.The Cmax of Cor and 3′-Deo were(5.4±3.4)and(142.0±50.0)ng·mL-1,and AUC0-360min min were(658.4±459.3)and(18 034.9±4 981.1)ng·min·mL-1,respectively.Conclusion The method is simple,sensi-tive,and accurate,which is suitable for determining Cor and 3′-Deo concentration in plasma and the pharmacokinetic study.

[摘 要] RUNX属于转录因子家族，是哺乳动物发育过程中不可或缺的调控因子，在哺乳动物的细胞增殖、分化、谱系发育、成骨和神经形成中发挥重要作用。围绕RUNX的研究已揭示了其功能的多样性以及在肿瘤发生发展过程中的功能。RUNX家族成员在不同类型的肿瘤中具有不一的作用，与肿瘤微环境中的各组分也有不同程度的关联。RUNX家族成员可以调节肿瘤微环境中CD4+辅助性T（Th）细胞和CD8+细胞毒性T细胞（CTL）的谱系发育分化，调控组织驻留T淋巴细胞的表型、分化和存活，驱动NK细胞的增殖活化和组织驻留。RUNX家族缺失会导致MDSC的增殖和成熟活化，从而诱导肿瘤免疫抑制微环境的产生。RUNX家族成员的表达也与肿瘤微环境中肿瘤相关成纤维细胞（CAF）的浸润程度、不同免疫细胞的浸润、免疫检查点基因表达和药物敏感性显著相关，它们可作为潜在的肿瘤预后标志物和免疫治疗靶点，与CAR-T细胞疗法的联用具有很大的应用前景。本文从RUNX的基本结构和功能研究及其参与调控肿瘤免疫和微环境中各类组分的作用进展进行综述，旨在为未来以RUNX为主要靶点的肿瘤免疫治疗提供新的视角。

Objective:To investigate the expression of CD133(also known as PROM1)in pancreatic cancer tissues and its association with clinicopathological features and prognosis of pancreatic cancer patients.Methods:The GEPIA website was used to analyze the expression of CD133 in pancreatic cancer patients from the TCGA database.The correlation between PROM1 mRNA expression and cancer stem cell family genes in human pancreatic cancer tissues was analyzed based on the TCGA database.The expression of CD133 in pancreatic cancer tissues and its clinical significance were studied by immunohistochemistry(IHC)staining.Wilcoxon rank sum test was used to analyze the difference in CD133 expression between pancreatic cancer tissues and adjacent tissues.Chi-square test was used to analyze the relationship between CD133 expression and clinicopathological characteristics in pancreatic cancer tissues.Kaplan-Meier method and Log-rank test were used to analyze the survival difference based on different levels of CD133 expression in pancreatic cancer tissues.The Cox model was used to evaluate the prognostic value of different indicators.Hazard ratio(HR)and 95%confidence interval(95%CI)were used to assess the strength of the association between CD133 expression and mortality risk in pancreatic cancer patients.Results:TCGA database analysis showed that the expression of CD133 was significantly up-regulated in pancreatic cancer tissues compared with adjacent tissues(P<0.05).The mRNA expression level of PROM1 in pancreatic cancer tissues was correlated with tumor stem cell family genes,including EPCAM,POU5F1,CD24,CD44 and CXCR4.The expression level of CD133 in pancreatic cancer tissues was significantly associated with tumor differentiation,TNM stage,and lymph node metastasis(all P<0.05).Univariate Cox model analysis showed that overall survival(OS)was significantly associated with age(HR=0.544,95%CI[0.299,0.990],P<0.05),depth of invasion(HR=0.496,95%CI[0.292,0.842],P<0.05),TNM stage(HR=2.148,95%CI[1.352,3.412],P<0.05),and CD133 expression(HR=1.935,95%CI[1.090,3.433],P<0.05).Multivariate Cox model analysis showed that TNM stage(HR=0.116,95%CI[0.025,0.551],P<0.05),lymph node metastasis(HR=0.392,95%CI[0.160,0.960],P<0.05)and CD133 expression(HR=2.080,95%CI[1.053,4.106],P<0.05)were independent prognostic risk factors.Conclusion:CD133 is highly expressed in pancreatic cancer tissues,and its expression is significantly associated with the prognosis of pancreatic cancer patients.CD133 may serve as a potential new target for immunotherapy in pancreatic cancer.

Objective:To investigate the mechanism of 6-sialyllactose (6-SL) in interfering the immune checkpoint inhibitor-induced colitis (ICIC) through the bacterial 16S rDNA sequencing.Methods:BALB/c mice were randomly divided into the normal control (NC) group ( n = 7), dextran sulfate sodium (DSS) group ( n = 6), ICIC group ( n = 6), and ICIC+6-SL group ( n = 6). The DSS group was continuously fed with 3.5% DSS drinking water for 7 days to induce colonic inflammation; the ICIC group was administered cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4, 150 μg) intraperitoneally on days 0 and 4 in addition to 3.5% DSS drinking water to establish the ICIC mouse model; the ICIC+6-SL group was given 6-SL [150 mg/ (kg·d) ] by gavage simultaneously with the establishment of the ICIC model. Changes in mouse body weight and disease activity index (DAI) were statistically analyzed, and all mice were sacrificed on day 7 to observe gross and histopathological morphological changes in the colon and to tally histopathological scores; the fresh colonic feces were collected for 16S rDNA sequencing to statistically analyze the diversity and species differences in the microbiota of mice of each group. Results:The success rate of the ICIC model was 100%, with all mice surviving. At the endpoint of the study (day 7), compared with the NC and DSS groups, the ICIC group had lower mouse body weight ( P < 0.05), higher DAI ( P < 0.05), damaged integrity of colonic mucosal tissue, and typical ulcerative lesions; the ICIC+6-SL group showed significant alleviation of body weight loss, significantly lower DAI scores, and lower pathological scores compared to the ICIC group, with all differences being statistically significant (all P < 0.05). 16S rDNA sequencing of mouse intestinal feces indicated that the alpha diversity of colonic microbiota in the ICIC group was lower than that in the NC and DSS groups (both P < 0.05), while the ICIC+6-SL group had higher alpha diversity than the ICIC group ( P < 0.05). In beta diversity analysis, the ANOSIM statistical value R = 0.376, P = 0.001 for the PCoA analysis of colonic microbiota and a Stress value of 0.125, P = 0.001 for the NMDS analysis indicated differences in the composition of colonic microbiota among the groups, with the greatest difference between the NC and ICIC groups, and the ICIC+6-SL group's microbiota composition was closer to that of the NC group compared to the ICIC group. Lefse analysis and Kruskal-Wallis test-based differential microbiota analysis showed that at the phylum level, compared to the NC group, the abundance of Bacteroidetes was significantly reduced in the ICIC group, while Campilobacterota was increased, and 6-SL administration could increase the abundance of Bacteroidetes and Campilobacterota in the ICIC group. At the genus level, compared to other groups, the abundance of unclassified_f_Lachnospiraceae and norank_f_Muribaculaceae was the lowest in the ICIC group, while Helicobacter, Akkermansia, and Escherichia-Shigella were enriched. Compared to the ICIC group, the abundance of unclassified_f_Lachnospiraceae and norank_f_ Muribaculaceae was increased in the ICIC+6-SL group, while the abundance of Helicobacter and Escherichia-Shigella was significantly suppressed. Conclusions:6-SL, an oligosaccharide derived from human milk, alleviates intestinal inflammatory injury in ICIC mice, reducing disease activity. This beneficial effect may be related to its regulation of gut microbiota profiling, an increased diversity of microbiota, a restoration of Bacteroidetes, and an inhibition of the growth advantage of pathogenic bacteria such as Helicobacter and Escherichia-Shigella.

Immunotherapy has provided new approaches for tumor treatment.The immune status within the tumor microenvironment of cancer patients,characterized as"cold"or"hot",determines whether they will respond to immunotherapy.This article innovatively proposes the concept of"cell batteries(or Tesla Cell)"to promote the"cold-hot switch"of the tumor microenvironment.It reviews the current research status and progress in tumor immunotherapy,focusing on the concepts of"cold tumors"and"hot tumors,"the conversion strategies between them,as well as the types and applications of"Tesla cell",aiming to provide a theoretical foundation for the development of new immunotherapeutic strategies for tumors.

[摘 要] PD-1/PD-L1抑制剂在乳腺癌免疫治疗中的应用已逐渐成为一种重要的治疗手段，然而对乳腺癌，尤其是三阴性乳腺癌（TNBC）的免疫治疗仍存在某些亟待解决的科学问题，包括PD-1/PD-L1抑制剂单药治疗的有效率欠佳，目前尚无明确的生物标志物来有效筛查治疗敏感人群，免疫相关不良反应（irAE）的发生率高。为了提高疗效和减少irAE的发生，采取以下措施是非常重要的：探讨PD-1/PD-L1抑制剂与其他药物的联合应用方案；采用纳米技术开发选择性靶向肿瘤细胞的纳米载体，降低抗肿瘤药物毒性并提高疗效；探寻开发可预测免疫治疗反应潜力的生物标志物；早期识别和诊疗irAE并建设多学科诊疗协作组（MDT）模式。随着这些措施的积极推进和问题的不断解决，PD-1/PD-L1抑制剂在乳腺癌的治疗中必将呈现出更为广阔的应用前景。

Objective:To improve the understanding of newly diagnosed multiple myeloma (NDMM) patients with bone marrow (BM) monoclonal plasma cell ratio of less than 10%.Methods:The clinical characteristics, laboratory examination, response to treatment, and prognosis of 36 NDMM patients with BM plasma cell ratio of less than 10% at Peking Union Medical College Hospital from January 2009 to December 2017 were summarized retrospectively. In the same period, other age- and gender-matched 72 NDMM patients were selected as the control group, whose BM plasma cell ratio was equal to or greater than 10%.Results:First, the patients in the study group accounted for 4.4% of the whole MM population (36/818) , among which only 11 (30.6%) were classified as International Staging System (ISS) Ⅲ, which was significantly lower than that in the control group[45 (62.5%) ] ( P=0.002) . Extramedullary disease (EMD) was more common in the study group (33.3% vs 5.6%, P<0.001) . The median quantity of serum M protein (g/L) in the less than 10% group was 1.04 (0-50.10) , which was significantly lower than that in the control group [4.50 (0-63.10) ] ( P=0.016) , similar to the median quantity of 24-h urinary light chain (510 mg vs 2800 mg, respectively, P=0.023) . Second, the median progression-free survival (PFS) times of front-line regimen in the study and control groups were 26.4 and 19.9 months, respectively ( HR=1.703, 95% CI 0.167-0.233, P=0.002) . In addition, the overall survival (OS) times were 65.8 and 46.2 months, respectively ( HR=2.626, 95% CI 0.439-0.541, P=0.058) . Third, the study group was reclassified based on the quantity of M protein. The median OS times in patients with low/high tumor load were 66.4 and 24.0 months, respectively ( HR=2.349, 95% CI 0.603-0.696, P=0.046) . The median PFS times were 33.1 and 15.5 months, respectively ( HR=1.806, 95% CI 0.121-0.399, P=0.077) . Bortezomib-based regimens did not affect the clinical outcomes. Conclusion:The subpopulation of patients with MM with BM monoclonal plasma cell ratio less than 10% has specific clinical characteristics, including an early disease stage and a lower overall tumor load. Although more patients of this minor group presented with an extramedullary disease, their response rate to the initial treatment and survival outcome are better than those of patients with BM monoclonal plasma cell ratio more than 10%.