Colonic adenocarcinoma (COAD) is a common gastrointestinal tract tumor, and its occurrence and progression are typically associated with genomic instability, tumor-suppressor gene and oncogene mutations, and tumor mutational load. N6-methyladenosine (m⁶A) modification of RNAs and long non-coding RNA (lncRNA) expression are important in tumorigenesis and progression. However, the regulatory roles of m⁶A-associated lncRNAs in the tumor microenvironment, stratification of prognosis, and immunotherapy are unclear.

METHODS:

We screened 43 prognostic lncRNAs linked to m⁶A and performed consistent molecular typing of COAD using consensus clustering. The single-sample Gene Set Enrichment Analysis and ESTIMATE algorithms were used to assess the immune characteristics of different subgroups. Covariation between methylation-related prognostic lncRNAs was eliminated by least absolute shrinkage and selection operator Cox regression. A nomogram was created and evaluated by combining the methylation-related prognostic lncRNA model with other clinical factors. The relationship between the prognostic model grouping and microsatellite instability, immunophenotype score, and tumor mutation burden was validated using R scripts. Finally, we used a linkage map to filter sensitive medicines to suppress the expression of high-risk genes. Three m⁶A-associated lncRNA modes were identified in 446 COAD specimens with different clinical endpoints and biological statuses. Risk scores were constructed based on the m⁶A-associated lncRNA signature genes. Patients with lower risk scores showed superior immunotherapy responses and clinical benefits compared to those with higher risk scores. Lower risk scores were also correlated with higher immunophenotype scores, tumor mutation burden, and mutation rates in significantly mutated genes (e.g., FAT4 and MUC16). Piperidolate, quinostatin, and mecamylamin were screened for their abilities to suppress the expression of high-risk genes in the model.

CONCLUSIONS:

Quantitative assessment of m⁶A-associated lncRNAs in single tumors can enhance the understanding of tumor microenvironment profiles. The prognostic model constructed using m⁶A-associated lncRNAs may facilitate prognosis and immunotherapy stratification of patients with COAD; finally, three drugs with potential therapeutic value were screened based on the model.

2012-06-28·Blood1区 · 医学

ICOS-LICOS interaction is critically involved in TGN1412-mediated T-cell activation

1区 · 医学

Article

作者: Waibler, Zoe ; Christians, Stefan ; Weissmüller, Sabrina ; Kalinke, Ulrich ; Semmler, Linda Y. ; Müller-Berghaus, Jan

TGN1412, a superagonistic CD28-specific antibody, was shown to require Fc-cross-linking or immobilization as a prerequisite to mediate T-cell proliferation and cytokine release in vitro. We used primary human umbilical vein endothelial cells (HUVECs) to study their ability to induce activation of TGN1412-treated T cells. We confirmed that peripheral primary human T cells do not show activation upon stimulation with soluble TGN1412 alone. Nevertheless, cocultivation of TGN1412-treated T cells with HUVECs induced T-cell activation that was further enhanced using cytokine prestimulated HUVECs. Unexpectedly, Fc-FcγR interaction was dispensable for endothelial cell–mediated proliferation of TGN1412-treated T cells. Transwell-culture assays showed that TGN1412-treated T cells need direct cell-to-cell contact to HUVECs to induce proliferation. We found that costimulatory ICOS-LICOS interaction between T cells and endothelial cells is critically involved in TGN1412-mediated effects. Blocking LICOS reduced TGN1412-mediated T-cell proliferation significantly, whereas recombinant LICOS fully conferred TGN1412-mediated T-cell proliferation. Of note, cytokine stimulation enhanced LICOS expression on HUVECs and ICOS-LICOS interaction up-regulated ICOS expression on TGN1412-treated T cells. Hence, we provide a model of positive feedback conferred by ICOS-LICOS interaction between TGN1412-treated T cells and endothelial cells.

2000-03-01·Current biology : CB1区 · 生物学

LICOS, a primordial costimulatory ligand?

1区 · 生物学

Article

作者: X N Xu ; A V Collins ; D Brodie ; L M Sparks ; P A van der Merwe ; J A Fennelly ; S J Davis ; A Iaboni

In mammals, the classical B7 molecules expressed on antigen-presenting cells, B7-1 (CD80) and B7-2 (CD86), bind the structurally related glycoproteins CD28 and CTLA-4 (CD152), generating costimulatory signals that regulate the activation state of T cells. A recently identified human CD28-like protein, ICOS, also induces costimulatory signals in T cells when crosslinked with antibodies, but it is unclear whether ICOS is part of a B7-mediated regulatory pathway of previously unsuspected complexity, or whether it functions independently and in parallel. Here, we report that, rather than binding B7-1 or B7-2, ICOS binds a new B7-related molecule of previously unknown function that we call LICOS (for ligand of ICOS). At 37 degrees C, LICOS binds only to ICOS but, at lower, non-physiological temperatures, it also binds weakly to CD28 and CTLA-4. Sequence comparisons suggest that LICOS is the homologue of a molecule expressed by avian macrophages and of a murine protein whose expression is induced in non-lymphoid organs by tumour necrosis factor alpha (TNFalpha). Our results define the components of a distinct and novel costimulatory pathway and raise the possibility that LICOS, rather than B7-1 or B7-2, is the contemporary homologue of a primordial vertebrate costimulatory ligand.

100 项与盐酸哌立度酯相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D01165	盐酸哌立度酯	A03AA30	DB13351

研发状态

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
流产	日本	KYORIN Pharmaceutical Co., Ltd.	1967-04-07
早产	日本	KYORIN Pharmaceutical Co., Ltd.	1967-04-07
痉挛	日本	KYORIN Pharmaceutical Co., Ltd.	1967-04-07