Purpose Recent studies suggest that tumor-infiltrating lymphocytes (TILs) are associated with disease-free (DFS) and overall survival (OS) in operable triple-negative breast cancer (TNBC). We seek to validate the prognostic impact of TILs in primary TNBCs in two adjuvant phase III trials conducted by the Eastern Cooperative Oncology Group (ECOG). Patients and methods Full-face hematoxylin and eosin–stained sections of 506 tumors from ECOG trials E2197 and E1199 were evaluated for density of TILs in intraepithelial (iTILs) and stromal compartments (sTILs). Patient cases of TNBC from E2197 and E1199 were randomly selected based on availability of sections. For the primary end point of DFS, association with TIL scores was determined by fitting proportional hazards models stratified on study. Secondary end points were OS and distant recurrence–free interval (DRFI). Reporting recommendations for tumor marker prognostic studies criteria were followed, and all analyses were prespecified. Results The majority of 481 evaluable cancers had TILs (sTILs, 80%; iTILs, 15%). With a median follow-up of 10.6 years, higher sTIL scores were associated with better prognosis; for every 10% increase in sTILs, a 14% reduction of risk of recurrence or death (P = .02), 18% reduction of risk of distant recurrence (P = .04), and 19% reduction of risk of death (P = .01) were observed. Multivariable analysis confirmed sTILs to be an independent prognostic marker of DFS, DRFI, and OS. Conclusion In two national randomized clinical trials using contemporary adjuvant chemotherapy, we confirm that stromal lymphocytic infiltration constitutes a robust prognostic factor in TNBCs. Studies assessing outcomes and therapeutic efficacies should consider stratification for this parameter.

Prognostic Value of Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancers From Two Phase III Randomized Adjuvant Breast Cancer Trials: ECOG 2197 and ECOG 1199

Hydrogen bonding induced lowering of the intra-chain metal–metal distance in single end-on azide bridged one-dimensional copper(II) complexes with tridentate Schiff bases as blocking ligands

The PP2A subunit PR130 is a key regulator of cell development and oncogenic transformation

In the title compound, C12H10N2O3, the dihedral angle between the benzene ring and the furan ring is 16.12 (13)°. The conformation is stabilized by an intra­molecular O—H⋯N hydrogen bond. Inter­molecular N—H⋯O hydrogen bonds with the keto group as acceptor lead to strands along [001]. The mol­ecule displays a trans configuration with respect to the C=N and N—N bonds.

https://journals.iucr.org/e/issues/2010/08/00/vm2028/vm2028.pdf

(E)-N'-(2-Hy-droxy-benzyl-idene)furan-2-carbohydrazide.

Although immune checkpoint blockade has emerged as a novel promising strategy for triple-negative breast cancer (TNBC), many patients fail response or acquire resistance to current agents. Consequently, our focus need to shift toward alternative inhibitory targets, predictor for responsiveness, and immune suppressive mechanisms. In this study, we performed systematic bioinformatics analyses to identify PPP2R2B as a robust tumor suppressor in TNBC. Meanwhile, breast cancer progression cell line model was applied in our research. Quantitative real-time PCR assay (Q-PCR) was carried out to assess the role of PPP2R2B in the onset and progression of breast cancer. Furthermore, we validated the effect of PPP2R2B on immune activity via in vitro experiments based on macrophages. To further decipher the roles of PPP2R2B in TNBC, we investigated the transcriptome level, genomic profiles, and its clinical prognostic value. In TNBC tissues, PPP2R2B expression was significantly downregulated compared to normal breast tissues. Kaplan‐Meier survival analysis revealed that patients with low PPP2R2B expression had shorter survival time than those with high PPP2R2B expression. Q-PCR analysis suggested that PPP2R2B downregulation could play a key role in breast-cancer initiation and progression. Additionally, our findings showed that PPP2R2B was positively related with CD8 T cells, CD4 Th1 helper cells, and M1 macrophages, but negatively related with M2 macrophages. Subsequent results identified that PPP2R2B was strongly related with immune inhibitor genes (GZMA, PRF1, and IFNG), which could improve T lymphocytes antitumor function and restrict immune evasion. Meanwhile, T cell receptor signaling pathway and antigen processing and presentation signaling pathway were significantly suppressed in low PPP2R2B expression group. Afterwards, distinct subgroups based on PPP2R2B expression exhibited several unique features in somatic mutations, copy numbers alterations, extent of copy number burden, and promoter methylation level. Our results indicated that PPP2R2B could serve as a promising biomarker for TNBC, and help predict immunotherapeutic response and guide personalized strategies in TNBC treatment.

/pdf/ppp2r2b-downregulation-is-associated-with-immune-evasion-and-28cg835rfw.pdf

PPP2R2B downregulation is associated with immune evasion and predicts poor clinical outcomes in triple-negative breast cancer.

The title compound, [Cu(C11H13Cl2N2O)(N3)]n, is an azide-bridged polymeric copper(II) complex. The Cu atom is penta­coordinated by one O and two N atoms of the Schiff base ligand and two bridging N atoms from two azide groups, forming a trigonal–bipyramidal geometry. The structure is further stabilized by an N—H⋯O hydrogen bond.

catena-Poly[[{2,4-dichloro-6-[2-(ethylamino)ethyliminomethyl]phenolato}copper(II)]-μ-azido]

In the title compound, C18H14N2O4, the dihedral angle between the benzene ring and the naphthyl ring system is 10.1 (2)°. The mol­ecule is nearly planar, with a mean deviation from the plane of 0.141 (2) A for 24 non-H atoms. An intra­molecular O—H⋯N hydrogen bond forms a pseudo-6-membered ring and the mol­ecules are linked into sheets by inter­molecular N—H⋯O and O—H⋯O hydrogen bonds.

/pdf/3-5-dihydr-oxy-n-2-hydr-oxy-1-naph-thyl-methyl-ene-1ej8m8pu3t.pdf

3,5-Dihydr-oxy-N'-[(2-hydr-oxy-1-naph-thyl)methyl-ene]benzohydrazide.

Triple negative breast cancer (TNBC), is defined as a type of tumor lacking the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). The ER, PR and HER2 are usually the molecular therapeutic targets for breast cancers, but they are ineffective for TNBC because of their negative expressions, so chemotherapy is currently the main treatment strategy in TNBC. However, drug resistance remains a major impediment to TNBC chemotherapeutic treatment. Recently, the protein phosphatase 2A (PP2A) has been found to regulate the phosphorylation of some substrates involved in the relevant target of TNBC, such as cell cycle control, DNA damage responses, epidermal growth factor receptor, immune modulation and cell death resistance, which may be the effective therapeutic strategies or influence drug sensitivity to TNBCs. Furthermore, PP2A has also been found that could induce ER re-expression in ER-negative breast cancer cells, and which suggests PP2A could promote the sensitivity of tamoxifen to TNBCs as a resistance reversal agent. In this review, we will summarize the potential therapeutic value of PP2A as the main node in developing targeting agents, disrupting resistance or restoring drug sensitivity in TNBC.

PP2A as the Main Node of Therapeutic Strategies and Resistance Reversal in Triple-Negative Breast Cancer.

The invention relates to thiopyrimidine heterocycle anti-tumor compounds as well as a preparation method and an application thereof. The anti-tumor compounds specifically have the structure shown in aformula (I). The invention also relates to the compounds shown in the formula (I), pharmaceutically acceptable salts of the compounds or pharmaceutical composition containing the compounds. The pharmaceutical composition can treat tumor diseases by inhibiting wild type EGFR (epidermal growth factor receptor) and mutant type EGFR-T790M PTK (protein tyrosine kinase) and is particularly applied to treatment of small cell lung cancer, non-small cell lung cancer and EGFR-T790M mutant type non-small cell lung cancer.

Yu-Hong Zhen

Papers

catena-Poly[[{2,4-dichloro-6-[2-(ethylamino)ethyliminomethyl]phenolato}copper(II)]-μ-azido]

3,5-Dihydr-oxy-N'-[(2-hydr-oxy-1-naph-thyl)methyl-ene]benzohydrazide.

PP2A as the Main Node of Therapeutic Strategies and Resistance Reversal in Triple-Negative Breast Cancer.

Thiopyrimidine heterocycle anti-tumor compounds as well as preparation method and application thereof