Background-Excessive myocardial fibrosis impairs cardiac function in hypertensive hearts. Roles of transforming growth factor (TGF)-␤ in myocardial remodeling and cardiac dysfunction were examined in pressure-overloaded rats. Methods and Results-Pressure overload was induced by a suprarenal aortic constriction in Wistar rats. Fibroblast activation (proliferation and phenotype transition to myofibroblasts) was observed after day 3 and peaked at days 3 to 7. Thereafter, myocyte hypertrophy and myocardial fibrosis developed by day 28. At day 28, echocardiography showed normal left ventricular fractional shortening, but the decreased ratio of early to late filling velocity of the transmitral Doppler velocity and hemodynamic measurement revealed left ventricular end-diastolic pressure elevation, indicating normal systolic but abnormal diastolic function. Myocardial TGF-␤ mRNA expression was induced after day 3, peaked at day 7, and remained modestly increased at day 28. An anti-TGF-␤ neutralizing antibody, which was administered intraperitoneally daily from 1 day before operation, inhibited fibroblast activation and subsequently prevented collagen mRNA induction and myocardial fibrosis, but not myocyte hypertrophy. Neutralizing antibody reversed diastolic dysfunction without affecting blood pressure and systolic function. Conclusions-TGF-␤ plays a causal role in myocardial fibrosis and diastolic dysfunction through fibroblast activation in pressure-overloaded hearts. Our findings may provide an insight into a new therapeutic strategy to prevent myocardial fibrosis and diastolic dysfunction in pressure-overloaded hearts.

Serial changes in serum MMP-2 and plasma MMP-9 were documented in patients with ACS. These findings provide an insight into the molecular mechanism of plaque destabilization.

The rapid spread of a novel coronavirus,

The hedgehog (Hh) signaling pathway is activated in various types of cancer including pancreatic ductal adenocarcinoma. It has been shown that extremely low oxygen tension (below 1% O 2 ) is found in tumor tissue including pancreatic ductal adenocarcinoma cells (PDAC) and increases the invasiveness of PDAC. To investigate the contribution of the Hh pathway to hypoxia-induced invasiveness, we examined how hypoxia affects Hh pathway activation and the invasiveness of PDAC. In the present study, three human PDAC lines were cultured under normoxic (20% O 2 ) or hypoxic (1% O 2 ) conditions. Hypoxia upregulated the transcription of Sonic hedgehog (Shh), Smoothened (Smo), Gli1 and matrix metalloproteinase9 (MMP9) and increased the invasiveness of PDAC. Significantly, neither the addition of recombinant Shh (rhShh) nor the silencing of Shh affected the transcription of these genes and the invasiveness of PDAC. On the other hand, silencing of Smo decreased the transcription of Gli1 and MMP9 and PDAC invasiveness. Silencing of Gli1 or MMP9 decreased PDAC invasiveness. These results suggest that hypoxia activates the Hh pathway of PDAC by increasing the transcription of Smo in a ligand-independent manner and increases PDAC invasiveness. (Cancer Sci 2011; 102: 1144-1150

This study included patients with primary triple-negative breast cancer (TNBC) who underwent resection without neoadjuvant chemotherapy between January 2004 and December 2014. Among the 248 TNBCs studied, programmed cell death ligand-1 (PD-L1) expression was detected in 103 (41.5%) tumors, and high levels of tumor-infiltrating lymphocytes (TILs) were present in 118 (47.6%) tumors. PD-L1 expression correlated with high levels of TILs, but was not a prognostic factor. Patients with TILs-high tumors had better overall survival than those with TILs-low tumors (P = 0.016). There was a strong interaction between PD-L1 expression and TILs that was associated with both recurrence-free survival (P = 0.0018) and overall survival (P = 0.015). Multivariate Cox proportional hazards model analysis showed that PD-L1-positive/TILs-low was an independent negative prognostic factor for both recurrence-free survival and overall survival. Our findings suggest that PD-L1-positive/TILs-low tumors are associated with a poor prognosis in patients with TNBC, and that it is important to focus on the combination of PD-L1 expression on tumor cells and TILs present in the tumor microenvironment. These biomarkers may be useful for stratification of TNBCs and for predicting prognosis and developing novel cancer immunotherapies.

The purpose of this study is to clarify the contribution of the Hedgehog signaling pathway (Hh pathway) to the progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC). A total of 149 surgically resected mammary disease specimens and 12 sentinel lymph nodes with micro-metastasis (Ly-met) were studied. The degree of Hh pathway activation was estimated from the Gli1 nuclear staining ratio (%Gli1 nuclear translocation) in cancer cells. The invasiveness of breast cancer cells was determined using Matrigel assays. A serial increase of %Gli1 nuclear translocation to IDC from non-neoplastic diseases was confirmed. In tumor specimens, %Gli1 nuclear translocation correlated with the invasiveness of each type of mammary disease and also correlated with invasion-related histopathological parameters. The %Gli1 nuclear translocation in lymph nodes with micro-metastasis was similar to that in primary sites and higher than that in DCIS with microinvasion and DCIS. Blockade of the Hh pathway decreased the invasiveness of breast cancer cells. In IDC, %Gli1 nuclear translocation correlated with the expression of estrogen receptor-a. Estrogen increased %Gli1 nuclear translocation and the invasiveness of estrogen receptor-a-positive cells. The Hh pathway mediates progression from a non-invasive phenotype to an invasive phenotype and %Gli1 nuclear translocation may be useful as a predictive marker for evaluating the ability of invasiveness. (Cancer Sci 2011; 102: 373-381) B reast cancer is the most common neoplasm among women worldwide. Although the development of new therapies has prolonged the survival time of breast cancer patients year on year,(1,2) we must understand more deeply the biological and molecular mechanisms underlying the progression of breast cancer in order to develop more suitable therapeutic strategies. Thus, we focused on the investigation of functional molecules that mediate the progression from non-invasive to invasive breast cancer. Ductal carcinoma in situ is generally considered to be a precursor of IDC. However, the molecular mechanisms underlying the progression from DCIS to IDC are still unclear.The Hh pathway plays a crucial role in growth and patterning during embryonic development.(3) In adults, the Hh pathway remains active in selected cells. (4,5) In mammary glands, the Hh pathway is strictly controlled to ensure normal mammary gland development and to avoid carcinogenesis.(6-9) The Hh pathway consists of Hh proteins (Shh, Indian Hh, and Desert Hh), 12 transmembrane Patched proteins (Patched 1 and Patched 2), the seven transmembrane protein, Smo, and the five-zinc finger transcription factors Gli2 and Gli3. (3,(10)(11)(12) In the absence of Hh, Patched suppresses the signaling activity of Smo. Hh binds to Patched, and Smo is no longer suppressed. Activated Smo allows the translocation of Glis to the nucleus, where it activates Hh target genes. Gli1 is one of these target genes and is itself a transcriptional factor for the Hh pathway.(3,13-15) Thus, Gli1 expression, esp...

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Abstract-A role of interferon-␥ is suggested in early development of atherosclerosis. However, the role of interferon-␥ in progression and destabilization of advanced atherosclerotic plaques remains unknown. Thus, the aim of this study was to determine whether postnatal inhibition of interferon-␥ signaling could inhibit progression of atherosclerotic plaques and stabilize the lipid-and macrophage-rich advanced plaques. Atherosclerotic plaques were induced in ApoE-knockout (KO) mice by feeding high-fat diet from 8 weeks old (w). Interferon-␥ function was postnatally inhibited by repeated gene transfers of a soluble mutant of interferon-␥ receptors (sIFN␥R), an interferon-␥ inhibitory protein, into the thigh muscle every 2 weeks. When sIFN␥R treatment was started at 12 w (atherosclerotic stage), sIFN␥R not only prevented plaque progression but also stabilized advanced plaques at 16 w: sIFN␥R decreased accumulations of the lipid and macrophages and increased fibrotic area with more smooth muscle cells. Moreover, sIFN␥R downregulated expressions of proinflammatory cytokines, chemokines, adhesion molecules, and matrix metalloproteinases but upregulated procollagen type I. sIFN␥R did not affect serum cholesterol levels. In conclusion, postnatal blocking of interferon-␥ function by sIFN␥R treatment would be a new strategy to inhibit plaque progression and to stabilize advanced plaques through the antiinflammatory effects.