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Notch ligand Dll1 mediates cross-talk between mammary stem cells and the macrophageal niche | Science
Evidence that for normal mammary gland the notch signaling can go the other way using Dll1 to induce wnts ! Also do a mammary cell macrophage spheroid coculture!

"The stem cell niche is a specialized environment that dictates stem cell function during development and homeostasis. We show that Dll1, a Notch pathway ligand, is enriched in mammary gland stem cells (MaSCs) and mediates critical interactions with stromal macrophages in the surrounding niche in mouse models. Conditional deletion of Dll1 reduced the number of MaSCs and impaired ductal morphogenesis in the mammary gland. Moreover, MaSC-expressed Dll1 activates Notch signaling in stromal macrophages, increasing their expression of Wnt family ligands such as Wnt3, Wnt10A, and Wnt16, thereby initiating a feedback loop that promotes the function of Dll1-expressing MaSCs. Together, these findings reveal functionally important cross-talk between MaSCs and their macrophageal niche through Dll1-mediated Notch signaling.
spheroid  Notch  mammary_development  Macrophage  dll1  stem_cells  mammary_stem_cells  wnt_signaling 
3 days ago by Segalllab
PI3K/Akt Cooperates with Oncogenic Notch by Inducing Nitric Oxide-Dependent Inflammation: Cell Reports
NOS or LOX stimulated by PI3K/AKT apparently can activate immune cells to support notch driven tumorigenesis. Drosophila eye model mainly and T ALL.

Altogether, these observations indicate that immunosuppression is driven by aberrant NOS promoted by activated PI3K/Akt in the tumor cells, which explains how activated PI3K/Akt unleashes the oncogenic potential of Notch.
NOS  lox  Notch  PI3K  AKT 
4 days ago by Segalllab
Chemotherapy Induces Breast Cancer Stemness in Association with Dysregulated Monocytosis | Clinical Cancer Research
Very nice paper showing that chemotherapy and neoadjuvant chemo can induce stemness in TNBC. Show stemness assays for 231 and BT474 cells in response to dox where macrophages (THP1) or CCL2/7/8 induce stemness including notch activation.


"Results: In human patients and mice, we detected a therapy-induced CSC-stimulatory activity in serum, which was attributed to therapy-associated monocytosis leading to systemic elevation of monocyte chemoattractant proteins (MCP). The post-NT hematopoietic regeneration in the bone marrow highlighted both altered monocyte–macrophage differentiation and biased commitment of stimulated hematopoietic stem cells toward monocytosis. Chemotherapeutic agents also induce monocyte expression of MCPs through a JNK-dependent mechanism. Genetic and pharmacologic inhibitions of the MCP-CCR2 pathway blocked chemotherapy's adverse effect on CSCs. Levels of nuclear Notch and ALDH1 were significantly elevated in primary breast cancers following NT, whereas higher levels of CCR2 in pre-NT tumors were associated with a poor response to NT.

Conclusions: Our data establish a mechanism of chemotherapy-induced cancer stemness by linking the cellular events in the bone marrow and tumors, and suggest pharmacologic inhibition of CCR2 as a potential cotreatment during conventional chemotherapy in neoadjuvant and adjuvant settings. Clin Cancer Res; 24(10); 2370–82. ©2018 AACR.

This article is featured in Highlights of This Issue, p. 2235
Translational Relevance

Preoperative or neoadjuvant therapy is increasingly administered to patients who are candidates for breast preservation and/or present with locally advanced or inflammatory breast cancer. However, some patients respond poorly to the treatment or relapse after neoadjuvant therapy. Our study using patient blood samples and experimental cell and mouse models shows that cytotoxic chemotherapy induces circulating monocyte-derived chemokines, which stimulate cancer stem–like cells (CSC) to potentially promote tumor relapse. Therefore, effective anticancer therapies need to block the concurrent CSC-stimulating effect to achieve better short-term and long-term outcomes. Using preclinical tumor models, we show that pharmacologic inhibition of CCR2 can serve as a potential cotreatment during conventional chemotherapy by targeting therapy-induced cancer stemness. In primary breast tumors, higher levels of CCR2 in tumor cells are associated with lack of a pathologic complete response to neoadjuvant therapy.
chemotherapy  chemoresistance  stem_cells  Notch  Macrophages  THP1  CCL2  mcps  neoadjuvant 
5 days ago by Segalllab
Notching a New Pathway in Vascular Flow Sensing - ScienceDirect
Function for the Notch transmembrane domain to couple VE cadherin to PTPase LAR to activate Rac1 in endothelial cells to result in increasedtight coupling. Notch cleavage is activated by flow.

"The Notch TMD allowed Rac1 to be activated by shear stress to reinforce junctions. Rac1 is activated when guanine nucleotide exchange factors promote its loading with GTP. Here Trio, which was recruited to VE-cadherin by LAR, a receptor protein tyrosine phosphatase, appears to be the most relevant. Both these proteins were necessary for shear stress to reinforce junctions and the endothelial barrier, and they were recruited to form complexes with VE-cadherin when stress was applied. Importantly, their recruitment was dependent on the Notch TMD
Notch  transmembrane_domain  endothelium  VE_cadherin  LAR  rac1 
19 days ago by Segalllab
The Lenovo Z5 is official, and it has a screen notch after all • Android Police
Ryan Whitwam:
<p>Lenovo's Chinese phone releases are not usually big international news, but this time was different. The company's teasers seemed to promise an all-screen design without a notch. That would certainly be refreshing in this day and age. However, the Z5 has been announced, and it looks like every other phone unveiled in the last six months. There's a notch, a glass back, and a chin.

This device has mid-range specs including a Snapdragon 636, 6GB of RAM, and 64-128GB of storage. The screen is 19:9 and measures 6.2-inches with a resolution of 2264x 1080. Around back, there's an iPhone-style camera array with a 16MP main sensor and 8MP secondary. It runs Android 8.1 with the ZUI software layer and no Google apps (because China). The phone comes in blue, black, and "aurora," the latter of which looks a lot like Huawei's fabulous "Twilight" finish on the P20 Pro.

<img src="https://www.androidpolice.com/wp-content/uploads/2018/06/lenovorendercompare.png" width="100%" />
<em>The teaser and the reality.</em>

The early teasers showed off what is clearly a phone without a screen notch. Now, it seems Lenovo was taking some creative liberties with the render…

[Later:] It looks like even Lenovo's full device renders are a lie. The real Z5 has <a href="https://twitter.com/UniverseIce/status/1003933134398808064">substantially larger bezels than you'd think</a> from the official press images above.</p>


Lenovo hasn't made a profit in smartphones since it bought Motorola (and it's hard to think it made much before). The marketing desperation is starting to show.
lenovo  notch 
6 weeks ago by charlesarthur
Notch ligand Dll1 mediates cross-talk between mammary stem cells and the macrophageal niche | Science
DLL1 on mammary stem cells binds notch on macrophages to induce secretion of wnts to support the mammary stem cells.

"In conclusion, our study establishes macrophages as important cellular components of the MaSC niche through intercellular coupling of Notch and Wnt signaling (Fig. 7N). It is possible that additional niche stromal cells may also play an important role for MaSC regulation, which requires future exploration. In the context of Dll1 mediated Notch signaling in MaSC-macrophage cross-talk, we found that Dll1 produced from MaSCs activates Notch signaling in macrophages to enhance the expression of Wnt ligands, which in turn supports Wnt signaling in MaSCs to maintain stem cell activity (Fig. 7N). Since Dll1-Notch signaling requires direct cell-cell contact, and Wnt ligands mostly act as short-range intercellular signals, the Dll1-mediated coupling of Notch-Wnt signaling ensures a spatially delimiting mechanism for localized MaSC-macrophageal niche interaction (23). As Notch and Wnt pathways have been reported to be key oncogenic pathways in breast cancer, and macrophages are a major component of the tumor microenvironment, future studies of Notch-Wnt dependent interaction between MaSCs and macrophage may provide novel insights into tumor initiation and progression in breast cancer."
Notch  mammary_gland  mammary_stem_cells  dll1  wnt 
9 weeks ago by Segalllab
Modulation of Phase Shift between Wnt and Notch Signaling Oscillations Controls Mesoderm Segmentation - ScienceDirect
Interesting that there are coordinated oscillations between wnt and notch signaling during development....

How signaling dynamics encode information is a central question in biology. During vertebrate development, dynamic Notch signaling oscillations control segmentation of the presomitic mesoderm (PSM). In mouse embryos, this molecular clock comprises signaling oscillations of several pathways, i.e., Notch, Wnt, and FGF signaling. Here, we directly address the role of the relative timing between Wnt and Notch signaling oscillations during PSM patterning. To this end, we developed a new experimental strategy using microfluidics-based entrainment that enables specific control of the rhythm of segmentation clock oscillations. Using this approach, we find that Wnt and Notch signaling are coupled at the level of their oscillation dynamics. Furthermore, we provide functional evidence that the oscillation phase shift between Wnt and Notch signaling is critical for PSM segmentation. Our work hence reveals that dynamic signaling, i.e., the relative timing between oscillatory signals, encodes essential information during multicellular development.
Notch  wnt  oscillations  development 
april 2018 by Segalllab
Interference of Notch 1 inhibits the proliferation and invasion of breast cancer cells: Involvement of the β‑catenin signaling pathway
role for notch in 231 and mcf7 invasion


Breast cancer is one of the most common types of carcinoma in humans. The aim of the present study was to identify the role of Notch 1 in the proliferation and invasion of human breast cancer cells. Firstly, the levels of Notch 1 were determined by western blot analysis in breast cancer cell lines, and the results revealed that the expression levels of Notch 1 were markedly higher in MDA‑MB‑231 and MCF‑7 cells, and lower in MCF‑10A cells, compared with human mammary epithelial cells. An MTT assay was used to determine the viability of breast cancer cells. The optical density (OD)490 values were significantly decreased in Notch 1 short hairpin (sh)RNA‑transfected MCF‑7 and MDA‑MB‑231 cells, compared with the OD490 values in the negative control shRNA‑transfected cells. The MCF‑7 cells and MDA‑MB‑231 cells were also treated with increasing concentrations of MRK003, a Notch 1 inhibitor, for 24, 48 and 72 h, respectively. The inhibition rate was gradually increased in the MRK003‑treated cells in a time‑ and dose‑dependent manner. The invasive ability of the cells was determined using a Transwell migration assay. The migration ability was significantly decreased in the Notch 1‑transfected MCF‑7 cells and MDA‑MB‑231 cells. The molecular mechanism was examined, and the knockdown of Notch 1 significantly decreased the expression levels of β‑catenin, matrix metalloproteinase (MMP)‑2 and MMP‑9, and was also correlated with the downregulation of β‑catenin in the nucleus. In conclusion, Notch 1 was key in the progression of breast cancer, and knocking down the expression of Notch 1 significantly suppressed the proliferation and invasion of breast cancer cells. This provides novel clues for cancer therapy in human breast cancer.
Notch  invasion  231  MCF-7 
april 2018 by Segalllab
The Xiaomi Mi MIX 2S - Same Style, Better Loadout, No Notch
If it’s not broken, why fix it? Xiaomi’s Mi MIX 2, a sleek, bezelless upgrade released December last year, didn’t look much different from the original Mi Mix itself. With the Mi MIX 2S, a new white colourway, and an iPhone X-esque dual camera unit on the rear would be the only differences immediately observable...

The post The Xiaomi Mi MIX 2S – Same Style, Better Loadout, No Notch appeared first on .
The  Xiaomi  Mi  MIX  2S    Same  Style  Better  Loadout  No  Notch 
march 2018 by vrzone

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