Even though metastasis, a hallmark of cancer, is responsible for up to 90% of cancer-related mortality, it is still the least understood aspect of cancer pathogenesis ...
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Smoking has a profound impact on tumor immunity, and nicotine, which is the major addictive component of smoke, is known to promote tumor progression despite being a non-carcinogen. In this study, we ...demonstrate that chronic exposure of nicotine plays a critical role in the formation of pre-metastatic niche within the lungs by recruiting pro-tumor N2-neutrophils. This pre-metastatic niche promotes the release of STAT3-activated lipocalin 2 (LCN2), a secretory glycoprotein from the N2-neutrophils, and induces mesenchymal-epithelial transition of tumor cells thereby facilitating colonization and metastatic outgrowth. Elevated levels of serum and urine LCN2 is elevated in early-stage breast cancer patients and cancer-free females with smoking history, suggesting that LCN2 serve as a promising prognostic biomarker for predicting increased risk of metastatic disease in female smoker(s). Moreover, natural compound, salidroside effectively abrogates nicotine-induced neutrophil polarization and consequently reduced lung metastasis of hormone receptor-negative breast cancer cells. Our findings suggest a pro-metastatic role of nicotine-induced N2-neutrophils for cancer cell colonization in the lungs and illuminate the therapeutic use of salidroside to enhance the anti-tumor activity of neutrophils in breast cancer patients.
Bone metastasis is an incurable complication of breast cancer. In advanced stages, patients with estrogen-positive tumors experience a significantly higher incidence of bone metastasis (>87%) ...compared to estrogen-negative patients (<56%). To understand the mechanism of this bone-tropism of ER
tumor, and to identify liquid biopsy biomarkers for patients with high risk of bone metastasis, the secreted extracellular vesicles and cytokines from bone-tropic breast cancer cells are examined in this study. Both exosomal miR-19a and Integrin-Binding Sialoprotein (IBSP) are found to be significantly upregulated and secreted from bone-tropic ER
breast cancer cells, increasing their levels in the circulation of patients. IBSP is found to attract osteoclast cells and create an osteoclast-enriched environment in the bone, assisting the delivery of exosomal miR-19a to osteoclast to induce osteoclastogenesis. Our findings reveal a mechanism by which ER
breast cancer cells create a microenvironment favorable for colonization in the bone. These two secreted factors can also serve as effective biomarkers for ER
breast cancer to predict their risks of bone metastasis. Furthermore, our screening of a natural compound library identifies chlorogenic acid as a potent inhibitor for IBSP-receptor binding to suppress bone metastasis of ER
tumor, suggesting its preventive use for bone recurrence in ER
patients.
The proper choice of nonprecious transition metals as single atom catalysts (SACs) remains unclear for designing highly efficient electrocatalysts for hydrogen evolution reaction (HER). Herein, ...reported is an activity correlation with catalysts, electronic structure, in order to clarify the origin of reactivity for a series of transition metals supported on nitrogen‐doped graphene as SACs for HER by a combination of density functional theory calculations and electrochemical measurements. Only few of the transition metals (e.g., Co, Cr, Fe, Rh, and V) as SACs show good catalytic activity toward HER as their Gibbs free energies are varied between the range of –0.20 to 0.30 eV but among which Co‐SAC exhibits the highest electrochemical activity at 0.13 eV. Electronic structure studies show that the energy states of active valence dz2 orbitals and their resulting antibonding state determine the catalytic activity for HER. The fact that the antibonding state orbital is neither completely empty nor fully filled in the case of Co‐SAC is the main reason for its ideal hydrogen adsorption energy. Moreover, the electrochemical measurement shows that Co‐SAC exhibits a superior hydrogen evolution activity over Ni‐SAC and W‐SAC, confirming the theoretical calculation. This systematic study gives a fundamental understanding about the design of highly efficient SACs for HER.
The origin of single atom catalytic activity for hydrogen evolution reaction is explored via mutual collaboration of computational prediction and experimental validation. It is found that single atom catalytic activity depends on their valence orbital states, showing excellent correlation with charge transfer and activity descriptors. This systematic study will open a new direction to design heterogeneous catalysts for hydrogen evolution reaction.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Up to 30% of patients with metastatic breast cancer eventually develop brain metastasis, yet the pathologic mechanism behind this development remains poorly understood. Here, we profiled long ...noncoding RNAs in brain metastatic tumors from patients with breast cancer and found that the X-inactive-specific transcript (XIST) was significantly downregulated in these tissues. XIST expression levels inversely correlated with brain metastasis, but not with bone metastasis in patients. Silencing of XIST preferentially promoted brain metastatic growth of XIST
cells in our xenograft models. Moreover, knockout of XIST in mice mammary glands accelerated primary tumor growth as well as metastases in the brain. Decreased expression of XIST stimulated epithelial-mesenchymal transition and activated c-Met via MSN-mediated protein stabilization, which resulted in the promotion of stemness in the tumor cells. Loss of XIST also augmented secretion of exosomal miRNA-503, which triggered M1-M2 polarization of microglia. This M1-M2 conversion upregulated immune suppressive cytokines in microglia that suppressed T-cell proliferation. Furthermore, we screened an FDA-approved drug library and identified fludarabine as a synthetic lethal drug for XIST
breast tumor cells and found that fludarabine blocked brain metastasis in our animal model. Our results indicate that XIST plays a critical role in brain metastasis in breast cancer by affecting both tumor cells and the tumor microenvironment and that the XIST-mediated pathway may serve as an effective target for treating brain metastasis.
These findings describe mechanisms of how loss of the lncRNA XIST promotes brain metastasis in breast cancer and identify fludarabine as a potential therapeutic agent that specifically eliminates XIST
tumor cells in the brain.
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Brain metastasis of breast cancer exhibits exceedingly poor prognosis, and both triple negative (TN) and Her2
subtypes have the highest incidence of brain metastasis. Although estrogen blockers are ...considered to be ineffective for their treatment, recent evidence indicates that estrogen blockade using tamoxifen showed certain efficacy. However, how estrogen affects brain metastasis of triple negative breast cancer (TNBC) remains elusive.
To examine the effect of estrogen on brain metastasis progression, nude mice were implanted with brain metastatic cells and treated with either estrogen supplement, tamoxifen, or ovariectomy for estrogen depletion. For clinical validation study, brain metastasis specimens from pre- and post-menopause breast cancer patients were examined for microglia polarization by immunohistochemistry. To examine the estrogen-induced M2 microglia polarization, microglia cells were treated with estrogen, and the M1/M2 microglia polarization was detected by qRT-PCR and FACS. The estrogen receptor-deficient brain metastatic cells, SkBrM and 231BrM, were treated with conditioned medium (CM) derived from microglia that were treated with estrogen in the presence or absence of tamoxifen. The effect of microglia-derived CM on tumor cells was examined by colony formation assay and sphere forming ability.
We found that M2 microglia were abundantly infiltrated in brain metastasis of pre-menopausal breast cancer patients. A similar observation was made in vivo, when we treated mice systemically with estrogen. Blocking of estrogen signaling either by tamoxifen treatment or surgical resection of mice ovaries suppressed M2 microglial polarization and decreased the secretion of C-C motif chemokine ligand 5, resulting in suppression of brain metastasis. The estrogen modulation also suppressed stemness in TNBC cells in vitro. Importantly, estrogen enhanced the expression of signal regulatory protein α on microglia and restricted their phagocytic ability.
Our results indicate that estrogen promotes brain metastasis by skewing polarity of M2 microglia and inhibiting their phagocytic ability, while tamoxifen suppresses brain metastasis by blocking the M2 polarization of microglia and increasing their anti-tumor phagocytic ability. Our results also highlight a potential therapeutic utility of tamoxifen for treating brain metastasis of hormone receptor-deficient breast cancer.
Breast cancer displays disparities in mortality between African Americans and Caucasian Americans. However, the exact molecular mechanisms remain elusive. Here, we identify miR-1304-3p as the most ...upregulated microRNA in African American patients. Importantly, its expression significantly correlates with poor progression-free survival in African American patients. Ectopic expression of miR-1304 promotes tumor progression in vivo. Exosomal miR-1304-3p activates cancer-associated adipocytes that release lipids and enhance cancer cell growth. Moreover, we identify the anti-adipogenic gene GATA2 as the target of miR-1304-3p. Notably, a single nucleotide polymorphism (SNP) located in the miR-1304 stem-loop region shows a significant difference in frequencies of the G allele between African and Caucasian American groups, which promotes the maturation of miR-1304-3p. Therefore, our results reveal a mechanism of the disparity in breast cancer progression and suggest a potential utility of miR-1304-3p and the associated SNP as biomarkers for predicting the outcome of African American patients.
This research focuses on estimating the stress-strength reliability in a system characterized by the influence of two random stresses on its strength, employing both frequentist and Bayesian ...approaches. The reliability of such systems is represented by the function
δ
=
P
(
U
<
V
<
W
)
, where
V
denotes the system’s strength, and
U
and
W
represent the stresses. The analysis is performed under a progressive Type-II censoring scheme, considering the random variables
U
,
V
, and
W
as independent and following the Burr-XII distribution. In a frequentist setup, both the maximum likelihood estimator and the maximum product spacings estimator of
δ
have been obtained. In the Bayesian paradigm, the Bayes estimator of
δ
under the squared error loss function is derived utilizing the Markov chain Monte Carlo method, considering independent gamma priors for the unknown parameters. In addition, asymptotic confidence intervals and highest probability density credible intervals for
δ
are also formulated. An extensive simulation experiment is carried out to compare the performances of the different developed estimators. Finally, a real-life application is presented to demonstrate the practical applicability of the proposed theory.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In this work, we provide a simple method to represent the contact line dynamics of an evaporating sessile droplet. As a droplet evaporates, two distinct contact line dynamics are observed. They are ...collectively known as modes of evaporation, namely Constant Contact Radius (CCR) and Constant Contact Angle (CCA). Another intermediate mode-Stick-Slide (SS) or mixed mode is also commonly observed. In this article, we are able to provide a graphical representation to these modes (named as MOE plot), which is visually more comprehensive especially for comparative studies. In addition, the method facilitates quantitative estimation for mode of evaporation (named as MOE fraction or MOEf), which doesn't exist in literature. Thus, various substrates can now be compared based on mode of evaporation (or contact line dynamics), which are governed by fluid property and surface characteristics.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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