Blockade of MMP14 Activity in Murine Breast Carcinomas: Implications for Macrophages, Vessels, and Radiotherapy

Background: Matrix metalloproteinase (MMP) 14 may mediate tumor progression through vascular and immune-modulatory effects. Methods: Orthotopic murine breast tumors (4T1 and E0771 with high and low MMP14 expression, respectively; n = 5-10 per group) were treated with an anti-MMP14 inhibitory antibody (DX-2400), IgG control, fractionated radiation therapy, or their combination. We assessed primary tumor growth, transforming growth factor β (TGFβ) and inducible nitric oxide synthase (iNOS) expression, macrophage phenotype, and vascular parameters. A linear mixed model with repeated observations, with Mann-Whitney or analysis of variance with Bonferroni post hoc adjustment, was used to determine statistical significance. All statistical tests were two-sided. Results: DX-2400 inhibited tumor growth compared with IgG control treatment, increased macrophage numbers, and shifted the macrophage phenotype towards antitumor M1-like. These effects were associated with a reduction in active TGFβ and SMAD2/3 signaling. DX-2400 also transiently increased iNOS expression and tumor perfusion, reduced tissue hypoxia (median % area: control, 20.2%, interquartile range (IQR) = 6.4%-38.9%; DX-2400: 1.2%, IQR = 0.2%-3.2%, P = .044), and synergistically enhanced radiation therapy (days to grow to 800mm3: control, 12 days, IQR = 9-13 days; DX-2400 plus radiation, 29 days, IQR = 26-30 days, P < .001) in the 4T1 model. The selective iNOS inhibitor, 1400W, abolished the effects of DX-2400 on vessel perfusion and radiotherapy. On the other hand, DX-2400 was not capable of inducing iNOS expression or synergizing with radiation in E0771 tumors. Conclusion: MMP14 blockade decreased immunosuppressive TGFβ, polarized macrophages to an antitumor phenotype, increased iNOS, and improved tumor perfusion, resulting in reduced primary tumor growth and enhanced response to radiation therapy, especially in high MMP14-expressing tumor

Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels

Cancer and stromal cells actively exert physical forces (solid stress) to compress tumour blood vessels, thus reducing vascular perfusion. Tumour interstitial matrix also contributes to solid stress, with hyaluronan implicated as the primary matrix molecule responsible for vessel compression because of its swelling behaviour. Here we show, unexpectedly, that hyaluronan compresses vessels only in collagen-rich tumours, suggesting that collagen and hyaluronan together are critical targets for decompressing tumour vessels. We demonstrate that the angiotensin inhibitor losartan reduces stromal collagen and hyaluronan production, associated with decreased expression of profibrotic signals TGF-β1, CCN2 and ET-1, downstream of angiotensin-II-receptor-1 inhibition. Consequently, losartan reduces solid stress in tumours resulting in increased vascular perfusion. Through this physical mechanism, losartan improves drug and oxygen delivery to tumours, thereby potentiating chemotherapy and reducing hypoxia in breast and pancreatic cancer models. Thus, angiotensin inhibitors—inexpensive drugs with decades of safe use—could be rapidly repurposed as cancer therapeutics.National Cancer Institute (U.S.) (Grant P01-CA080124)National Cancer Institute (U.S.) (Grant R01-CA126642)National Cancer Institute (U.S.) (Grant R01-CA085140)National Cancer Institute (U.S.) (Grant R01-CA115767)National Cancer Institute (U.S.) (Grant R01-CA098706)United States. Dept. of Defense. Breast Cancer Research Program (Innovator Award W81XWH-10-1-0016)Lustgarten Foundation (Dana-Farber Cancer Institute/David H. Koch Institute for Integrative Cancer Research at MIT Bridge Project Grant

[Rev.] From precarious employment to precarization of life. Ed. by Zh.T. Toshchenko. Moscow: Ves’ Mir publ., 2022

This article is a review of the recently published collective monograph edited by corresponding member of the Russian Academy of Sciences, Doctor of Philosophy, Professor Zh. Toshchenko, titled “From precarious employment to precarization of life” (2022). The publication of the reviewed book was made possible thanks to financial assistance from “ARB-Forum M”. It is based on an extensive database of representative all-Russian sociological research conducted between 2014 and 2021. The two main goals of the book were: (a) to substantiate that “precarization of labor” has a pronounced tendency to project instability onto other areas of life; (b) to identify a creative and applied concept of “precarization of life” in relation to the emerging proto-class — the precariat. According to the reviewers, the author’s team managed, as usual, to give the reader a good understanding of the origins of how the precariat came about and its further development in society. At the same time, the authors of the work note that precarization is a complex phenomenon that should not be viewed through the prism of a single scientific discipline or sphere, as it was clearly illustrated to us in the book that precarization has already found its way into such spheres as healthcare, culture, education, politics, economics, household needs, i.e. into the public and private life of Russian people. But perhaps the most significant question is whether precarization can cease? The authors do not give the reader their own unambiguous answer to this question, but recognize that it is on the rise all around the world. In the reviewers’ opinion, this collective monograph makes a worthy contribution to the study of the precarization of life (and the precariat in general). At the end of the article, its authors summarize the main propositions of the book, briefly mentioning them, and also point out the weak and rather contradictory (controversial) sides of the reviewed monograph that require much more thorough study in the future.</p

Insights into the Cardiotoxic Effects of <i>Veratrum Lobelianum</i> Alkaloids: Pilot Study

Jervine, protoveratrine A (proA), and protoveratrine B (proB) are Veratrum alkaloids that are presented in some remedies obtained from Veratrum lobelianum, such as Veratrum aqua. This paper reports on a single-center pilot cardiotoxic mechanism study of jervine, proA, and proB in case series. The molecular aspects were studied via molecular dynamic simulation, molecular docking with cardiac sodium channel NaV1.5, and machine learning-based structure–activity relationship modeling. HPLC-MS/MS method in combination with clinical events were used to analyze Veratrum alkaloid cardiotoxicity in patients. Jervine demonstrates the highest docking score (−10.8 kcal/mol), logP value (4.188), and pKa value (9.64) compared with proA and proB. Also, this compound is characterized by the lowest calculated IC50. In general, all three analyzed alkaloids show the affinity to NaV1.5 that highly likely results in cardiotoxic action. The clinical data of seven cases of intoxication by Veratrum aqua confirms the results of molecular modeling. Patients exhibited nausea, muscle weakness, bradycardia, and arterial hypotension. The association between alkaloid concentrations in blood and urine and severity of patient condition is described. These experiments, while primary, confirmed that jervine, proA, and proB contribute to cardiotoxicity by NaV1.5 inhibition

Evidence for incorporation of bone marrow–derived endothelial cells into perfused blood vessels in tumors

Recent studies have demonstrated that the cellular contribution of the bone marrow to tumor neovascularization is highly complex. In this context, the extent to which bone marrow–derived cells incorporate as bona fide endothelial (nonhematopoietic) cells into perfused tumor vessels, or any new vessels formed postnatally (vasculogenesis), is unclear. To this end, we developed models to characterize local vessel–derived and bone marrow–derived endothelial cells (BMD-ECs). Then, we characterized the BMD-ECs based on a set of endothelial markers and morphology. Finally, we quantified their contribution to perfused blood vessels in tumors using transplanted as well as spontaneous primary and metastatic tumor models. We demonstrate that BMD-ECs incorporate in perfused tumor vessels, and that this contribution varies with organ site and mouse strain

Minimal Zn2+ Binding Site of Amyloid-β

Zinc-induced aggregation of amyloid-β peptide (Aβ) is a hallmark molecular feature of Alzheimer's disease. Here we provide direct thermodynamic evidence that elucidates the role of the Aβ region 6–14 as the minimal Zn2+ binding site wherein the ion is coordinated by His6, Glu11, His13, and His14. With the help of isothermal titration calorimetry and quantum mechanics/molecular mechanics simulations, the region 11–14 was determined as the primary zinc recognition site and considered an important drug-target candidate to prevent Zn2+-induced aggregation of Aβ

[Pb2F2](SeO4): a heavier analogue of grandreefite, the first layered fluoride selenate

Текст статьи не публикуется в открытом доступе в соответствии с политикой журнала.Co-precipitation of PbF 2 and PbSeO 4 in weakly acidic media results in the formation of [Pb 2 F 2 ](SeO 4 ), the selenate analogue of the naturally occurring mineral grandreefite, [Pb 2 F 2 ](SO 4 ). The new compound is monoclinic, C2/c, a = 14.0784(2) Å, b = 4.6267(1) Å, c = 8.8628(1) Å, β = 108.98(1)°, V = 545.93(1) Å 3 . Its structure has been refined from powder data to R B = 1.55%. From thermal studies, it is established that the compound is stable in air up to about 300 °C, after which it gradually converts into a single phase with composition [Pb 2 O](SeO 4 ), space group C2/m, and lattice parameters a = 14.0332(1) Å, b = 5.7532(1) Å, c = 7.2113(1) Å, β = 115.07(1)°, V = 527.37(1) Å 3 . It is the selenate analogue of lanarkite, [Pb 2 O](SO 4 ), and phoenicochroite, [Pb 2 O](CrO 4 ), and its crystal structure was refined to R B = 1.21%. The formation of a single decomposition product upon heating in air suggests that this happens by a thermal hydrolysis mechanism, i.e., Pb 2 F 2 SeO 4 + H 2 O (vapor) → Pb 2 OSeO 4 + 2HF↑