Explore the vast range of titles available.

The extracellular, matrix-modifying enzyme lysyl oxidase (LOX) has recently been linked to colorectal cancer (CRC) progression, in particular to the stages of invasion and metastasis. In this report, we use cell lines expressing a catalytically inactive mutant form of LOX to show that catalytic activity is required for LOX-mediated effects on proliferation and invasion in both in vitro and in vivo models of CRC. Furthermore, we use rheology to measure the relative stiffness of modified collagen matrices and subcutaneous tumors, and show that LOX-induced collagen cross-linking results in stiffening of the matrix both in vitro and in vivo . We observe a strong association between matrix stiffness and activation of the FAK (focal adhesion kinase)/SRC-signaling pathway, with a stiffer environment resulting in increased FAK/SRC phosphorylation and a more proliferative and invasive phenotype. We are the first to show a direct relationship between LOX enzymatic activity and tissue stiffness, and to demonstrate a role for stiffness in driving CRC progression. Our findings provide significant evidence to suggest that therapeutic inhibition of LOX activity may provide a novel effective treatment option for patients with metastatic CRC.

The United States in Crisis: Citizenship, Immigration, and the Nation State argues that to preserve our freedom Americans must mount a defense of the nation state against the progressive forces who advocate for global government. The Founders of America were convinced that freedom would flourish only in a nation state. A nation state is a collection of citizens who share a commitment to the same principles. Today, the nation state is under attack by the progressive Left, who allege that it is the source of almost every evil in the world.

Working with the underlying premise that America's founding principles continue to be vital in the modern era, Erler, Marini, and West take a conservative look at immigration, one of today's most pressing political issues. Character_the capacity to live a life befitting republican citizens_is, as the Founders knew, crucial to the debate about immigration. The Founders on Citizenship and Immigration seeks to revive the issue of republican character in the current immigration debate and to elucidate the constitutional foundations of American citizenship. Published in cooperation with the Claremont Institute.

Within the nuclear density functional theory (DFT) we study the effect of reflection-asymmetric shapes on ground-state binding energies and binding energy differences. To this end, we developed the new DFT solver AXIALHFB that uses an approximate second-order gradient to solve the Hartree-Fock-Bogoliubov equations of superconducting DFT with the quasi-local Skyrme energy density functionals. Illustrative calculations are carried out for even-even isotopes of radium and thorium.

We overview the methodology behind the large-scale mass table calculations based on the nuclear density functional theory (DFT) with Skyrme energy density functionals (EDFs). The calculations employing massively parallel computers are done in a large configuration space of an axially deformed harmonic oscillator. Nuclear mass tables tabulating global nuclear properties such as binding energies, radii, shape deformations, and pairing gaps are obtained for several Skyrme EDFs augmented by a mixed-type pairing functional, using an approximate particle number projection before variation. Specialty visualization tools have been developed to analyze the results. As an illustrative example of our current capabilities, we show some results for a wide range of even-even nuclei with Z ≤ 120 and N ≤ 300.

A high-precision parity-violating electron–quark scattering experiment provides measurements of a combination of electron–quark weak couplings with a precision five times higher than the single previous direct study, confirming the predictions of the electroweak particle-physics theory and providing constraints on parity-violating interactions beyond the standard model. Parity-violating asymmetry revisited Parity symmetry — or mirror-image symmetry — implies that flipping left and right does not change the laws of physics. Violation of parity symmetry in the weak nuclear force was discovered in the mid-1950s and parity violation in electron scattering was important in establishing, and is now used to test, the standard model of particle physics. This study reports a high-precision electron–quark scattering experiment that provides a measurement of the parity-violating asymmetry with a precision of five times higher than the single previous direct study via this scattering process. The results confirm the predictions of electroweak particle-physics theory, while providing constraints on parity-violating interactions beyond the standard model. Symmetry permeates nature and is fundamental to all laws of physics. One example is parity (mirror) symmetry, which implies that flipping left and right does not change the laws of physics. Laws for electromagnetism, gravity and the subatomic strong force respect parity symmetry, but the subatomic weak force does not 1 , 2 . Historically, parity violation in electron scattering has been important in establishing (and now testing) the standard model of particle physics. One particular set of quantities accessible through measurements of parity-violating electron scattering are the effective weak couplings C 2 q , sensitive to the quarks’ chirality preference when participating in the weak force, which have been measured directly 3 , 4 only once in the past 40 years. Here we report a measurement of the parity-violating asymmetry in electron–quark scattering, which yields a determination of 2 C 2 u  −  C 2 d (where u and d denote up and down quarks, respectively) with a precision increased by a factor of five relative to the earlier result. These results provide evidence with greater than 95 per cent confidence that the C 2 q couplings are non-zero, as predicted by the electroweak theory. They lead to constraints on new parity-violating interactions beyond the standard model, particularly those due to quark chirality. Whereas contemporary particle physics research is focused on high-energy colliders such as the Large Hadron Collider, our results provide specific chirality information on electroweak theory that is difficult to obtain at high energies. Our measurement is relatively free of ambiguity in its interpretation, and opens the door to even more precise measurements in the future.

Silicon nanopowders were prepared by hot-wire chemical vapour deposition (CVD) from monosilane. Wire materials including Hf, Nb, Ta, Mo, W, Rh, Re, Ir, Pd, and Pt were tested. The filament temperature was varied in the range of 400–2000 ℃ and pressures between 1.0–1.5 bar. Products were characterised by bulk elemental analysis and a laser granulometer. The powders were investigated by TG-DSC-MS under inert, O 2 , and H 2 O containing atmosphere, respectively, in a temperature range of 20–700 ℃. Hydrogen evolution occurred in three separate steps, depending on the applied gas atmosphere. The oxidation mechanism was explored by the characteristic O x Si-H bands (x = 0–3) observed in ex situ DRIFT experiments. The oxidation of hydrogen terminated silicon surfaces was investigated employing oxygen (O 2 ), hydrogen peroxide (H 2 O 2 ), permanganate (MnO 4 − ), or peroxodisulfate S 2 O 8 2 − in a temperature range of 0–120 ℃. The oxidation was stepwise and strongly enhanced after pretreatment by alkyl lithium salts or Grignard reagents.

A desmoplastic colorectal cancer stroma, characterized by excess turnover of the cancer-associated fibroblast derived collagens type III and VI, can lead to reduced drug-uptake and poor treatment response. We investigated the association between biomarkers of collagen type III and VI and overall survival (OS) in patients with metastatic colorectal cancer (mCRC). Serum samples were collected from 252 patients with mCRC prior to treatment with bevacizumab and chemotherapy. Serum concentrations of biomarkers reflecting formation of collagen type III (PRO-C3) and VI (PRO-C6) and degradation of collagen type VI (C6M and C6Mα3) were determined by ELISA. The biomarkers were evaluated for associations with OS, individually, combined, and after adjusting for carcinoembryonic antigen (CEA), lactate dehydrogenase (LDH) and performance status (PS). High baseline levels (> median) of each collagen biomarker were significantly associated with shorter OS (PRO-C3: HR = 2.0, 95%CI = 1.54–2.63; PRO-C6: HR = 1.6, 95%CI = 1.24–2.11; C6M: HR = 1.4, 95%CI = 1.05–1.78; C6Mα3: HR = 1.6, 95%CI = 1.16–2.07). PRO-C3 and PRO-C6 remained significant after adjustment for CEA, LDH and PS. Weak correlations were seen between the collagen biomarkers (r = 0.03–0.59) and combining all improved prognostic capacity (HR = 3.6, 95%CI = 2.30–5.76). Collagen biomarkers were predictive of shorter OS in patients with mCRC. This supports that collagen- and CAF biology is important in CRC.

Hypoxia in tumours Tumours contain areas of low oxygen (hypoxia) because cancer cells grow and divide so fast that the blood vessels can't keep up with their oxygen requirement. Cells in a hypoxic region are prone to metastasis, but the reasons for this are unknown. Erler et al . have now discovered high levels of the enzyme lysyl oxidase (LOX) in hypoxic cells. High LOX content was associated with a poor prognosis in breast cancer patients. In mice, LOX inhibition reduced metastases, suggesting that it is a possible therapeutic target. Metastasis is a multistep process responsible for most cancer deaths, and it can be influenced by both the immediate microenvironment (cell–cell or cell–matrix interactions) and the extended tumour microenvironment (for example vascularization) 1 . Hypoxia (low oxygen) is clinically associated with metastasis and poor patient outcome, although the underlying processes remain unclear 2 . Microarray studies have shown the expression of lysyl oxidase (LOX) to be elevated in hypoxic human tumour cells 3 . Paradoxically, LOX expression is associated with both tumour suppression and tumour progression, and its role in tumorigenesis seems dependent on cellular location, cell type and transformation status 4 , 5 , 6 , 7 , 8 , 9 . Here we show that LOX expression is regulated by hypoxia-inducible factor (HIF) and is associated with hypoxia in human breast and head and neck tumours. Patients with high LOX-expressing tumours have poor distant metastasis-free and overall survivals. Inhibition of LOX eliminates metastasis in mice with orthotopically grown breast cancer tumours. Mechanistically, secreted LOX is responsible for the invasive properties of hypoxic human cancer cells through focal adhesion kinase activity and cell to matrix adhesion. Furthermore, LOX may be required to create a niche permissive for metastatic growth. Our findings indicate that LOX is essential for hypoxia-induced metastasis and is a good therapeutic target for preventing and treating metastases.

The extracellular matrix (ECM) is the physical scaffold where cells are organized into tissues and organs. The ECM may be modified during cancer to allow and promote proliferation, invasion, and metastasis. The family of lysyl oxidase (LOX) enzymes cross-links collagens and elastin and, therefore, is a central player in ECM deposition and maturation. Extensive research has revealed how the LOX proteins participate in every stage of cancer progression, and two family members, LOX and LOX-like 2, have been linked to metastasis, the final stage of cancer responsible for over 90% of cancer patient deaths. However, LOX biosynthesis results in by-product with antiproliferative properties in certain cancers, and LOX enzymes may have different effects depending on the molecular network in which they are active. Therefore, the design of therapies targeting the LOX family needs to be guided by the molecular makeup of the individual disease and will probably require other agents to act on both the LOX enzymes and their associated network.