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In the middle of the last centuary, large resources of Paleocene–Eocene diatomites were discovered in the Transuralian region. By now, more than 100 near-surface diatomite deposits and potential sites have been identified within the Serov–Shadrinsk lithofacial zone. Despite the large diatomite resources, relatively simple mining–engineering conditions, proximity of some well-known outcrops of diatomite to transportation facilities and large industrial towns, the matter of effective practical application of diatomites from the Transuralian region is still debatable. This work presents results of studying the material composition and textural features of Eocene diatomites of the deposits at Agirish, Irbit, and Kamyshlov, Eocene diatomaceous clays of the Shadrinsk deposit and, for the first time, Paleocene diatomites of the Brusyana deposit. Diatomites of these Transuralian deposits are similar in SiO 2 to other large diatomite deposits of the Russian Federation. They are characterized by thin horizontal lamination and a large microporosity, as well as similar textural peculiarities. Diatomites are mostly composed of well-preserved diatoms (85–95%); the SiO 2 content in some fossils is as high as 98–100%. According to chemical and mineralogical composition, Paleocene diatomites from the Brusyana outcrop are considered as the most “pure” varieties among all Transuralian diatomites. Diatomaceous clays of the Transuralian region are characterized by lower SiO 2 contents, a higher proportion of clay and a low preservation degree of siliceous fossils. The results of analytical studies suggest that Transuralian diatomites can be used as both raw material for production of construction materials and potential raw material for filter materials, catalysts, and sorbents.

Inflammatory and oncogenic signaling converge in disease evolution of BCR–ABL-negative myeloproliferative neoplasms, clonal hematopoietic stem cell disorders characterized by gain-of-function mutation in JAK2 kinase (JAK2V617F), with highest prevalence in patients with polycythemia vera (PV). Despite the high risk, DNA-damaging inflammatory microenvironment, PV progenitors tend to preserve their genomic stability over decades until their progression to post-PV myelofibrosis/acute myeloid leukemia. Using induced pluripotent stem cells-derived CD34 + progenitor-enriched cultures from JAK2V617F + PV patient and from JAK2 wild-type healthy control, CRISPR-modified HEL cells and patients’ bone marrow sections from different disease stages, we demonstrate that JAK2V617F induces an intrinsic IFNγ- and NF-κB-associated inflammatory program, while suppressing inflammation-evoked DNA damage both in vitro and in vivo. We show that cells with JAK2V617F tightly regulate levels of inflammatory cytokines-induced reactive oxygen species, do not fully activate the ATM/p53/p21waf1 checkpoint and p38/JNK MAPK stress pathway signaling when exposed to inflammatory cytokines, suppress DNA single-strand break repair genes’ expression yet overexpress the dual-specificity phosphatase (DUSP) 1. RNAi-mediated knock-down and pharmacological inhibition of DUSP1, involved in p38/JNK deactivation, in HEL cells reveals growth addiction to DUSP1, consistent with enhanced DNA damage response and apoptosis in DUSP1-inhibited parental JAK2V617F + cells, but not in CRISPR-modified JAK2 wild-type cells. Our results indicate that the JAK2V617F + PV progenitors utilize DUSP1 activity as a protection mechanism against DNA damage accumulation, promoting their proliferation and survival in the inflammatory microenvironment, identifying DUSP1 as a potential therapeutic target in PV.

Chromatin DNA damage response (DDR) is orchestrated by the E3 ubiquitin ligase ring finger protein 168 (RNF168), resulting in ubiquitin-dependent recruitment of DDR factors and tumor suppressors breast cancer 1 (BRCA1) and p53 binding protein 1 (53BP1). This ubiquitin signaling regulates pathway choice for repair of DNA double-strand breaks (DSB), toxic lesions whose frequency increases during tumorigenesis. Recruitment of 53BP1 curbs DNA end resection, thereby limiting homologous recombination (HR) and directing DSB repair toward error-prone non-homologous end joining (NHEJ). Under cancer-associated ubiquitin starvation conditions reflecting endogenous or treatment-evoked proteotoxic stress, the ubiquitin-dependent accrual of 53BP1 and BRCA1 at the DNA damage sites is attenuated or lost. Challenging this current paradigm, here we identified diverse human cancer cell lines that display 53BP1 recruitment to DSB sites even under proteasome inhibitor-induced proteotoxic stress, that is, under substantial depletion of free ubiquitin. We show that central to this unexpected phenotype is overabundance of RNF168 that enables more efficient exploitation of the residual-free ubiquitin. Cells with elevated RNF168 are more resistant to combined treatment by ionizing radiation and proteasome inhibition, suggesting that such aberrant RNF168-mediated signaling might reflect adaptation to chronic proteotoxic and genotoxic stresses experienced by tumor cells. Moreover, the overabundant RNF168 and the ensuing unorthodox recruitment patterns of 53BP1, RIF1 and REV7 (monitored on laser micro-irradiation-induced DNA damage) shift the DSB repair balance from HR toward NHEJ, a scenario accompanied by enhanced chromosomal instability/micronuclei formation and sensitivity under replication stress-inducing treatments with camptothecin or poly(ADP-ribose) polymerase (PARP) inhibitor. Overall, our data suggest that the deregulated RNF168/53BP1 pathway could promote tumorigenesis by selecting for a more robust, better stress-adapted cancer cell phenotype, through altered DNA repair, fueling genomic instability and tumor heterogeneity. Apart from providing insights into cancer (patho)biology, the elevated RNF168, documented here also by immunohistochemistry on human clinical tumor specimens, may impact responses to standard-of-care and some emerging targeted cancer therapies.

Cancer incidence is rising and this global challenge is further exacerbated by tumour resistance to available medicines. A promising approach to meet the need for improved cancer treatment is drug repurposing. Here we highlight the potential for repurposing disulfiram (also known by the trade name Antabuse), an old alcohol-aversion drug that has been shown to be effective against diverse cancer types in preclinical studies. Our nationwide epidemiological study reveals that patients who continuously used disulfiram have a lower risk of death from cancer compared to those who stopped using the drug at their diagnosis. Moreover, we identify the ditiocarb–copper complex as the metabolite of disulfiram that is responsible for its anti-cancer effects, and provide methods to detect preferential accumulation of the complex in tumours and candidate biomarkers to analyse its effect on cells and tissues. Finally, our functional and biophysical analyses reveal the molecular target of disulfiram’s tumour-suppressing effects as NPL4, an adaptor of p97 (also known as VCP) segregase, which is essential for the turnover of proteins involved in multiple regulatory and stress-response pathways in cells. Disulfiram is metabolized into copper–diethyldithiocarbamate, which binds to NPL4 and induces its aggregation in cells, leading to blockade of the p97–NPL4–UFD1 pathway and induction of a complex cellular phenotype that results in cell death. Drug repurposing against cancer Disulfiram (trade names Antabuse and Antabus) has been used to treat alcohol dependence for several decades. Jiri Bartek and colleagues report epidemiological data from Danish nationwide registries showing that individuals who continued to take disulfiram after a cancer diagnosis had lower cancer-related mortality than individuals who stopped taking the drug. The authors show that disulfiram has anti-cancer effects in vitro and in vivo and identify the NPL4 protein as a drug target. NPL4 is involved in protein turnover, including stress-response pathways that promote tumorigenesis. These findings suggest that re-purposing disulfiram as an anti-cancer drug is a potential future therapeutic strategy.

We formulate natural conformally invariant conditions on a 4-manifold for the existence of a metric whose Schouten tensor satisfies a quadratic inequality. This inequality implies that the eigenvalues of the Ricci tensor are positively pinched.

Aldehyde dehydrogenase (ALDH) is a proposed biomarker and possible target to eradicate cancer stem cells. ALDH inhibition as a treatment approach is supported by anti-cancer effects of the alcohol-abuse drug disulfiram (DSF, Antabuse). Given that metabolic products of DSF, rather than DSF itself inhibit ALDH in vivo, and that DSF’s anti-cancer activity is potentiated by copper led us to investigate the relevance of ALDH as the suggested molecular cancer-relevant target of DSF. Here we show that DSF does not directly inhibit ALDH activity in diverse human cell types, while DSF’s in vivo metabolite, S-methyl-N,N-diethylthiocarbamate-sulfoxide inhibits ALDH activity yet does not impair cancer cell viability. Our data indicate that the anti-cancer activity of DSF does not involve ALDH inhibition, and rather reflects the impact of DSF’s copper-containing metabolite (CuET), that forms spontaneously in vivo and in cell culture media, and kills cells through aggregation of NPL4, a subunit of the p97/VCP segregase. We also show that the CuET-mediated, rather than any ALDH-inhibitory activity of DSF underlies the preferential cytotoxicity of DSF towards BRCA1- and BRCA2-deficient cells. These findings provide evidence clarifying the confusing literature about the anti-cancer mechanism of DSF, a drug currently tested in clinical trials for repositioning in oncology.

In this note, we study some conformal invariants of a Riemannian manifold ($M^{n}$, g) equipped with a smooth measure m. In particular, we show that there is a natural definition of the Ricci and scalar curvatures associated to such a space, both of which are conformally invariant. We also adapt the methods of Fefferman and Graham [Fefferman, C. & Graham, C. R. (1985) Astérisque, Numero Hors Serie, 95-116] and Graham, Jenne, Mason, and Sparling [Graham, C. R., Jenne, R., Mason, L. J., & Sparling, G. A. J. (1992) J. London Math. Soc. 46, 557-565] to construct families of conformally covariant operators defined on these spaces. Certain variational problems in this setting are considered, including a generalization of the Einstein-Hilbert action.

We study the problem of conformally deforming a metric to a prescribed symmetric function of the eigenvalues of the Ricci tensor. We prove an existence theorem for a wide class of symmetric functions on manifolds with positive Ricci curvature, provided the conformal class admits an admissible metric.

It is proved that every compact Riemannian manifold of dimension n ≥ 3 with negative Ricci curvature is conformal to a metric with det(Ric) = constant. This is a special case of a more general theorem involving symmetric functions of the eigenvalues of the Ricci tensor.