Novel pyrimidine-2,4-diamine derivative suppresses the cell viability and spindle assembly checkpoint activity by targeting Aurora kinases

Mitosis represents a clinically important determination point in the life cycle of proliferating cells. One potential drug target within the mitotic machinery is the spindle assembly checkpoint (SAC), an evolutionarily conserved signaling pathway that monitors the connections between microtubules (MTs) and chromosomes. Mistakes in SAC signaling may lead to cell division errors that can trigger elimination of cancer cells at M phase or soon after exit from mitosis. In this study, we describe the cellular effects of a novel pyrimidine-2,4-diamine derivative that we discovered to inhibit the activity of SAC. The compound caused rapid escape from the mitotic arrest induced by lack of interkinetochore tension but not by lack of MT-kinetochore attachments. In cycling cells, the compound disrupted the architecture of mitotic spindle that triggered a transient M-phase arrest that was rapidly followed by a forced mitotic exit. The premature termination of M phase was found to be a consequence of precocious inactivation of SAC caused by a direct inhibitory effect of the compound on Aurora B kinase in vitro and in cells. The compound also targets Aurora A kinase and tubulin in vitro and in cells, which can explain the observed spindle anomalies. The reduced activity of Aurora B kinase resulted in polyploidy and suppression of cancer cell viability. Our data suggest that this new pharmacophore possesses interesting anticancer properties that could be exploited in development of mitosis-targeting therapies

Test of the Kolmogorov-Johnson-Mehl-Avrami picture of metastable decay in a model with microscopic dynamics

The Kolmogorov-Johnson-Mehl-Avrami (KJMA) theory for the time evolution of the order parameter in systems undergoing first-order phase transformations has been extended by Sekimoto to the level of two-point correlation functions. Here, this extended KJMA theory is applied to a kinetic Ising lattice-gas model, in which the elementary kinetic processes act on microscopic length and time scales. The theoretical framework is used to analyze data from extensive Monte Carlo simulations. The theory is inherently a mesoscopic continuum picture, and in principle it requires a large separation between the microscopic scales and the mesoscopic scales characteristic of the evolving two-phase structure. Nevertheless, we find excellent quantitative agreement with the simulations in a large parameter regime, extending remarkably far towards strong fields (large supersaturations) and correspondingly small nucleation barriers. The original KJMA theory permits direct measurement of the order parameter in the metastable phase, and using the extension to correlation functions one can also perform separate measurements of the nucleation rate and the average velocity of the convoluted interface between the metastable and stable phase regions. The values obtained for all three quantities are verified by other theoretical and computational methods. As these quantities are often difficult to measure directly during a process of phase transformation, data analysis using the extended KJMA theory may provide a useful experimental alternative.Comment: RevTex, 21 pages including 14 ps figures. Submitted to Phys. Rev. B. One misprint corrected in Eq.(C1

Assessment of Enterovirus Antibodies during Early Childhood Using a Multiplex Immunoassay

Enteroviruses are a group of positive single-stranded viruses that belong to the Picornaviridae family. They regularly infect humans and cause symptoms ranging from the common cold and hand-foot-and-mouth disease to life-threatening conditions, such as dilated cardiomyopathy and poliomyelitis. Enteroviruses have also been associated with chronic immune-mediated diseases, such as type 1 diabetes, celiac disease, and asthma. Studying these disease-pathogen connections is challenging due to the high prevalence of enterovirus infections in the population and the transient appearance of the virus during the acute infection phase, which limit the identification of the causative agent via methods based on the virus genome. Serological assays can detect the antibodies induced by acute and past infections, which is useful when direct virus detection is not possible. We describe in this immuno-epidemiological study how the antibody levels against VP1 proteins from eight different enterovirus types, representing all seven of the human infecting enterovirus species, vary over time. VP1 responses first significantly (P < 0.001) decline until 6 months of age, reflecting maternal antibodies, and they then start to increase as the infections accumulate and the immune system develops. All 58 children in this study were selected from the DiabImmnune cohort for having PCR-confirmed enterovirus infections. Additionally, we show that there is great, although not complete, cross-reactivity of VP1 proteins from different enteroviruses and that the response against 3C-pro could reasonably well reflect the recent Enterovirus infection history (ρ = 0.94, P = 0.017). The serological analysis of enterovirus antibodies in sera from children paves the way for the development of tools for monitoring the Enterovirus epidemics and associated diseases. IMPORTANCE Enteroviruses cause a wide variety of symptoms ranging from a mild rash and the common cold to paralyzing poliomyelitis. While enteroviruses are among the most common human pathogens, there is a need for new, affordable serological assays with which to study pathogen-disease connections in large cohorts, as enteroviruses have been linked to several chronic illnesses, such as type 1 diabetes mellitus and asthma exacerbations. However, proving causality remains an issue. In this study, we describe the use of an easily customizable multiplexed assay that is based on structural and nonstructural enterovirus proteins to study antibody responses in a cohort of 58 children from birth to 3 years of age. We demonstrate how declining maternal antibody levels can obscure the serological detection of enteroviruses before the age of six months and how antibody responses to nonstructural enterovirus proteins could be interesting targets for serodiagnosis.Peer reviewe

Additive Benefits of Radium-223 Dichloride and Bortezomib Combination in a Systemic Multiple Myeloma Mouse Model

Osteolytic bone disease is a hallmark of multiple myeloma (MM) mediated by MM cell proliferation, increased osteoclast activity, and suppressed osteoblast function. The proteasome inhibitor bortezomib targets MM cells and improves bone health in MM patients. Radium-223 dichloride (radium-223), the first targeted alpha therapy approved, specifically targets bone metastases, where it disrupts the activity of both tumor cells and tumor-supporting bone cells in mouse models of breast and prostate cancer bone metastasis. We hypothesized that radium-223 and bortezomib combination treatment would have additive effects on MM. In vitro experiments revealed that the combination treatment inhibited MM cell proliferation and demonstrated additive efficacy. In the systemic, syngeneic 5TGM1 mouse MM model, both bortezomib and radium-223 decreased the osteolytic lesion area, and their combination was more effective than either monotherapy alone. Bortezomib decreased the number of osteoclasts at the tumor-bone interface, and the combination therapy resulted in almost complete eradication of osteoclasts. Furthermore, the combination therapy improved the incorporation of radium-223 into MM-bearing bone. Importantly, the combination therapy decreased tumor burden and restored body weights in MM mice. These results suggest that the combination of radium-223 with bortezomib could constitute a novel, effective therapy for MM and, in particular, myeloma bone disease

Effect of remdesivir post hospitalization for COVID-19 infection from the randomized SOLIDARITY Finland trial

We report the first long-term follow-up of a randomized trial (NCT04978259) addressing the effects of remdesivir on recovery (primary outcome) and other patient-important outcomes one year after hospitalization resulting from COVID-19. Of the 208 patients recruited from 11 Finnish hospitals, 198 survived, of whom 181 (92%) completed follow-up. At one year, self-reported recovery occurred in 85% in remdesivir and 86% in standard of care (SoC) (RR 0.94, 95% CI 0.47-1.90). We infer no convincing difference between remdesivir and SoC in quality of life or symptom outcomes (p > 0.05). Of the 21 potential long-COVID symptoms, patients reported moderate/major bother from fatigue (26%), joint pain (22%), and problems with memory (19%) and attention/concentration (18%). In conclusion, after a one-year follow-up of hospitalized patients, one in six reported they had not recovered well from COVID-19. Our results provide no convincing evidence of remdesivir benefit, but wide confidence intervals included possible benefit and harm.Peer reviewe

Maternal and fetal effects of low-dosage bupivacaine paracervical block

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Perinatal aspects of pregnancy complicated by fetal ovarian cyst

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Placental blood flow and epidural analgesia during labour in hypertensive pregnancies

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