Co-Targeting PIM Kinase and PI3K/mTOR in NSCLC

PIM kinases are constitutively active proto-oncogenic serine/threonine kinases that play a role in cell cycle progression, metabolism, inflammation and drug resistance. PIM kinases interact with and stabilize p53, c-Myc and parallel signaling pathway PI3K/Akt. This study evaluated PIM kinase expression in NSCLC and in response to PI3K/mTOR inhibition. It investigated a novel preclinical PI3K/mTOR/PIM inhibitor (IBL-301) in vitro and in patient-derived NSCLC tumor tissues. Western blot analysis confirmed PIM1, PIM2 and PIM3 are expressed in NSCLC cell lines and PIM1 is a marker of poor prognosis in patients with NSCLC. IBL-301 decreased PIM1, c-Myc, pBAD and p4EBP1 (Thr37/46) and peIF4B (S406) protein levels in-vitro and MAP kinase, PI3K-Akt and JAK/STAT pathways in tumor tissue explants. IBL-301 significantly decreased secreted pro-inflammatory cytokine MCP-1. Altered mRNA expression, including activated PIM kinase and c-Myc, was identified in Apitolisib resistant cells (H1975GR) by an IL-6/STAT3 pathway array and validated by Western blot. H1975GR cells were more sensitive to IBL-301 than parent cells. A miRNA array identified a dysregulated miRNA signature of PI3K/mTOR drug resistance consisting of regulators of PIM kinase and c-Myc (miR17-5p, miR19b-3p, miR20a-5p, miR15b-5p, miR203a, miR-206). Our data provides a rationale for co-targeting PIM kinase and PI3K-mTOR to improve therapeutic response in NSCLC

Anti-Neoplastic Activity of Two Flavone Isomers Derived From Gnaphalium Elegans and Achyrocline Bogotensis

Over 4000 flavonoids have been identified so far and among these, many are known to have antitumor activities. The basis of the relationships between chemical structures, type and position of substituent groups and the effects these compounds exert specifically on cancer cells are not completely elucidated. Here we report the differential cytotoxic effects of two flavone isomers on human cancer cells from breast (MCF7, SK-BR-3), colon (Caco-2, HCT116), pancreas (MIA PaCa, Panc 28), and prostate (PC3, LNCaP) that vary in differentiation status and tumorigenic potential. These flavones are derived from plants of the family Asteraceae, genera Gnaphalium and Achyrocline reputed to have anti-cancer properties. Our studies indicate that 5,7-dihydroxy-3,6,8-trimethoxy-2-phenyl-4H-chromen-4-one (5,7-dihydroxy-3,6,8-trimethoxy flavone) displays potent activity against more differentiated carcinomas of the colon (Caco-2), and pancreas (Panc28), whereas 3,5-dihydroxy-6,7,8-trimethoxy-2-phenyl-4H-chromen-4-one (3,5-dihydroxy-6,7,8-trimethoxy flavone) cytototoxic action is observed on poorly differentiated carcinomas of the colon (HCT116), pancreas (Mia PaCa), and breast (SK-BR3). Both flavones induced cell death (\u3e50%) as proven by MTT cell viability assay in these cancer cell lines, all of which are regarded as highly tumorigenic. At the concentrations studied (5-80 μM), neither flavone demonstrated activity against the less tumorigenic cell lines, breast cancer MCF-7 cells, androgen-responsive LNCaP human prostate cancer line, and androgen-unresponsive PC3 prostate cancer cells. 5,7-dihydroxy-3,6,8-trimethoxy-2-phenyl-4H-chromen-4-one (5,7-dihydroxy-3,6,8-trimethoxy flavone) displays activity against more differentiated carcinomas of the colon and pancreas, but minimal cytotoxicity on poorly differentiated carcinomas of these organs. On the contrary, 3,5-dihydroxy-6,7,8-trimethoxy-2-phenyl-4H-chromen-4-one (3,5-dihydroxy-6,7,8-trimethoxy flavone) is highly cytotoxic to poorly differentiated carcinomas of the colon, pancreas, and breast with minimal activity against more differentiated carcinomas of the same organs. These differential effects suggest activation of distinct apoptotic pathways. In conclusion, the specific chemical properties of these two flavone isomers dictate mechanistic properties which may be relevant when evaluating biological responses to flavones

Anti-Neoplastic Activity of Two Flavone Isomers Derived from Gnaphalium elegans and Achyrocline bogotensis

Over 4000 flavonoids have been identified so far and among these, many are known to have antitumor activities. The basis of the relationships between chemical structures, type and position of substituent groups and the effects these compounds exert specifically on cancer cells are not completely elucidated. Here we report the differential cytotoxic effects of two flavone isomers on human cancer cells from breast (MCF7, SK-BR-3), colon (Caco-2, HCT116), pancreas (MIA PaCa, Panc 28), and prostate (PC3, LNCaP) that vary in differentiation status and tumorigenic potential. These flavones are derived from plants of the family Asteraceae, genera Gnaphalium and Achyrocline reputed to have anti-cancer properties. Our studies indicate that 5,7-dihydroxy-3,6,8-trimethoxy-2-phenyl-4H-chromen-4-one (5,7-dihydroxy-3,6,8-trimethoxy flavone) displays potent activity against more differentiated carcinomas of the colon (Caco-2), and pancreas (Panc28), whereas 3,5-dihydroxy-6,7,8-trimethoxy-2-phenyl-4H-chromen-4-one (3,5-dihydroxy-6,7,8-trimethoxy flavone) cytototoxic action is observed on poorly differentiated carcinomas of the colon (HCT116), pancreas (Mia PaCa), and breast (SK-BR3). Both flavones induced cell death (\u3e50%) as proven by MTT cell viability assay in these cancer cell lines, all of which are regarded as highly tumorigenic. At the concentrations studied (5–80 µM), neither flavone demonstrated activity against the less tumorigenic cell lines, breast cancer MCF-7 cells, androgen-responsive LNCaP human prostate cancer line, and androgen-unresponsive PC3 prostate cancer cells. 5,7-dihydroxy-3,6,8-trimethoxy-2-phenyl-4H-chromen-4-one (5,7-dihydroxy-3,6,8-trimethoxy flavone) displays activity against more differentiated carcinomas of the colon and pancreas, but minimal cytotoxicity on poorly differentiated carcinomas of these organs. On the contrary, 3,5-dihydroxy-6,7,8-trimethoxy-2-phenyl-4H-chromen-4-one (3,5-dihydroxy-6,7,8-trimethoxy flavone) is highly cytotoxic to poorly differentiated carcinomas of the colon, pancreas, and breast with minimal activity against more differentiated carcinomas of the same organs. These differential effects suggest activation of distinct apoptotic pathways. In conclusion, the specific chemical properties of these two flavone isomers dictate mechanistic properties which may be relevant when evaluating biological responses to flavones

Detection of a tropospheric ozone anomaly using a newly developed ozone retrieval algorithm for an up-looking infrared interferometer

Author Posting. © American Geophysical Union, 2009. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 114 (2009): D06304, doi:10.1029/2008JD010270.On 2 June 2003, the Baltimore Bomem Atmospheric Emitted Radiance Interferometer (BBAERI) recorded an infrared spectral time series indicating the presence of a tropospheric ozone anomaly. The measurements were collected during an Atmospheric Infrared Sounder (AIRS) validation campaign called the 2003 AIRS BBAERI Ocean Validation Experiment (ABOVE03) conducted at the United States Coast Guard Chesapeake Light station located 14 miles due east of Virginia Beach, Virginia (36.91°N, 75.71°W). Ozone retrievals were performed with the Kurt Lightner Ozone BBAERI Retrieval (KLOBBER) algorithm, which retrieves tropospheric column ozone, surface to 300 mbar, from zenith-viewing atmospheric thermal emission spectra. KLOBBER is modeled after the AIRS retrieval algorithm consisting of a synthetic statistical regression followed by a physical retrieval. The physical retrieval is implemented using the k-Compressed Atmospheric Radiative Transfer Algorithm (kCARTA) to compute spectra. The time series of retrieved integrated ozone column on 2 June 2003 displays spikes of about 10 Dobson units, well above the error of the KLOBBER algorithm. Using instrumentation at Chesapeake Light, satellite imaging, trace gas retrievals from satellites, and Potential Vorticity (PV) computations, it was determined that these sudden increases in column ozone likely were caused by a combination of midtropospheric biomass burning products from forest fires in Siberia, Russia, and stratospheric intrusion by a tropopause fold occurring over central Canada and the midwestern United States.NASA for its support through grant NAG5- 1156-7 for AIRS Validation and grant NNG04GN42G for development of AIRS trace gas products, and through a subcontract with JPL on the AIRS Project prime contract NAS7-03001 for continuing optimization and validation of AIRS trace gas products.

Genetic Signature of Rapid IHHNV (Infectious Hypodermal and Hematopoietic Necrosis Virus) Expansion in Wild Penaeus Shrimp Populations

Infectious hypodermal and hematopoietic necrosis virus (IHHNV) is a widely distributed single-stranded DNA parvovirus that has been responsible for major losses in wild and farmed penaeid shrimp populations on the northwestern Pacific coast of Mexico since the early 1990's. IHHNV has been considered a slow-evolving, stable virus because shrimp populations in this region have recovered to pre-epizootic levels, and limited nucleotide variation has been found in a small number of IHHNV isolates studied from this region. To gain insight into IHHNV evolutionary and population dynamics, we analyzed IHHNV capsid protein gene sequences from 89 Penaeus shrimp, along with 14 previously published sequences. Using Bayesian coalescent approaches, we calculated a mean rate of nucleotide substitution for IHHNV that was unexpectedly high (1.39×10−4 substitutions/site/year) and comparable to that reported for RNA viruses. We found more genetic diversity than previously reported for IHHNV isolates and highly significant subdivision among the viral populations in Mexican waters. Past changes in effective number of infections that we infer from Bayesian skyline plots closely correspond to IHHNV epizootiological historical records. Given the high evolutionary rate and the observed regional isolation of IHHNV in shrimp populations in the Gulf of California, we suggest regular monitoring of wild and farmed shrimp and restriction of shrimp movement as preventative measures for future viral outbreaks

Gods are watching and so what? Moralistic supernatural punishment across 15 cultures

Research transparency and reproducibility: Pre-registration materials, supplementary analyses and plots, as well as data and analysis scripts for this study are openly available at: https://github.com/tbendixen/moral-freelist-econ .Supplementary material: Supplemental materials are available at https://doi.org/10.1017/ehs.2023.15 .Copyright © The Author(s), 2023. Psychological and cultural evolutionary accounts of human sociality propose that beliefs in punitive and monitoring gods that care about moral norms facilitate cooperation. While there is some evidence to suggest that belief in supernatural punishment and monitoring generally induce cooperative behaviour, the effect of a deity's explicitly postulated moral concerns on cooperation remains unclear. Here, we report a pre-registered set of analyses to assess whether perceiving a locally relevant deity as moralistic predicts cooperative play in two permutations of two economic games using data from up to 15 diverse field sites. Across games, results suggest that gods’ moral concerns do not play a direct, cross-culturally reliable role in motivating cooperative behaviour. The study contributes substantially to the current literature by testing a central hypothesis in the evolutionary and cognitive science of religion with a large and culturally diverse dataset using behavioural and ethnographically rich methods.‘The Emergence of Prosocial Religions’ from the John Templeton Foundation, and the Cultural Evolution of Religion Research Consortium, funded by a generous partnership grant (895-2011-1009) from the Social Sciences and Humanities Research Council of Canada; CH and SM were funded by the John Templeton Foundation grant no. 48952; TB, ADL and BGP acknowledge funding from Aarhus University Research Foundation

Towards the genetic architecture of seed lipid biosynthesis and accumulation in Arabidopsis thaliana

We report the quantitative genetic analysis of seed oil quality and quantity in six Arabidopsis thaliana recombinant inbred populations, in which the parent accessions were from diverse geographical origins, and were selected on the basis of variation for seed oil content and lipid composition. Although most of the biochemical steps involved in lipid biosynthesis are known and the key genes have been identified, the regulation of the processes that results in the final oil composition and total amount is not understood. By using physically anchored markers it was possible to compare results across populations. A total of 219 quantitative trait loci (QTLs) were identified, of which 81 were significant at P<0.001. Some of these colocalise with QTLs identified previously, but many novel QTLs were also identified. The results highlight the importance of studying traits in multiple populations, which will lead to a better understanding of the contribution that natural variation makes to the genetic architecture of a phenotype

Diagnostic and prognostic performance and longitudinal changes in plasma neurofilament light chain concentrations in adults with Down syndrome: a cohort study

Background Adults with Down syndrome are at an ultra-high risk of Alzheimer's disease, but diagnosis of Alzheimer's disease in this population is challenging. We aimed to validate the clinical utility of plasma neurofilament light chain (NfL) for the diagnosis of symptomatic Alzheimer's disease in Down syndrome, assess its prognostic value, and establish longitudinal changes in adults with Down syndrome. Methods We did a multicentre cohort study, including adults with Down syndrome (>= 18 years), recruited from six hospitals and university medical centres in France, Germany, Spain, the UK, and the USA, who had been assessed, followed up, and provided at least two plasma samples. Participants were classified by local clinicians, who were masked to biomarker data, as asymptomatic (ie, no clinical suspicion of Alzheimer's disease), prodromal Alzheimer's disease, or Alzheimer's disease dementia. We classified individuals who progressed along the Alzheimer's disease continuum during follow-up as progressors. Plasma samples were analysed retrospectively;NfL concentrations were measured centrally using commercial kits for biomarker detection. We used ANOVA to evaluate differences in baseline NfL concentrations, Cox regression to study their prognostic value, and linear mixed models to estimate longitudinal changes. To account for potential confounders, we included age, sex, and intellectual disability as covariates in the analyses. Findings Between Aug 2, 2010, and July 16, 2019, we analysed 608 samples from 236 people with Down syndrome: 165 (70%) were asymptomatic, 32 (14%) had prodromal Alzheimer's disease, and 29 (12%) had Alzheimer's disease dementia;ten [4%] participants were excluded because their classification was uncertain. Mean follow-up was 3.6 years (SD 1.6, range 0.6-9.2). Baseline plasma NfL concentrations showed an area under the receiver operating characteristic curve of 0.83 (95% CI 0.76-0.91) in the prodromal group and 0.94 (0.90-0.97) in the dementia group for differentiating from participants who were asymptomatic. An increase of 1 pg/mL in baseline NfL concentrations was associated with a 1.04-fold risk of clinical progression (95% CI 1.01-1.07;p=0.0034). Plasma NfL concentrations showed an annual increase of 3.0% (95% CI 0.4-5.8) per year in the asymptomatic non-progressors group, 11.5% (4.9-18.5) per year in the asymptomatic progressors group, and 16.0% (8.4-24.0) per year in the prodromal Alzheimer's disease progressors group. In participants with Alzheimer's disease dementia, NfL concentrations increased by a mean of 24.3% (15.3-34.1). Interpretation Plasma NfL concentrations have excellent diagnostic and prognostic performance for symptomatic Alzheimer's disease in Down syndrome. The longitudinal trajectory of plasma NfL supports its use as a theragnostic marker in clinical trials. Copyright (C) 2021 Elsevier Ltd. All rights reserved