Blocking hepatocarcinogenesis by a cytochrome P450 family member with female-preferential expression

ObjectsThe incidence of hepatocellular carcinoma (HCC) shows an obvious male dominance in rodents and humans. We aimed to identify the key autosomal liver-specific sex-related genes and investigate their roles in hepatocarcinogenesis.DesignTwo HCC cohorts (n=551) with available transcriptome and metabolome data were used. Class comparisons of omics data and ingenuity pathway analysis were performed to explore sex-related molecules and their associated functions. Functional assays were employed to investigate roles of the key candidates, including cellular assays, molecular assays and multiple orthotopic HCC mouse models.ResultsA global comparison of multiple omics data revealed 861 sex-related molecules in non-tumour liver tissues between female and male HCC patients, which denoted a significant suppression of cancer-related diseases and functions in female liver than male. A member of cytochrome P450 family, CYP39A1, was one of the top liver-specific candidates with significantly higher levels in female vs male liver. In HCC tumours, CYP39A1 expression was dramatically reduced in over 90% HCC patients. Exogenous CYP39A1 significantly blocked tumour formation in both female and male mice and partially reduced the sex disparity of hepatocarcinogenesis. The HCC suppressor role of CYP39A1 did not rely on its known P450 enzyme activity but its C-terminal region, by which CYP39A1 impeded the transcriptional activation activity of c-Myc, leading to a significant inhibition of hepatocarcinogenesis.ConclusionsThe liver-specific CYP39A1 with female-preferential expression was a strong suppressor of HCC development. Strategies to up-regulate CYP39A1 might be promising methods for HCC treatment in both women and men in future.

The availability of priority medicines for children under 5 years in eThekwini, South Africa

Background Globally, an estimated 8.1 million children under 5 years die annually in developing countries. Ensuring essential medicines are accessible and affordable to the population is key to saving lives. This study investigated accessibility, availability and affordability of a basket of priority medicines for children under 5 years in public and private healthcare sector pharmacies in the eThekwini Metropolitan area in Durban, South Africa. Methods The WHO/HAI survey tool for assessing medicine prices, availability and affordability was adapted and employed for a basket of WHO Priority life-saving medicines for children under 5 years. Six district hospitals in the north, south and central eThekwini Metropolitan were selected as major facility reference points and for data collection and pharmacies within a 5 km radius from each major facility were also invited to participate in the study, as outlined in the WHO/HAI tool methodology. Of the 58 pharmacies selected, a total of 27 pharmacies from both private and public healthcare sectors agreed to participate and were surveyed, representing a 47% response rate. Data was analysed using Microsoft excel. Results All participating pharmacies (and hence the selected basket of priority medicines at these facilities) were deemed accessible. Overall the public sector had more medicines available on the shelf (averaging 64%) than the private sector (48%) which had more medicines available on order (84%). At least one medicine for each of the eight (8) conditions was available at both sectors which meant patients could be treated for these conditions. Medicines for priority conditions (except HIV, which was a 28-day course) were deemed affordable as these regimens were obtainable within a day’s wage for the lowest paid unskilled worker. Priority medicines for children under 5 years were more available and more affordable in the public sector. Conclusion The basket of WHO essential medicines for priority conditions for children under 5 years were accessible, available and affordable in the eThekwini Metropolitan areas. This was the first study in eThekwini to determine access to the WHO basket of priority medicines for children and can be scaled-up to a national study to provide a holistic comparison of these medicines in the country, and also for global comparison.

Inequality, welfare and punishment. Comparative notes between the Global North and South

In this paper, I will describe how two strong connections between, on the one hand, income inequality and welfare generosity, and, on the other, punitiveness, have been built in both theoretical and empirical explorations in the contemporary comparative literature on the sociology of punishment. Then, I will point out the strong concentration of these explorations on national cases from the Global North as a potential limitation. From there, I will try to ‘southernize’ this debate, through three empirical exercises related to a region of the Global South, Latin America. First, I will include this region in a global comparison of clusters of countries to define whether there is an association between the levels of income inequality and welfare generosity and the levels of punitiveness, both now and in the recent past. Second, I will analyse if the same relationships exist within Latin America countries, both now and in the recent past. Finally, I will examine whether these same relationships are relevant for understanding the evolution of the levels of punitiveness in Latin America over the last three decades. Based on the results of these three exercises, I will examine the shortcomings stemming from assuming these strong statements as universal, placeless and timeless, warning that the styles of comparison that have generated them have to be taken as starting points rather than as arrival points of the analysis and stressing that our analyses about contemporary penal differences, while taking macroscopic dimensions into account, should give a strong centrality to the ‘proximate’ processes that mould penal actions and results.

Elevated Post K-Pg Export Productivity in the Gulf of Mexico and Caribbean

The global heterogeneity in export productivity after the Cretaceous-Paleogene (K-Pg) mass extinction is well documented, with some sites showing no change on geologic timescales, some demonstrating sustained decline, and a few showing a somewhat surprising increase. However, these records come from sites so widespread that a key outstanding question is the geographic scale of changes in export productivity, and whether similar environments (open ocean gyres, western boundary currents) responded similarly or whether heterogeneity is unrelated to environment. To address this, we developed three new Ba/Ti export productivity records from sites in the Gulf of Mexico and Caribbean which, combined with published data from a fourth site in the Chicxulub Crater itself, allows us to reconstruct regional changes in post K-Pg export productivity for the first time. We find that, on a regional scale, export productivity change is homogenous, with all four sites showing a ~300 kyr period of elevated export production just after the boundary, followed by a longer period of decline. Interestingly, this interval of elevated export production appears to coincide with the post K-Pg global micrite layer, which is thought to at least partially have been produced by blooms of carbonate-producing cyanobacteria and other picophytoplankton. We note from a global comparison of sites that elevated export productivity appears to be most common in tropical waters, which suggests that changing plankton ecology evidenced by the micrite layer altered the biological pump in a way that encouraged a temporary increase in export production in the tropics.

Intercomparison of CO measurements from TROPOMI, ACE-FTS, and a high-Arctic ground-based Fourier transform spectrometer

The TROPOspheric Monitoring Instrument (TROPOMI) provides a daily, spatially resolved (initially 7×7 km2, upgraded to 7×5.6 km2 in August 2019) global dataset of CO columns; however, due to the relative sparseness of reliable ground-based data sources, it can be challenging to characterize the validity and accuracy of satellite data products in remote regions such as the high Arctic. In these regions, satellite intercomparisons can supplement model- and ground-based validation efforts and serve to verify previously observed differences. In this paper, we compare the CO products from TROPOMI, the Atmospheric Chemistry Experiment (ACE) Fourier transform spectrometer (FTS), and a high-Arctic ground-based FTS located at the Polar Environment Atmospheric Research Laboratory (PEARL) in Eureka, Nunavut (80.05∘ N, 86.42∘ W). A global comparison of TROPOMI reference profiles scaled by the retrieved total column with ACE-FTS CO partial columns for the period from 28 November 2017 to 31 May 2020 displays excellent agreement between the two datasets (R=0.93) and a small relative bias of -0.83±0.26% (bias ± standard error of the mean). Additional comparisons were performed within five latitude bands: the north polar region (60 to 90∘ N), northern mid-latitudes (20 to 60∘ N), the equatorial region (20∘ S to 20∘ N), southern mid-latitudes (60 to 20∘ S), and the south polar region (90 to 60∘ S). Latitudinal comparisons of the TROPOMI and ACE-FTS CO datasets show strong correlations ranging from R=0.93 (southern mid-latitudes) to R=0.86 (equatorial region) between the CO products but display a dependence of the mean differences on latitude. Positive mean biases of 7.93±0.61 % and 7.21±0.52 % were found in the northern and southern polar regions, respectively, while a negative bias of -9.41±0.55% was observed in the equatorial region. To investigate whether these differences are introduced by cloud contamination, which is reflected in the TROPOMI averaging kernel shape, the latitudinal comparisons were repeated for cloud-covered pixels and clear-sky pixels only, as well as for the unsmoothed and smoothed cases. Clear-sky pixels were found to be biased higher with poorer correlations on average than clear+cloudy scenes and cloud-covered scenes only. Furthermore, the latitudinal dependence on the biases was observed in both the smoothed and unsmoothed cases. To provide additional context to the global comparisons of TROPOMI with ACE-FTS in the Arctic, both satellite datasets were compared against measurements from the ground-based PEARL-FTS. Comparisons of TROPOMI with smoothed PEARL-FTS total columns in the period of 3 March 2018 to 27 March 2020 display a strong correlation (R=0.88); however, a positive mean bias of 14.7±0.16 % was also found. A partial column comparison of ACE-FTS with the PEARL-FTS in the period from 25 February 2007 to 18 March 2020 shows good agreement (R=0.79) and a mean positive bias of 7.89±0.21 % in the ACE-FTS product relative to the ground-based FTS. The magnitude and sign of the mean relative differences are consistent across all intercomparisons in this work, as well as with recent ground-based validation efforts, suggesting that the current TROPOMI CO product exhibits a positive bias in the high-Arctic region. However, the observed bias is within the TROPOMI mission accuracy requirement of ±15 %, providing further confirmation that the data quality in these remote high-latitude regions meets this specification.

A Qualitative 5-Country Comparison of the Perceived Impacts of COVID-19 on People Living with Dementia and Unpaid Carers

Background Emerging evidence shows an impact of the COVID-19 pandemic on people living with dementia and informal carers, without any evidence-based global comparison to date. The aim of this international study was to explore and compare the perceived impact of COVID-19 and associated public health restrictions on the lives of people living with dementia and informal carers and access to dementia care across five countries. Methods Informal carers and people living with dementia who were residing in the community in the UK, Australia, Italy, India, and Poland were interviewed remotely between April and December 2020. Participants were asked about their experiences of the pandemic and how restrictions have impacted on their lives and care. Transcripts were analysed by researchers in each country using inductive thematic analysis. Results Fifteen people living with dementia and 111 informal carers participated across the five countries. Four themes emerged: (1) Limited access and support; (2) Technology and issues accessing remote support; (3) Emotional impact; and (4) Decline of cognitive and physical health reported by carers. Whilst variations were noted, the pandemic has indirectly affected people with dementia and carers across all five countries. The pandemic removed access to social support services and thus increased carer burden. Remote services were not always provided and were very limited in benefit and usability for those with dementia. As a result, carers appeared to notice reduced cognitive and physical health in people with dementia. Particular differences were noted between India and Poland vs. the UK, Italy, and Australia, with less impact on care provision in the former due to limited uptake of support services pre-pandemic based on cultural settings. Conclusions The pandemic has amplified dementia as a global public health problem, and people affected by the condition need support to better access vital support services to live well.

The cytosolic iron–sulfur cluster assembly (CIA) pathway is required for replication stress tolerance of cancer cells to Chk1 and ATR inhibitors

The relationship between ATR/Chk1 activity and replication stress, coupled with the development of potent and tolerable inhibitors of this pathway, has led to the clinical exploration of ATR and Chk1 inhibitors (ATRi/Chk1i) as anticancer therapies for single-agent or combinatorial application. The clinical efficacy of these therapies relies on the ability to ascertain which patient populations are most likely to benefit, so there is intense interest in identifying predictive biomarkers of response. To comprehensively evaluate the components that modulate cancer cell sensitivity to replication stress induced by Chk1i, we performed a synthetic-lethal drop-out screen in a cell line derived from a patient with triple-negative breast cancer (TNBC), using a pooled barcoded shRNA library targeting ~350 genes involved in DNA replication, DNA damage repair, and cycle progression. In addition, we sought to compare the relative requirement of these genes when DNA fidelity is challenged by clinically relevant anticancer breast cancer drugs, including cisplatin and PARP1/2 inhibitors, that have different mechanisms of action. This global comparison is critical for understanding not only which agents should be used together for combinatorial therapies in breast cancer patients, but also the genetic context in which these therapies will be most effective, and when a single-agent therapy will be sufficient to provide maximum therapeutic benefit to the patient. We identified unique potentiators of response to ATRi/Chk1i and describe a new role for components of the cytosolic iron–sulfur assembly (CIA) pathway, MMS19 and CIA2B-FAM96B, in replication stress tolerance of TNBC.

The role of process mining tools in STEMI networks: where should we build a new primary PCI centre?

Background In ST-segment elevation myocardial infarction (STEMI), time delay between symptom onset and treatment is critical to improve outcome. The expected transport delay between patient location and percutaneous coronary intervention (PCI) centre is paramount for choosing the adequate reperfusion therapy. The “Centre” region of Portugal has heterogeneity in PCI assess due to geographical reasons. Purpose We aimed to explore time delays between regions using process mining (PM) tools. Methods We retrospectively assessed the Portuguese Registry of Acute Coronary Syndromes for patients with STEMI from October 2010 to September 2019, collecting information on geographical area of symptom onset, reperfusion option, and in-hospital mortality. We used a PM toolkit (PM4H – PMApp Version) to build two models (one national and one regional) that represent the flow of patients in a healthcare system, enhancing time differences between groups. One-way analysis of variance was employed for the global comparison of study variables between groups and post hoc analysis with Bonferroni correction was used for multiple comparisons. Results Overall, 8956 patients (75% male, 48% from 51 to 70 years) were included in the national model (Fig. 1A), in which primary PCI was the treatment of choice (73%), with the median time between admission and primary PCI <120 minutes in every region; “Lisboa” and “Centro” had the longest delays, (orange arrows). Fibrinolysis was performed in 4.5%, with a median time delay <1 hour in every region. In-hospital mortality was 5%, significantly higher for those without reperfusion therapy compared to PCI and fibrinolysis (10% vs. 4% vs. 4%, P<0.001). In the regional model (Fig. 1B) corresponding to the “Centre” region of Portugal divided by districts (n=773, 74% male, 47% from 51 to 70 years), only 61% had primary PCI, with “Guarda” (05:04) and “Castelo Branco” (06:50) showing significant longer delays between diagnosis and reperfusion treatment (orange and red arrows, respectively) than “Coimbra” (01:19) (green arrow); only 15% of patients from “Castelo Branco” had primary PCI. Fibrinolysis was chosen in 10% of patients, mostly in “Castelo Branco” (53%), followed by “Guarda” (30%), with a median time delay of 39 and 48 minutes, respectively. Regarding mortality, PCI and fibrinolysis groups had similar death rates while those patients without reperfusion had higher mortality (5% vs. 3% vs. 13%, P=0.001). Conclusion Process mining tools help to understand referencing networks visually, easily highlighting inefficiencies and potential needs for improvement. The “Centre” region of Portugal has lower rates and longer delay to primary PCI partially due to the geographical reasons, with worse outcomes in remote regions. The implementation of a new PCI centre in one of these districts, is critical to offer timely first-line treatment to their population. Funding Acknowledgement Type of funding sources: None. Figure 1

Pluripotent stem cells related to embryonic disc exhibit common self-renewal requirements in diverse livestock species

ABSTRACT Despite four decades of effort, robust propagation of pluripotent stem cells from livestock animals remains challenging. The requirements for self-renewal are unclear and the relationship of cultured stem cells to pluripotent cells resident in the embryo uncertain. Here, we avoided using feeder cells or serum factors to provide a defined culture microenvironment. We show that the combination of activin A, fibroblast growth factor and the Wnt inhibitor XAV939 (AFX) supports establishment and continuous expansion of pluripotent stem cell lines from porcine, ovine and bovine embryos. Germ layer differentiation was evident in teratomas and readily induced in vitro. Global transcriptome analyses highlighted commonality in transcription factor expression across the three species, while global comparison with porcine embryo stages showed proximity to bilaminar disc epiblast. Clonal genetic manipulation and gene targeting were exemplified in porcine stem cells. We further demonstrated that genetically modified AFX stem cells gave rise to cloned porcine foetuses by nuclear transfer. In summary, for major livestock mammals, pluripotent stem cells related to the formative embryonic disc are reliably established using a common and defined signalling environment. This article has an associated ‘The people behind the papers’ interview.