Human liver cancer research currently lacks in vitro models that can faithfully recapitulate the pathophysiology of the original tumor. We recently described a novel, near-physiological organoid ...culture system, wherein primary human healthy liver cells form long-term expanding organoids that retain liver tissue function and genetic stability. Here we extend this culture system to the propagation of primary liver cancer (PLC) organoids from three of the most common PLC subtypes: hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and combined HCC/CC (CHC) tumors. PLC-derived organoid cultures preserve the histological architecture, gene expression and genomic landscape of the original tumor, allowing for discrimination between different tumor tissues and subtypes, even after long-term expansion in culture in the same medium conditions. Xenograft studies demonstrate that the tumorogenic potential, histological features and metastatic properties of PLC-derived organoids are preserved in vivo. PLC-derived organoids are amenable for biomarker identification and drug-screening testing and led to the identification of the ERK inhibitor SCH772984 as a potential therapeutic agent for primary liver cancer. We thus demonstrate the wide-ranging biomedical utilities of PLC-derived organoid models in furthering the understanding of liver cancer biology and in developing personalized-medicine approaches for the disease.
Native biodiversity decline and non-native species spread are major features of the Anthropocene. Both processes can drive biotic homogenization by reducing trait and phylogenetic differences in ...species assemblages between regions, thus diminishing the regional distinctiveness of biotas and likely have negative impacts on key ecosystem functions. However, a global assessment of this phenomenon is lacking. Here, using a dataset of >200,000 plant species, we demonstrate widespread and temporal decreases in species and phylogenetic turnover across grain sizes and spatial extents. The extent of homogenization within major biomes is pronounced and is overwhelmingly explained by non-native species naturalizations. Asia and North America are major sources of non-native species; however, the species they export tend to be phylogenetically close to recipient floras. Australia, the Pacific and Europe, in contrast, contribute fewer species to the global pool of non-natives, but represent a disproportionate amount of phylogenetic diversity. The timeline of most naturalisations coincides with widespread human migration within the last ~500 years, and demonstrates the profound influence humans exert on regional biotas beyond changes in species richness.
Somatic mutations have been extensively characterized in breast cancer, but the effects of these genetic alterations on the proteomic landscape remain poorly understood. Here we describe quantitative ...mass-spectrometry-based proteomic and phosphoproteomic analyses of 105 genomically annotated breast cancers, of which 77 provided high-quality data. Integrated analyses provided insights into the somatic cancer genome including the consequences of chromosomal loss, such as the 5q deletion characteristic of basal-like breast cancer. Interrogation of the 5q trans-effects against the Library of Integrated Network-based Cellular Signatures, connected loss of CETN3 and SKP1 to elevated expression of epidermal growth factor receptor (EGFR), and SKP1 loss also to increased SRC tyrosine kinase. Global proteomic data confirmed a stromal-enriched group of proteins in addition to basal and luminal clusters, and pathway analysis of the phosphoproteome identified a G-protein-coupled receptor cluster that was not readily identified at the mRNA level. In addition to ERBB2, other amplicon-associated highly phosphorylated kinases were identified, including CDK12, PAK1, PTK2, RIPK2 and TLK2. We demonstrate that proteogenomic analysis of breast cancer elucidates the functional consequences of somatic mutations, narrows candidate nominations for driver genes within large deletions and amplified regions, and identifies therapeutic targets.
Environmental and endocrine factors have been implicated in the aetiology of recurrent abortion, with poorly understood roles. Luteal phase insufficiency marked with insufficient progesterone ...secretion has been reported.
To define the involvement of progesterone, trace metals, and Vitamin E in pregnant women with history of recurrent spontaneous abortion.
Convenience sampling method was used to recruit 69 pregnant women aged 21-41 years with gestational age of 0-20 weeks in this case-control study. Thirty five (cases) and thirty four (controls) had previous and no history of recurrent spontaneous abortion respectively. Demographic characteristics and 10 mls of blood samples were obtained from each subject. Serum obtained was used for the determination of progesterone, zinc, copper, selenium, iron, magnesium, manganese, chromium, lead, cadmium, and serum vitamin E by standard methods.
Results showed statistically significant decreases (p<0.05) in the serum zinc, copper, and vitamin E and a significant elevation (p<0.05) in the serum selenium, lead, and cadmium in cases compared with controls. Insignificant decrease (p=0.07) was observed in the serum progesterone when cases were compared with controls.
Results suggest that elevated serum heavy metals (cadmium and lead) and reduction of essential micronutrients (zinc, copper and vitamin E) may contribute to recurrent spontaneous abortion.
Summary Background Bullous pemphigoid is a blistering skin disorder with increased mortality. We tested whether a strategy of starting treatment with doxycycline gives acceptable short-term blister ...control while conferring long-term safety advantages over starting treatment with oral corticosteroids. Methods We did a pragmatic, multicentre, parallel-group randomised controlled trial of adults with bullous pemphigoid (three or more blisters at two or more sites and linear basement membrane IgG or C3). Participants were randomly assigned to doxycycline (200 mg per day) or prednisolone (0·5 mg/kg per day) using random permuted blocks of randomly varying size, and stratified by baseline severity (3–9, 10–30, and >30 blisters for mild, moderate, and severe disease, respectively). Localised adjuvant potent topical corticosteroids (<30 g per week) were permitted during weeks 1–3. The non-inferiority primary effectiveness outcome was the proportion of participants with three or fewer blisters at 6 weeks. We assumed that doxycycline would be 25% less effective than corticosteroids with a 37% acceptable margin of non-inferiority. The primary safety outcome was the proportion with severe, life-threatening, or fatal (grade 3–5) treatment-related adverse events by 52 weeks. Analysis (modified intention to treat mITT for the superiority safety analysis and mITT and per protocol for non-inferiority effectiveness analysis) used a regression model adjusting for baseline disease severity, age, and Karnofsky score, with missing data imputed. The trial is registered at ISRCTN, number ISRCTN13704604. Findings Between March 1, 2009, and Oct 31, 2013, 132 patients were randomly assigned to doxycycline and 121 to prednisolone from 54 UK and seven German dermatology centres. Mean age was 77·7 years (SD 9·7) and 173 (68%) of 253 patients had moderate-to-severe baseline disease. For those starting doxycycline, 83 (74%) of 112 patients had three or fewer blisters at 6 weeks compared with 92 (91%) of 101 patients on prednisolone, an adjusted difference of 18·6% (90% CI 11·1–26·1) favouring prednisolone (upper limit of 90% CI, 26·1%, within the predefined 37% margin). Related severe, life-threatening, and fatal events at 52 weeks were 18% (22 of 121) for those starting doxycycline and 36% (41 of 113) for prednisolone (mITT), an adjusted difference of 19·0% (95% CI 7·9–30·1), p=0·001. Interpretation Starting patients on doxycycline is non-inferior to standard treatment with oral prednisolone for short-term blister control in bullous pemphigoid and significantly safer in the long-term. Funding NIHR Health Technology Assessment Programme.
Summary Recent years have seen substantial improvements in life expectancy and access to antimicrobials, especially in low-income and lower-middle-income countries, but increasing pathogen resistance ...to antimicrobials threatens to roll back this progress. Resistant organisms in health-care and community settings pose a threat to survival rates from serious infections, including neonatal sepsis and health-care-associated infections, and limit the potential health benefits from surgeries, transplants, and cancer treatment. The challenge of simultaneously expanding appropriate access to antimicrobials, while restricting inappropriate access, particularly to expensive, newer generation antimicrobials, is unique in global health and requires new approaches to financing and delivering health care and a one-health perspective on the connections between pathogen transmission in animals and humans. Here, we describe the importance of effective antimicrobials. We assess the disease burden caused by limited access to antimicrobials, attributable to resistance to antimicrobials, and the potential effect of vaccines in restricting the need for antibiotics.
Cadmium (Cd) is currently of great concern in rapidly industrializing countries-India, China. Their products consumed especially due to increase demand in many developing countries like Nigeria can ...result in adverse effects. Cd is a ubiquitous environmental pollutant and toxicant and humans are continually exposed to the toxic effects of Cd primarily through food as well as from environmental pollution through industrial activities. Maternal exposure to Cd has been associated with the delivery of low-birth weight babies and an increase incidence of spontaneous abortion. Cd a toxic metal can displace zinc (Zn) an essential element necessary for normal fetal development and growth. With this consideration, 160 subjects comprising of 125 pregnant and 35 non-pregnant subjects as controls were recruited for this study. The pregnant subjects were classified according to the three trimesters of pregnancy as followed; 35, 35, and 55 from the first to the third trimesters respectively. The third trimester subjects were followed-up until after delivery where neonatal parameters (birth weight, head circumference, and length) of babies were measured. 32 (58%) of the women delivered babies with normal birth weight, 19 women (35%) delivered babies with low-birth weight while four women (7%) delivered babies with high- birth weight. Subject who delivered low-birth weight babies had significantly higher Cd concentration and lower Zn concentration and body mass index when compared with those with normal weight babies. These results suggest that Cd indeed has some toxic effects on neonatal birth weight.
Galactic archaeology based on star counts is instrumental to reconstruct the past mass assembly of Local Group galaxies. The development of new observing techniques and data reduction, coupled with ...the use of sensitive large field of view cameras, now allows us to pursue this technique in more distant galaxies exploiting their diffuse low surface brightness (LSB) light. As part of the ATLAS3D project, we have obtained with the MegaCam camera at the Canada–France–Hawaii Telescope extremely deep, multiband images of nearby early-type galaxies (ETGs). We present here a catalogue of 92 galaxies from the ATLAS3D sample, which are located in low- to medium-density environments. The observing strategy and data reduction pipeline, which achieve a gain of several magnitudes in the limiting surface brightness with respect to classical imaging surveys, are presented. The size and depth of the survey are compared to other recent deep imaging projects. The paper highlights the capability of LSB-optimized surveys at detecting new prominent structures that change the apparent morphology of galaxies. The intrinsic limitations of deep imaging observations are also discussed, among those, the contamination of the stellar haloes of galaxies by extended ghost reflections, and the cirrus emission from Galactic dust. The detection and systematic census of fine structures that trace the present and past mass assembly of ETGs are one of the prime goals of the project. We provide specific examples of each type of observed structures – tidal tails, stellar streams and shells – and explain how they were identified and classified. We give an overview of the initial results. The detailed statistical analysis will be presented in future papers.
INTRODUCTION: Many studies on female breast cancer patients do not consider the differences between the follicular and luteal phases when collecting blood samples for laboratory investigations. ...Therefore, this study was designed to investigate the effects of the phases of the menstrual cycle on reproductive and thyroid hormones, endocrine disruptors, blood pressure, and body adiposity. METHODS: Participants (n=107) aged 28-50 years, comprising 54 newly diagnosed breast cancer patients (cases were menstrual phase and age-matched to 53 seemingly healthy women without breast cancer that served as controls. Anthropometric indices and blood pressure (BP) were obtained. Serum hormones-estradiol, progesterone, luteinizing hormone (LH), free triiodothyronine (FT3), thyroid-stimulating hormone (TSH), stimulating follicle hormone (FSH), and free thyroxine (FT4) were quantified by enzyme immunoassay. Endocrine disruptors (EDs)- arsenic, lead and cadmium were quantified by atomic absorption spectrophotometry (AAS). Data were analyzed using Student’s t-test and Pearson correlation coefficient with p<0.05 considered significant. RESULTS: Bodyweight, hip circumference, waist-height ratio, and FT3 varied between the luteal and follicular phases, higher in cases than controls. EDs were significantly higher in cases than controls in both phases. Progesterone, estradiol and LH levels were significantly higher in luteal cases and controls when compared with follicular cases and controls.FT3 was significantly lower in luteal controls compared with follicular controls. There were significant direct and inverse correlations among adiposity measures, BP, EDs, and hormones in each phase in both cases and controls. CONCLUSION: The menstrual cycle appears to influence blood pressure, measures of adiposity, endocrine disruptors, and reproductive hormones in women with normal and cancerous breasts. This requires consideration in the collection of blood samples for investigations of these parameters.
PDF
