Dissecting Tumor Growth: The Role of Cancer Stem Cells in Drug Resistance and Recurrence

Emerging evidence suggests that a small subpopulation of cancer stem cells (CSCs) is responsible for initiation, progression, and metastasis cascade in tumors. CSCs share characteristics with normal stem cells, i.e., self-renewal and differentiation potential, suggesting that they can drive cancer progression. Consequently, targeting CSCs to prevent tumor growth or regrowth might offer a chance to lead the fight against cancer. CSCs create their niche, a specific area within tissue with a unique microenvironment that sustains their vital functions. Interactions between CSCs and their niches play a critical role in regulating CSCs’ self-renewal and tumorigenesis. Differences observed in the frequency of CSCs, due to the phenotypic plasticity of many cancer cells, remain a challenge in cancer therapeutics, since CSCs can modulate their transcriptional activities into a more stem-like state to protect themselves from destruction. This plasticity represents an essential step for future therapeutic approaches. Regarding self-renewal, CSCs are modulated by the same molecular pathways found in normal stem cells, such as Wnt/β-catenin signaling, Notch signaling, and Hedgehog signaling. Another key characteristic of CSCs is their resistance to standard chemotherapy and radiotherapy treatments, due to their capacity to rest in a quiescent state. This review will analyze the primary mechanisms involved in CSC tumorigenesis, with particular attention to the roles of CSCs in tumor progression in benign and malignant diseases; and will examine future perspectives on the identification of new markers to better control tumorigenesis, as well as dissecting the metastasis process

Foods for a Mission to Mars: Equivalent System Mass and Development of a Multipurpose Small-Scale Seed Processor

The candidate crops for planetary food systems include: wheat, white and sweet potatoes, soybean, peanut, strawberry, dry bean including le ntil and pinto, radish, rice, lettuce, carrot, green onion, tomato, p eppers, spinach, and cabbage. Crops such as wheat, potatoes, soybean, peanut, dry bean, and rice can only be utilized after processing, while others are classified as ready-to-eat. To process foods in space, the food processing subsystem must be capable of producing a variety of nutritious, acceptable, and safe edible ingredients and food produ cts from pre-packaged and resupply foods as well as salad crops grown on the transit vehicle or other crops grown on planetary surfaces. D esigning, building, developing, and maintaining such a subsystem is b ound to many constraints and restrictions. The limited power supply, storage locations, variety of crops, crew time, need to minimize waste , and other equivalent system mass (ESM) parameters must be considere d in the selection of processing equipment and techniques

The landscape of molecular chaperones across human tissues reveals a layered architecture of core and variable chaperones

The sensitivity of the protein-folding environment to chaperone disruption can be highly tissue-specific. Yet, the organization of the chaperone system across physiological human tissues has received little attention. Through computational analyses of large-scale tissue transcriptomes, we unveil that the chaperone system is composed of core elements that are uniformly expressed across tissues, and variable elements that are differentially expressed to fit with tissue-specific requirements. We demonstrate via a proteomic analysis that the muscle-specific signature is functional and conserved. Core chaperones are significantly more abundant across tissues and more important for cell survival than variable chaperones. Together with variable chaperones, they form tissue-specific functional networks. Analysis of human organ development and aging brain transcriptomes reveals that these functional networks are established in development and decline with age. In this work, we expand the known functional organization of de novo versus stress-inducible eukaryotic chaperones into a layered core-variable architecture in multi-cellular organisms

Survival benefit and additional value of preoperative chemoradiotherapy in resectable gastric and gastro-oesophageal junction cancer: a direct and adjusted indirect comparison meta-analysis

Several phase I/II studies of chemoradiotherapy for gastric cancer have reported promising results, but the significance of preoperative radiotherapy in addition to chemotherapy has not been proven. In this study, a systematic literature search was performed to capture survival and postoperative morbidity and mortality data in randomised clinical studies comparing preoperative (chemo)radiotherapy or chemotherapy versus surgery alone, or preoperative chemoradiotherapy versus chemotherapy for gastric and/or gastro-oesophageal junction (GOJ) cancer. Hazard ratios (HRs) for overall mortality were extracted from the original studies, individual patient data provided from the principal investigators of eligible studies or the earlier published meta-analysis. The incidences of postoperative morbidities and mortalities were also analysed. In total 18 studies were eligible and data were available from 14 of these. The meta-analysis on overall survival yielded HRs of 0.75 (95% CI 0.65–0.86, P < 0.001) for preoperative (chemo)radiotherapy and 0.83 (95% CI 0.67–1.01, P = 0.065) for preoperative chemotherapy when compared to surgery alone. Direct comparison between preoperative chemoradiotherapy and chemotherapy resulted in an HR of 0.71 (95% CI 0.45–1.12, P = 0.146). Combination of direct and adjusted indirect comparisons yielded an HR of 0.86 (95% CI 0.69–1.07, P = 0.171). No statistically significant differences were seen in the risk for postoperative morbidity or mortality between preoperative treatments and surgery alone, or preoperative (chemo)radiotherapy and chemotherapy. Preoperative (chemo)radiotherapy for gastric and GOJ cancer showed significant survival benefit over surgery alone. In comparisons between preoperative chemotherapy and (chemo)radiotherapy, there is a trend towards improved survival when adding radiotherapy, without increased postoperative morbidity or mortality

HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype.

Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P &lt; 5.0 × 10-8). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein-deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification

Social work and the penal state

The Criminal Justice System (CJS) has historically been a key site of social work intervention. Wacquant (2008, 2009a and 2009b) argues that the growth of social insecurity and the expansion of the penal state are endogenous features of the neo-liberal political project. The key premises of neo-liberalism have been accepted by parties of both the left and the right. Wacquant identifies that the “doxa” of the penal state such as “prison works” “zero tolerance” and “broken windows” have been widely accepted in an uncritical fashion. This shift alongside an increase in inequality had led to increasing social anxiety and mistrust. One manifestation of these trends is the “decline of the rehabilitative ideal” (Garland, 2001). Offenders, who were once generally viewed as marginalised individuals in need of social and welfare support are now regarded as sites of risk. The USA has led a penal arms race, in which, the use of imprisonment has grown significantly. In Europe, England and Wales has followed this trend most closely. Whilst acknowledging that penal policy is the result of a complex inter-relationship between social, cultural and historical factors, there are lessons to be learnt from the US experience. These include the impact of race and class inequalities as manifest in the CJS. The act of imprisonment is arguably an act of state violence and alongside the impact on individuals, communities and families, it has huge symbolic significance and value. The expansion of the penal state: the increasing numbers, poor conditions and the over-representation of minority groups mean that it should be a core social work concern. The paper outlines the ways, in which, risk and managerialism have sidelined core social work values in the CJS. It concludes that developments in the USA, particularly the decision in Brown v. Plata highlight a way out of the current impasse. Penal policy and conditions can only be reformed if the inherent dignity of offenders is rediscovered and placed at its centre

Local Treatment of Unresectable Colorectal Liver Metastases: Results of a Randomized Phase II Trial

BACKGROUND: Tumor ablation is often employed for unresectable colorectal liver metastases. However, no survival benefit has ever been demonstrated in prospective randomized studies. Here, we investigate the long-term benefits of such an aggressive approach. METHODS: In this randomized phase II trial, 119 patients with unresectable colorectal liver metastases (n  38%) was met. We now report on long-term OS results. All statistical tests were two-sided. The analyses were according to intention to treat. RESULTS: At a median follow up of 9.7 years, 92 of 119 (77.3%) patients had died: 39 of 60 (65.0%) in the combined modality arm and 53 of 59 (89.8%) in the systemic treatment arm. Almost all patients died of progressive disease (35 patients in the combined modality arm, 49 patients in the systemic treatment arm). There was a statistically significant difference in OS in favor of the combined modality arm (hazard ratio [HR] = 0.58, 95% confidence interval [CI] = 0.38 to 0.88, P = .01). Three-, five-, and eight-year OS were 56.9% (95% CI = 43.3% to 68.5%), 43.1% (95% CI = 30.3% to 55.3%), 35.9% (95% CI = 23.8% to 48.2%), respectively, in the combined modality arm and 55.2% (95% CI = 41.6% to 66.9%), 30.3% (95% CI = 19.0% to 42.4%), 8.9% (95% CI = 3.3% to 18.1%), respectively, in the systemic treatment arm. Median OS was 45.6 months (95% CI = 30.3 to 67.8 months) in the combined modality arm vs 40.5 months (95% CI = 27.5 to 47.7 months) in the systemic treatment arm. CONCLUSIONS: This phase II trial is the first randomized study demonstrating that aggressive local treatment can prolong OS in patients with unresectable colorectal liver metastases

Is the Presence of Microalbuminuria a Relevant Marker of Kidney Disease?

Levels of urinary albumin excretion that are below the usual limit of detection by qualitative testing, but are above normal levels (microalbuminuria; MA), can be readily identified by simple measures, such as the urinary albumin to creatinine ratio in untimed urine samples. Such measurements, particularly when combined with assessment of estimated glomerular filtration rate (eGFR), have utility as biomarkers for enhanced risk of all-cause mortality, cardiovascular events, progressive chronic kidney disease, and end-stage renal disease in diabetic and nondiabetic subjects. However, it is controversial whether “isolated” MA (MA in the absence of a clear reduction in eGFR, urine sediment abnormalities, or structural renal disease) should be regarded as kidney disease. Such MA could also be regarded as a manifestation of a diffuse endothelial (microvascular) injury and thereby collateral kidney damage. This article reviews the current evidence concerning MA as a marker of kidney disease or kidney damage

Pharmacokinetic analysis of two different docetaxel dose levels in patients with non-small cell lung cancer treated with docetaxel as monotherapy or with concurrent radiotherapy

<p>Abstract</p> <p>Background</p> <p>Previous pharmacokinetic studies with docetaxel have mostly used 3-weekly (75 mg/m²and 100 mg/m²) or weekly regimens (35–40 mg/m²). The pharmacokinetics and radiosensitizing efficacy of weekly 20 mg/m²docetaxel, has however not been well characterized. We examined the pharmacokinetics of weekly docetaxel when administered with concurrent radiotherapy and compared the results with a 3-weekly 100 mg/m²regimen.</p> <p>Methods</p> <p>Thirty-four patients with non small cell lung cancer (NSCLC) were included in this study, 19 receiving 100 mg/m²docetaxel 3-weekly as single therapy, and 15 receiving 20 mg/m²docetaxel weekly with concurrent radiotherapy. A newly developed HPLC method was used for measuring docetaxel levels, capable of quantifying docetaxel in plasma down to the nanomolar level.</p> <p>Results</p> <p>The HPLC method showed detectable concentrations of docetaxel in plasma even after 72 hours. In the present study we have demonstrated that median docetaxel plasma levels of 3 nM can be obtained 72 hours after a dose of 20 mg/m².</p> <p>Conclusion</p> <p>The pharmacokinetics of docetaxel is characterized by great inter-individual variability and at some time points plasma concentrations for 20 mg/m²and 100 mg/m²docetaxel were overlapping. Extrapolation of these results indicates that radio sensitizing docetaxel concentrations may be present for as long as 1 week, thus supporting the use of 20 mg/m²weekly docetaxel.</p