Quality of life in lung cancer patients: does socioeconomic status matter?

BACKGROUND: As part of a prospective study on quality of life in newly diagnosed lung cancer patients an investigation was carried out to examine whether there were differences among patients' quality of life scores and their socioeconomic status. METHODS: Quality of life was measured at two points in time (baseline and three months after initial treatment) using three standard instruments; the Nottingham Health Profile (NHP), the European Organization for Research and Cancer Treatment Quality of Life Questionnaire (EORTC QLQ-C30) and its lung cancer supplement (QLQ-LC13). Socioeconomic status for each individual patient was derived using Carstairs and Morris Deprivation Category ranging from 1 (least deprived) to 7 (most deprived) on the basis of the postcode sector of their address. RESULTS: In all, 129 lung cancer patients entered into the study. Of these data for 82 patients were complete (at baseline and follow-up). 57% of patients were of lower socioeconomic status and they had more health problems, less functioning, and more symptoms as compared to affluent patients. Of these, physical mobility (P = 0.05), energy (P = 0.01), role functioning (P = 0.04), physical functioning (P = 0.03), and breathlessness (P = 0.02) were significant at baseline. However, at follow-up assessment there was no significant difference between patient groups nor did any consistent pattern emerge. CONCLUSION: At baseline assessment patients of lower socioeconomic status showed lower health related quality of life. Since there was no clear trend at follow-up assessment this suggests that patients from different socioeconomic status responded to treatment similarly. In general, the findings suggest that quality of life is not only the outcome of the disease and its treatment, but is also highly dependent on each patients' socioeconomic characteristics

Exploring the Law of Detrital Zircon: LA-ICP-MS and CA-TIMS Geochronology of Jurassic Forearc Strata, Cook Inlet, Alaska, USA

Uranium-lead (U-Pb) geochronology studies commonly employ the law of detrital zircon: A sedimentary rock cannot be older than its youngest zircon. This premise permits maximum depositional ages (MDAs) to be applied in chronostratigraphy, but geochronologic dates are complicated by uncertainty. We conducted laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) and chemical abrasion-thermal ionization mass spectrometry (CA-TIMS) of detrital zircon in forearc strata of southern Alaska (USA) to assess the accuracy of several MDA approaches. Six samples from Middle–Upper Jurassic units are generally replete with youthful zircon and underwent three rounds of analysis: (1) LA-ICP-MS of ∼115 grains, with one date per zircon; (2) LA-ICP-MS of the ∼15 youngest grains identified in round 1, acquiring two additional dates per zircon; and (3) CA-TIMS of the ∼5 youngest grains identified by LA-ICP-MS. The youngest single-grain LA-ICP-MS dates are all younger than—and rarely overlap at 2σ uncertainty with—the CA-TIMS MDAs. The youngest kernel density estimation modes are typically several million years older than the CA-TIMS MDAs. Weighted means of round 1 dates that define the youngest statistical populations yield the best coincidence with CA-TIMS MDAs. CA-TIMS dating of the youngest zircon identified by LA-ICP-MS is indispensable for critical MDA applications, eliminating laser-induced matrix effects, mitigating and evaluating Pb loss, and resolving complexities of interpreting lower-precision, normally distributed LA-ICP-MS dates. Finally, numerous CA-TIMS MDAs in this study are younger than Bathonian(?)–Callovian and Oxfordian faunal correlations suggest, highlighting the need for additional radioisotopic constraints—including CA-TIMS MDAs—for the Middle–Late Jurassic geologic time scale

Identification and Validation Model for Informative Liquid Biopsy-Based microRNA Biomarkers:Insights from Germ Cell Tumor In Vitro, In Vivo and Patient-Derived Data

Liquid biopsy-based biomarkers, such as microRNAs, represent valuable tools for patient management, but often do not make it to integration in the clinic. We aim to explore issues impeding this transition, in the setting of germ cell tumors, for which novel biomarkers are needed. We describe a model for identifying and validating clinically relevant microRNAs for germ cell tumor patients, using both in vitro, in vivo (mouse model) and patient-derived data. Initial wide screening of candidate microRNAs is performed, followed by targeted profiling of potentially relevant biomarkers. We demonstrate the relevance of appropriate (negative) controls, experimental conditions (proliferation), and issues related to sample origin (serum, plasma, cerebral spinal fluid) and pre-analytical variables (hemolysis, contaminants, temperature), all of which could interfere with liquid biopsy-based studies and their conclusions. Finally, we show the value of our identification model in a specific scenario, contradicting the presumed role of miR-375 as marker of teratoma histology in liquid biopsy setting. Our findings indicate other putative microRNAs (miR-885-5p, miR-448 and miR-197-3p) fulfilling this clinical need. The identification model is informative to identify the best candidate microRNAs to pursue in a clinical setting

Does knowledge of cancer diagnosis affect quality of life? A methodological challenge

BACKGROUND: As part of an assessment of quality of life in lung cancer patients an investigation was carried out to examine whether the knowledge of their diagnosis affected their quality of life. METHODS: Every patient in a defined geographical area with a potential diagnosis of lung cancer was interviewed at first consultation and after a definitive treatment has been given. Quality of life was assessed using three standard measures: the Nottingham Health Profile (NHP), the EORTC quality of life questionnaire (QLQ-C30) and its lung cancer supplementary questionnaire (QLQ-LC13). Comparison was made in quality of life scores between patients who knew their cancer diagnosis and those who did not. RESULTS: In all, 129 lung cancer patients were interviewed. Of these, 30 patients (23%) knew and 99 (78%) did not know their cancer diagnosis at the time of baseline assessment. The patient groups were similar in their characteristics except for age (P = 0.04) and cell type (P < 0.0001). Overall, there were no significant differences between these two groups with regard to their scores on the three instruments used. A major finding was that both group scored almost the same on emotional reactions (P = 0.8) and social isolation (P = 1.0) as measured by the NHP, and emotional (P = 0.7) and social functioning (P = 1.0) as measured by the EORTC QLQ-C30. In addition there were no significant differences in patients' symptom scores between those who knew their diagnosis and those who did not, nor did any consistent pattern emerge. The only significant difference was for sleep difficulties (P = 0.02). CONCLUSION: The findings suggest that the knowledge of cancer diagnosis does not affect the way in which patients respond to quality of life questionnaires

Low intrinsic efficacy for G protein activation can explain the improved side-effect profile of new opioid agonists

Biased agonism at G protein–coupled receptors describes the phenomenon whereby some drugs can activate some downstream signaling activities to the relative exclusion of others. Descriptions of biased agonism focusing on the differential engagement of G proteins versus β-arrestins are commonly limited by the small response windows obtained in pathways that are not amplified or are less effectively coupled to receptor engagement, such as β-arrestin recruitment. At the μ-opioid receptor (MOR), G protein–biased ligands have been proposed to induce less constipation and respiratory depressant side effects than opioids commonly used to treat pain. However, it is unclear whether these improved safety profiles are due to a reduction in β-arrestin–mediated signaling or, alternatively, to their low intrinsic efficacy in all signaling pathways. Here, we systematically evaluated the most recent and promising MOR-biased ligands and assessed their pharmacological profile against existing opioid analgesics in assays not confounded by limited signal windows. We found that oliceridine, PZM21, and SR-17018 had low intrinsic efficacy. We also demonstrated a strong correlation between measures of efficacy for receptor activation, G protein coupling, and β-arrestin recruitment for all tested ligands. By measuring the antinociceptive and respiratory depressant effects of these ligands, we showed that the low intrinsic efficacy of opioid ligands can explain an improved side effect profile. Our results suggest a possible alternative mechanism underlying the improved therapeutic windows described for new opioid ligands, which should be taken into account for future descriptions of ligand action at this important therapeutic target

Measuring the capability to raise revenue process and output dimensions and their application to the Zambia revenue authority

The worldwide diffusion of the good governance agenda and new public management has triggered a renewed focus on state capability and, more specifically, on the capability to raise revenue in developing countries. However, the analytical tools for a comprehensive understanding of the capability to raise revenue remain underdeveloped. This article aims at filling this gap and presents a model consisting of the three process dimensions ‘information collection and processing’, ‘merit orientation’ and ‘administrative accountability’. ‘Revenue performance’ constitutes the fourth capability dimension which assesses tax administration’s output. This model is applied to the case of the Zambia Revenue Authority. The dimensions prove to be valuable not only for assessing the how much but also the how of collecting taxes. They can be a useful tool for future comparative analyses of tax administrations’ capabilities in developing countries.Die weltweite Verbreitung der Good-Governance- und New-Public-Management-Konzepte hat zu einer zunehmenden Konzentration auf staatliche Leistungsfähigkeit und, im Besonderen, auf die Leistungsfähigkeit der Steuererhebung in Entwicklungsländern geführt. Allerdings bleiben die analytischen Werkzeuge für ein umfassendes Verständnis von Leistungsfähigkeit unterentwickelt. Dieser Artikel stellt hierfür ein Modell vor, das die drei Prozess-Dimensionen „Sammeln und Verarbeiten von Informationen“, „Leistungsorientierung der Mitarbeiter“ und „Verantwortlichkeit der Verwaltung“ beinhaltet. „Einnahmeperformanz“ ist die vierte Dimension und erfasst den Output der Steuerverwaltung. Das mehrdimensionale Modell wird für die Analyse der Leistungsfähigkeit der Steuerbehörde Zambias (Zambia Revenue Authority) genutzt. Es erweist sich nicht nur für die Untersuchung des Wieviel, sondern auch des Wie des Erhebens von Steuern als wertvoll. Die vier Dimensionen können in Zukunft zur umfassenden und vergleichenden Analyse der Leistungsfähigkeit verschiedener Steuerverwaltungen in Entwicklungsländern genutzt werden

A tetrapeptide class of biased analgesics from an Australian fungus targets the μ-opioid receptor

An Australian estuarine isolate ofPenicilliumsp. MST-MF667 yielded3 tetrapeptides named the bilaids with an unusual alternating LDLDchirality. Given their resemblance to known short peptide opioidagonists, we elucidated that they were weak (Kilow micromolar)μ-opioid agonists, which led to the design of bilorphin, a potent andselectiveμ-opioid receptor (MOPr) agonist (Ki1.1 nM). In sharp con-trast to all-natural product opioid peptides that efficaciously recruitβ-arrestin, bilorphin is G protein biased, weakly phosphorylatingthe MOPr and marginally recruitingβ-arrestin, with no receptorinternalization. Importantly, bilorphin exhibits a similar G proteinbias to oliceridine, a small nonpeptide with improved overdosesafety. Molecular dynamics simulations of bilorphin and thestrongly arrestin-biased endomorphin-2 with the MOPr indicatedistinct receptor interactions and receptor conformations thatcould underlie their large differences in bias. Whereas bilorphinis systemically inactive, a glycosylated analog, bilactorphin, isorally active with similar in vivo potency to morphine. Bilorphinis both a unique molecular tool that enhances understanding ofMOPr biased signaling and a promising lead in the development ofnext generation analgesics

POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors

Human germ cell tumors (GCTs) may have variable histology and clinical behavior, depending on factors such as sex of the patient, age at clinical diagnosis, and anatomical site of the tumor. Some types of GCT, i.e., the seminomas/germinomas/dysgerminomas and embryonal carcinomas (the stem cell component of nonseminomas), have pluripotent potential, which is demonstrated by their capacity to differentiate into somatic and/or extraembryonic elements. Although embryonal carcinoma cells are intrinsically pluripotent, seminoma/germinoma/dysgerminoma cells, as well as their precursor carcinoma in situ/gonadoblastoma cells, have the phenotype of early germ cells that can be activated to pluripotency. The other types of GCT (teratomas and yolk sac tumors of infants and newborn, dermoid cyst of the ovary, and spermatocytic seminoma of elderly) are composed of (fully) differentiated tissues and lack the appearance of undifferentiated and pluripotent stem cells. OCT3/4, a transcription factor also known as OTF3 and POU5F1, is involved in regulation of pluripotency during normal development and is detectable in embryonic stem and germ cells. We analyzed the presence of POU5F1 in GCT and other tumor types using immunohistochemistry. The protein was consistently detected in carcinoma in situ/gonadoblasto