Background Anaplastic pancreatic cancer (APC) is a rare subtype of pancreatic ductal adenocarcinoma (PDA) that can carry a worse overall survival (OS) when compared with other variants. However, the ...presence of osteoclast-like giant cells (OCGCs) in APC specimens can predict improved OS. The aim of this study was to evaluate the OS of patients with APC (with and without OCGCs) compared with patients with other subtypes of PDA using a population-based registry. Study Design We identified all patients in the Surveillance, Epidemiology and End Results (SEER) database with pathologically confirmed APC and PDA diagnosed between 1988 and 2008. Overall survival was evaluated using Kaplan-Meier and Cox proportional hazard regression. Results The study cohort included 5,859 (94.3%) patients with PDA and 353 (5.7%) with APC. Overall survival for all patients with APC was significantly worse than for patients with PDA (hazard ratio HR = 1.9; 95% CI, 1.7−2.1; p < 0.001); however, in the subgroup of resected patients, APC (n = 81) had similar OS to PDA (n = 3,517) (HR = 0.9; 95% CI, 0.7−1.2; p = 0.37). Patients with APC tumors with OCGCs (n = 11) demonstrated improved OS when compared with all other APC variants without OCGCs (n = 342) (HR = 0.3; 95% CI, 0.1−0.7; p = 0.004), but this survival difference was not observed in the subgroup of resected patients (HR = 0.5; 95% CI, 0.2−1.4; p = 0.18). Conclusions Anaplastic pancreatic cancer is a rare malignancy with poor OS. The diagnosis of APC with OCGCs is predictive of improved OS compared with other patients with APC. This survival benefit, however, is not observed in patients with resected disease.
Staging of hepatocellular carcinoma (HCC) is complex and relies on multiple factors including tumor extent and hepatic function. No single staging system is applicable to all patients with HCC. The ...staging of the American Joint Committee on Cancer / International Union for Cancer Control should be used to predict outcome following resection or liver transplantation. The Barcelona Clinic Liver Cancer scheme is appropriate in patients with advanced HCC not candidate for surgery. Dual phase computed tomography or magnetic resonance imaging can be used for pretreatment assessment of tumor extent but the accuracy of these methods remains poor to characterize <1cm lesions. Assessment of tumor response should not rely only on tumor size and new imaging methods are available to evaluate response to therapy in HCC patients. Liver volumetry is part of the preoperative assessment of patients with HCC candidate for resection as it reflects liver function. Preoperative portal vein embolization is indicated in patients with small future liver remnant (≤ 20% in normal liver; ≤ 40% in fibrotic or cirrhotic liver). Tumor size is not a contraindication to liver resection. Liver resection can be proposed in selected patients with multifocal HCC. Besides tumor extent, surgical resection of HCC may be performed in selected patients with chronic liver disease.
Objective
To better characterize the ways that migraine affects multiple domains of life.
Background
Further understanding of migraine burden is needed.
Methods
Adults with migraine randomized to ...mindfulness‐based stress reduction or headache education arms (n = 81) in two separate randomized clinical trials participated in semistructured in‐person qualitative interviews conducted after the interventions. Interviews queried participants on migraine impact on life and were audio‐recorded, transcribed, and summarized into a framework matrix. A master codebook was created until meaning saturation was reached and magnitude coding established code frequency. Themes and subthemes were identified using a constructivist grounded theory approach.
Results
Despite most participants being treated with acute and/or prophylactic medications, 90% (73/81) reported migraine had a negative impact on overall life, with 68% (55/81) endorsing specific domains of life impacted and 52% (42/81) describing impact on emotional health. Six main themes of migraine impact emerged: (1) global negative impact on overall life; (2) impact on emotional health; (3) impact on cognitive function; (4) impact on specific domains of life (work/career, family, social); (5) fear and avoidance (pain catastrophizing and anticipatory anxiety); and (6) internalized and externalized stigma. Participants reported how migraine (a) controls life, (b) makes life difficult, and (c) causes disability during attacks, with participants (d) experiencing a lack of control and/or (e) attempting to push through despite migraine. Emotional health was affected through (a) isolation, (b) anxiety, (c) frustration/anger, (d) guilt, (e) mood changes/irritability, and (f) depression/hopelessness. Cognitive function was affected through concentration and communication difficulties.
Conclusions
Migraine has a global negative impact on overall life, cognitive and emotional health, work, family, and social life. Migraine contributes to isolation, frustration, guilt, fear, avoidance behavior, and stigma. A greater understanding of the deep burden of this chronic neurological disease is needed to effectively target and treat what is most important to those living with migraine.
Commercial cultivars of perennial ryegrass infected with selected Epichloë fungal endophytes are highly desirable in certain pastures as the resulting mutualistic association has the capacity to ...confer agronomic benefits (such as invertebrate pest deterrence) largely due to fungal produced secondary metabolites (e.g., alkaloids). In this study, we investigated T
segregating populations derived from two independent transformation events expressing diacylglycerol acyltransferase (DGAT) and cysteine oleosin (CO) genes designed to increase foliar lipid and biomass accumulation. These populations were either infected with Epichloë festucae var. lolii strain AR1 or Epichloë sp. LpTG-3 strain AR37 to examine relationships between the introduced trait and the endophytic association. Here we report on experiments designed to investigate if expression of the DGAT + CO trait in foliar tissues of perennial ryegrass could negatively impact the grass-endophyte association and vice versa. Both endophyte and plant characters were measured under controlled environment and field conditions.
Expected relative increases in total fatty acids of 17-58% accrued as a result of DGAT + CO expression with no significant difference between the endophyte-infected and non-infected progeny. Hyphal growth in association with DGAT + CO expression appeared normal when compared to control plants in a growth chamber. There was no significant difference in mycelial biomass for both strains AR1 and AR37, however, Epichloë-derived alkaloid concentrations were significantly lower on some occasions in the DGAT + CO plants compared to the corresponding null-segregant progenies, although these remained within the reported range for bioactivity.
These results suggest that the mutualistic association formed between perennial ryegrass and selected Epichloë strains does not influence expression of the host DGAT + CO technology, but that endophyte performance may be reduced under some circumstances. Further investigation will now be required to determine the preferred genetic backgrounds for introgression of the DGAT + CO trait in combination with selected endophyte strains, as grass host genetics is a major determinant to the success of the grass-endophyte association in this species.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose It is important for clinical practice and research that measurement scales of well-being and quality of life exhibit only minimal differential item functioning (DIF). DIF occurs where ...different groups of people endorse items in a scale to different extents after being matched by the intended scale attribute. We investigate the equivalence or otherwise of common methods of assessing DIF. Method Three methods of measuring age- and sex-related DIF (ordinal logistic regression, Rasch analysis and Mantel χ2 procedure) were applied to Hospital Anxiety Depression Scale (HADS) data pertaining to a sample of 1,068 patients consulting primary care practitioners. Results Three items were flagged by all three approaches as having either age- or sex-related DIF with a consistent direction of effect; a further three items identified did not meet stricter criteria for important DIF using at least one method. When applying strict criteria for significant DIF, ordinal logistic regression was slightly less sensitive. Conclusions Ordinal logistic regression, Rasch analysis and contingency table methods yielded consistent results when identifying DIF in the HADS depression and HADS anxiety scales. Regardless of methods applied, investigators should use a combination of statistical significance, magnitude of the DIF effect and investigator judgement when interpreting the results.
Background & Aims Fibrolamellar carcinoma (FLC) is a rare liver cancer that primarily affects adolescents and young adults. It is characterized by a heterozygous approximately 400-kb deletion on ...chromosome 19 that results in a unique fusion between DnaJ heat shock protein family member B1 (DNAJB1) and the alpha catalytic subunit of protein kinase A (PRKACA). The role of microRNAs (miRNAs) in FLC remains unclear. We identified dysregulated miRNAs in FLC and investigated whether dysregulation of 1 key miRNA contributes to FLC pathogenesis. Methods We analyzed small RNA sequencing (smRNA-seq) data from The Cancer Genome Atlas to identify dysregulated miRNAs in primary FLC tumors and validated the findings in 3 independent FLC cohorts. smRNA-seq also was performed on a FLC patient-derived xenograft model as well as purified cell populations of the liver to determine whether key miRNA changes were tumor cell–intrinsic. We then used clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (Cas9) technology and transposon-mediated gene transfer in mice to determine if the presence of DNAJB1-PRKACA is sufficient to suppress miR-375 expression. Finally, we established a new FLC cell line and performed colony formation and scratch wound assays to determine the functional consequences of miR-375 overexpression. Results We identified miR-375 as the most dysregulated miRNA in primary FLC tumors (27-fold down-regulation; P = .009). miR-375 expression also was decreased significantly in a FLC patient-derived xenograft model compared to 4 different cell populations of the liver. Introduction of DNAJB1-PRKACA by clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 engineering and transposon-mediated somatic gene transfer in mice was sufficient to induce significant loss of miR-375 expression ( P < .05). Overexpression of miR-375 in FLC cells inhibited Hippo signaling pathway proteins, including yes-associated protein 1 and connective tissue growth factor, and suppressed cell proliferation and migration ( P < .05). Conclusions We identified miR-375 as the most down-regulated miRNA in FLC tumors and showed that overexpression of miR-375 mitigated tumor cell growth and invasive potential. These findings open a potentially new molecular therapeutic approach. Further studies are necessary to determine how DNAJB1-PRKACA suppresses miR-375 expression and whether miR-375 has additional important targets in this tumor. Transcript profiling: GEO accession numbers: GSE114974 and GSE125602.
CASE DESCRIPTION 10 large felids at 8 facilities were determined or suspected to have developed gastric dilatation with or without enterotoxemia over a 20-year period. Four felids were found dead ...with no premonitory signs. CLINICAL FINDINGS 4 felids (2 male snow leopards Uncia uncia, 1 male Amur tiger Panthera tigris altaica, and 1 male Sumatran tiger Panthera tigris sumatrae) were found dead or died before they could be evaluated. Six felids had hematemesis (1 male and 1 female African lion Panthera leo and 1 male jaguar Panthera onca) or abdominal distention and signs of lethargy with or without vomiting (1 male African lion, 1 male Malayan tiger Panthera tigris jacksoni, and 1 female Sumatran tiger). Gastric dilatation was radiographically and surgically confirmed in the male Malayan and female Sumatran tigers and the jaguar. TREATMENT AND OUTCOME In 3 felids with an antemortem diagnosis, the gastric dilatation resolved with decompressive laparotomy but then recurred in 1 felid, which subsequently died. Three others died at various points during hospitalization. Although Clostridium perfringens type A was recovered from 3 of the 5 felids for which microbial culture was performed, and 2 felids had a recent increase in the amount fed, no single factor was definitively identified that might have incited or contributed to the gastric dilatation. CLINICAL RELEVANCE Gastric dilatation was a life-threatening condition in the large felids of this report, causing sudden death or clinical signs of hematemesis, abdominal distention, or vomiting. Even with rapid diagnosis and surgical decompression, the prognosis was poor. Research is needed into the factors that contribute to this emergent condition in large felids so that preventive measures might be taken.
Human erythropoietin is a haematopoietic cytokine required for the differentiation and proliferation of precursor cells into red blood cells. It activates cells by binding and orientating two ...cell-surface erythropoietin receptors (EPORs) which trigger an intracellular phosphorylation cascade. The half-maximal response in a cellular proliferation assay is evoked at an erythropoietin concentration of 10 pM (ref. 3), 10−2 of its K d value for erythropoietin-EPOR binding site 1 (Kd 1 nM), and 10−5 of the K d for erythropoietin-EPOR binding site 2 (Kd 1 μM). Overall half-maximal binding (IC50) of cell-surface receptors is produced with ∼0.18 nM erythropoietin, indicating that only ∼6% of the receptors would be bound in the presence of 10 pM erythropoietin. Other effective erythropoietin-mimetic ligands that dimerize receptors can evoke the same cellular responses, but much less efficiently, requiring concentrations close to their K d values (∼0.1 μM). The crystal structure of erythropoietin complexed to the extracellular ligand-binding domains of the erythropoietin receptor, determined at 1.9 Å from two crystal forms, shows that erythropoietin imposes a unique 120° angular relationship and orientation that is responsible for optimal signalling through intracellular kinase pathways.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The purpose of this study was to examine whether Latino adolescents’ perceptions of maternal and paternal behaviors (support, psychological control) were related to their general self‐efficacy and ...relational self‐esteem. Self‐report surveys were collected from 662 Latino ninth graders from three public high schools in Los Angeles. The results were consistent with the looking glass self and self‐efficacy theory. The results showed that perceived supportive behaviors from mothers and fathers were significantly and positively related to boys’ and girls’ general self‐efficacy and relational self‐esteem, while perceived psychologically controlling behaviors from mothers and fathers were significantly and negatively related to general self‐efficacy. Extension educators and human service professionals serving Latino families should encourage supportive parenting behaviors, caution against the use of psychological control, help Latino youth recognize supportive behaviors by parents, and teach Latino youth strategies to buffer themselves from the impact of parents’ psychological control.
Current hypotheses concerning the mechanism of neuronal cell death in Parkinson's disease (PD) and related synucleopathies propose a functional interaction between parkin and alpha-synuclein ...(alphaS). Recently parkin was shown to suppress mutant alphaS-induced toxicity in primary neurons, providing a basis for an association between these proteins and neuronal loss Neuron 36 (2000) 1007-1019. We have asked if a similar association could be made between wild-type (wt) alphaS and parkin. We examined inducible over-expression of alphaS in SHSY-5Y cells through adenoviral infection under conditions which produce cellular toxicity through a reduction in ATP levels. We demonstrate that parkin suppresses toxicity induced by mutant (A53T) and wt alphaS. Parkin over-expression was also associated with the appearance of higher molecular weight alphaS-immunoreactive bands by Western blot analysis. These data, consistent with a protective role for parkin, extend previous findings to include a functional association between parkin and the wt form of alphaS.
PDF
