Discriminant validity, responsiveness and reliability of the arthritis-specific Work Productivity Survey assessing workplace and household productivity within and outside the home in patients with axial spondyloarthritis, including nonradiographic axial spondyloarthritis and ankylosing spondylitis.
The arthritis-specific Work Productivity Survey (WPS) was developed to evaluate productivity limitations associated with arthritis within and outside the home. There is an unmet need for an instrument assessing similar productivity limitations in axial spondyloarthritis (axSpA), including nonradiographic axSpA and ankylosing spondylitis. Following its validation in rheumatoid and psoriatic arthritis, we aimed to assess psychometric properties of WPS in adult-onset active axSpA in this analysis. Psychometric properties were assessed using data from the RAPID-axSpA trial (NCT01087762) in which researchers investigated certolizumab pegol efficacy and safety in axSpA. WPS was completed at baseline and every 4 weeks until week 24. Validity was evaluated at study baseline via known-groups defined by the first and third quartile cutoffs of patient scores to Ankylosing Spondylitis Disease Activity Score (ASDAS), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), back pain, Bath Ankylosing Spondylitis Functional Index (BASFI), Short Form 36 health survey (SF-36) and Ankylosing Spondylitis Quality of Life Scale (ASQoL). Responsiveness and reliability were assessed by comparing WPS mean changes in ASAS 20% improvement criteria (ASAS20), BASDAI50, ASDAS clinically important improvement/major improvement (CII/MI) and BASFI minimum clinically important difference (MCID) responders versus nonresponders at week 12. All comparisons were conducted on observed cases in the randomized set using a nonparametric bootstrap-t method. The results confirmed the psychometric properties of WPS. AxSpA patients with a worse health state had significantly more days of household work lost, household work with reduced productivity, social activities missed and outside help hired, as well as a higher interference rate of arthritis, than patients with a better health state. Similarly, employed patients with a worse health state had significantly more work days lost or with productivity reduced, and a higher interference of arthritis on work productivity. Similar findings were also observed in the nonradiographic (nr) axSpA and AS subpopulations. The WPS was responsive to clinical changes, with responders reporting larger improvements at week 12 in WPS scores versus nonresponders. Effect sizes in responders were generally moderate to large (standardized response mean >0.5). These analyses demonstrate that WPS is a valid, responsive and reliable instrument for the measurement of productivity within and outside the home in adult-onset axSpA, as well as the in subpopulations of AS and nr-axSpA.


What factors influence the treatment decisions of women with breast cancer? Does residential location play a role?
Inequalities in cancer outcomes continue to exist throughout the world. In Australia, rural women diagnosed with breast cancer have significantly poorer 5-year survival, with variations in clinical management additionally observed. While factors impacting clinical management have been identified, there is little understanding about the factors that influence treatment decisions of women diagnosed with breast cancer. A mixed-methods study was conducted with women diagnosed with either pre-invasive or invasive breast cancer in Australia. The study included qualitative interviews and an online survey utilising Breast Cancer Network Australia's membership. Semi-structured interviews were conducted with rural women focusing on topics such as decision-making and factors influencing this. The online survey amongst metropolitan and rural (including regional, remote, very remote) women examined involvement in, and preference for, decision-making, and to what degree certain factors influenced treatment decisions. Sociodemographics included age, residential location, education and household income. Qualitative interviews were analysed using NVivo, and descriptive analyses were used to examine differences in frequency distributions across survey questions by residential location and age group for the online survey. Multivariable logistic regression analysis was conducted to examine factors associated with treatment decision-making. Nine women participated in the qualitative interviews and 815 (365 metropolitan and 450 rural) completed the online survey. Interviews found most women concurred with the recommendations of their doctor(s) and did not see this experience as 'making a decision'. In the online survey, 83.2% of women indicated at least some involvement in the decision-making with this being similar between rural and metropolitan women. Compared to women educated at an under- or postgraduate level, those educated at high school or less were about 50% less likely to be involved in treatment decision(s) (OR=0.51, 95% confidence interval=0.30-0.86). In both interviews and the online survey, factors having the strongest influence on treatment decisions centred around survival and reducing risk of progression or recurrence. Significantly more rural compared to metropolitan women indicated their decision was strongly influenced by treatment service location (42.8% and 28.1%, respectively, p<0.001). Rural women more frequently cited financial costs of treatment influenced their decision compared to metropolitan women (30.4% and 21.3%, respectively, p=0.04). Significantly fewer rural, (16.2%) compared to metropolitan (23.6%) women, had breast reconstruction (p=0.009). The option of having reconstructive surgery was less frequently cited as influencing treatment decisions for rural compared to metropolitan women (27.7% v 44.1% respectively, p<0.001). The treatment decisions of the majority of women were strongly influenced by the need to do everything possible to get better; however, rural women additionally indicated their decisions were also influenced by factors such as access to treatment services and the financial costs of treatment. Addressing travel and costs issues for rural women with breast cancer should be prioritised. Additionally, the finding that women with lower levels of education were significantly less likely to be involved in the decision-making process highlights the need to develop new or tailor existing resources. Further work could also examine the reasons why rural women are less likely to consider breast reconstruction important in decision-making.


[Laparoscopic bowel resection for early colon cancer].
Following the successful introduction of laparoscopic cholecystectomy, many reports confirming the feasibility of using laparoscopy for bowel resection and predicting that it would be advantageous in terms of its minimal invasiveness have been published. In the context of cancer treatment, however, the feasibility of lymphadenectomy, the risk of recurrence, and survival have emerged as major concerns. Even though mucosal cancer (Tis) can be treated by endoscopic resection (ER), when this is not possible open surgery (OS) must be performed. In patients with T1 cancer, tumors showing slight submucosal layer invasion (sm 1) can be treated in the same way as Tis (in cancer) cancers. But 5% to 10% of patients with T1 cancer have massive submucosal layer invasion (sm 2-3) with paracolic lymph node metastasis. At least partial bowel resection with paracolic lymphadenectomy is considered necessary for T1 (sm 2-3) cancers in principle. In summary, laparoscopic local excision of Tis cancers that are endoscopically unresectable and laparoscopically assisted partial resection with paracolic lymphadenectomy for T1 cancers have become accepted because local excision and partial resection with paracolic lymphnedectomy are fairly simple to perform laparoscopically. Therefore as a strategy for the treatment of early colorectal cancer (CRC), minimally invasive laparoscopic bowel resection (LBR) has been positioned between endoscopic resection (ER) and open surgery (OS). While the difficulty of performing radical lymphadenectomy is considered one of the greatest obstacles to the introduction of laparoscopic bowel resection (LBR) for the treatment of advanced colorectal cancer (CRC), early colon cancer is a good indication for laparoscopic bowel resection.


Antigenic diversity of H5 highly pathogenic avian influenza viruses of clade 126.96.36.199 isolated in Asia.
H5 highly pathogenic avian influenza viruses (HPAIV) have spread in both poultry and wild birds since late 2003. Continued circulation of HPAIV in poultry in several regions of the world has led to antigenic drift. In the present study, we analyzed the antigenic properties of H5 HPAIV isolated in Asia using four neutralizing mAbs recognizing hemagglutinin, which were established using A/chicken/Kumamoto/1-7/2014 (H5N8), belonging to clade 126.96.36.199 and also using polyclonal antibodies. Viruses of clades 1.1, 188.8.131.52, 2.3.4, and 184.108.40.206 had different reactivity patterns to the panel of mAbs, thereby indicating that the antigenicity of the viruses of clade 18.104.22.168 were similar but differed from the other clades. In particular, the antigenicity of the viruses of clade 18.104.22.168 differed from those of the viruses of clades 2.3.4 and 22.214.171.124, which suggests that the recent H5 HPAIV have further evolved antigenically divergent. In addition, reactivity of antiserum suggests that the antigenicity of viruses of clade 220.127.116.11 differed slightly among groups A, B, and C. Vaccines are still used in poultry in endemic countries, so the antigenicity of H5 HPAIV should be monitored continually to facilitate control of avian influenza. The panel of mAbs established in the present study will be useful for detecting antigenic drift in the H5 viruses that emerge from the current strains.


Age of onset in schizophrenia: relations to psychopathology and gender.
This retrospective study evaluated differences between patients with first manifestation of schizophrenic psychosis (ICD 295) or paranoid syndrome (ICD 297) between the ages of 18 and 23 or 40 and 63 years. Gender-specific variations in psychopathology were also examined. The numerous analyses of variance gave few significant differences. Patients with a late onset of the disease scored higher on depressive and autonomic syndrome scales at admission, whereas patients with an early onset showed more psychosocial impairment at discharge and their stay in hospital was longer. Among schizophrenic patients only (ICD 297 excluded), only the higher score for autonomic syndrome of the older patients at admission was confirmed. Men were more apathetic at admission and discharge than were women. Excluding patients with a paranoid syndrome, these differences were again significant. Moreover, schizophrenic men had higher depressive and psycho-organic syndrome scores at discharge. The demonstration of only marginal differences between early- and late-onset schizophrenia does not support the assumption that age of onset markedly influences psychopathology.


Evolution of morphological novelty: a phylogenetic analysis of growth patterns in Streptocarpus (Gesneriaceae).
Streptocarpus shows great variation in vegetative architecture. In some species a normal shoot apical meristem never forms and the entire vegetative plant body may consist of a single giant cotyledon, which may measure up to 0.75 m (the unifoliate type) or with further leaves arising from this structure (the rosulate type). A molecular phylogeny of 87 taxa (77 Streptocarpus species, seven related species, and three outgroup species) using the internal transcribed spacers and 5.8S region of nuclear ribosomal DNA suggests that Streptocarpus can be divided into two major clades. One of these broadly corresponds to the caulescent group (with conventional shoot architecture) classified as subgenus Streptocarpella, whereas the other is mainly composed of acaulescent species with unusual architecture (subgenus Streptocarpus). Some caulescent species (such as S. papangae) are anomalously placed with the acaulescent clade. Available cytological data are, however, completely congruent with the two major clades: the caulescent clade is x = 15 and the acaulescent clade (including the caulescent S. papangae) is x = 16 (or polyploid multiples of 16). The genera Linnaeopsis, Saintpaulia, and Schizoboea are nested within Streptocarpus. The sequenced region has evolved, on average, 2.44 times faster in the caulescent clade than in the acaulescent clade and this is associated with the more rapid life cycle of the caulescents. Morphological variation in plant architecture within the acaulescent clade is homoplastic and does not appear to have arisen by unique abrupt changes. Instead, rosulate and unifoliate growth forms have evolved several times, reversals have occurred, and intermediate architectures are found. An underlying developmental plasticity seems to be a characteristic of the acaulescent clade and is reflected in a great lability of form.


Cellular traction stresses mediate extracellular matrix degradation by invadopodia.
During tumorigenesis, matrix rigidity can drive oncogenic transformation via altered cellular proliferation and migration. Cells sense extracellular matrix (ECM) mechanical properties with intracellular tensile forces generated by actomyosin contractility. These contractile forces are transmitted to the matrix surface as traction stresses, which mediate mechanical interactions with the ECM. Matrix rigidity has been shown to increase proteolytic ECM degradation by cytoskeletal structures known as invadopodia that are critical for cancer progression, suggesting that cellular contractility promotes invasive behavior. However, both increases and decreases in traction stresses have been associated with metastatic behavior. Therefore, the role of cellular contractility in invasive migration leading to metastasis is unclear. To determine the relationship between cellular traction stresses and invadopodia activity, we characterized the invasive and contractile properties of an aggressive carcinoma cell line utilizing polyacrylamide gels of different rigidities. We found that ECM degradation and traction stresses were linear functions of matrix rigidity. Using calyculin A to augment myosin contractility, we also found that traction stresses were strongly predictive of ECM degradation. Overall, our data suggest that cellular force generation may play an important part in invasion and metastasis by mediating invadopodia activity in response to the mechanical properties of the tumor microenvironment.


Assessing white matter microstructure of the newborn with multi-shell diffusion MRI and biophysical compartment models.
Brain white matter connections have become a focus of major interest with important maturational processes occurring in newborns. To study the complex microstructural developmental changes in-vivo, it is imperative that non-invasive neuroimaging approaches are developed for this age-group. Multi-b-value diffusion weighted imaging data were acquired in 13 newborns, and the biophysical compartment diffusion models CHARMED-light and NODDI, providing new microstructural parameters such as intra-neurite volume fraction (νin) and neurite orientation dispersion index (ODI), were developed for newborn data. Comparative analysis was performed and twenty ROIs in the white matter were investigated. Diffusion tensor imaging and both biophysical compartment models highlighted the compact and oriented structure of the corpus-callosum with the highest FA and νin values and the smallest ODI values. We could clearly differentiate, using the FA, νin and ODI, the posterior and anterior internal capsule representing similar cellular structure but with different maturation (i.e. partially myelinated and absence of myelin, respectively). Late maturing regions (external capsule and periventricular crossroads of pathways) had lower νin values, but displayed significant differences in ODI. The compartmented models CHARMED-light and NODDI bring new indices corroborating the cellular architectures, with the lowest νin, reflecting the late maturation of areas with thin non-myelinated fibers, and with highest ODI indicating the presence of fiber crossings and fanning. The application of biophysical compartment diffusion models adds new insights to the brain white matter development in vivo.


Vascular access types in hemodialysis patients in palestine and factors affecting their distribution: A cross-sectional study.
The incidence of end-stage renal disease (ESRD) patients is increasing considerably worldwide, and most of the patients start their therapy by hemodialysis (HD). Arteriovenous fistula (AVF) is the best type of vascular access due to its decreased rate of complications followed by arteriovenous graft (AVG) and finally, central venous catheters which are associated with increased mortality and morbidity. In this study, we aim to find out the proportion of each vascular access type used in HD patients and to evaluate the epidemiology of HD access in Palestine. Six hundred and fifty-eight patients were enrolled in this study from 10 dialysis units distributed in Palestine. The patients were divided into incident patients or prevalent patients. Data were collected by the researchers by regular visits to the units. AVFs were the most common access type (69.3%), catheters came second (27.8%) finally, AVGs (2.9%). Temporary catheters composed 59% of all catheters, followed by the permanent catheters. The subclavian vein was the most common insertion site (68.3%), internal jugular vein (26.8%), and femoral vein (4.9%). Temporary catheters were most commonly used among incident patients (41.5%) and AVFs were the most common in the prevalent patients (75%). There was no statistically significant association between the type of dialysis access use with gender, body mass index, or diabetic status. We recommend close follow-up and early AVF creation when the patients are expected to need HD. We also highly recommend decreasing the duration of temporary catheters. Finally, further prospective studies to follow-up and evaluate the progression in the vascular access status in Palestine are needed.


Flex-rigid pleuroscopic biopsy with the SB knife Jr is a novel technique for diagnosis of malignant or benign fibrothorax.
Diagnosing pleural effusion is challenging, especially in patients with malignant or benign fibrothorax, which is difficult to sample using standard flexible forceps (SFF) via flex-rigid pleuroscopy. An adequate sample is crucial for the differential diagnosis of malignant fibrothorax (malignant pleural mesothelioma, metastatic lung carcinoma, etc.) from benign fibrothorax (benign asbestos pleural disease, tuberculous pleuritis, etc.). Novel biopsy techniques are required in flex-rigid pleuroscopy to improve the sample size and quality. The SB knife Jr, which is a scissor forceps that uses a mono-pole high frequency, was developed to allow convenient and accurate resection of larger lesions during endoscopic dissection (ESD). Herein, we report two patients with fibrothorax who underwent a pleural biopsy using an SB knife Jr to investigate the potential use of this tool in flex-rigid pleuroscopy when pleural lesions are difficult to biopsy via SFF. The biopsies were successful, with sufficient size and quality for definitive diagnosis. We also successfully performed adhesiolysis with the SB knife Jr in one case, and adequate biopsies were conducted. No complications were observed. Electrosurgical biopsy with the SB knife Jr during flex-rigid pleuroscopy allowed us to obtain adequate samples for the diagnosis of malignant versus benign fibrothorax, which is usually not possible with SFF. The SB knife Jr also demonstrated a potential use for pleuropulmonary adhesions.


Cannabis use and psychotic disorders in diverse settings in the Global South: findings from INTREPID II.
Cannabis use has been linked to psychotic disorders but this association has been primarily observed in the Global North. This study investigates patterns of cannabis use and associations with psychoses in three Global South (regions within Latin America, Asia, Africa and Oceania) settings. Case-control study within the International Programme of Research on Psychotic Disorders (INTREPID) II conducted between May 2018 and September 2020. In each setting, we recruited over 200 individuals with an untreated psychosis and individually-matched controls (Kancheepuram India; Ibadan, Nigeria; northern Trinidad). Controls, with no past or current psychotic disorder, were individually-matched to cases by 5-year age group, sex and neighbourhood. Presence of psychotic disorder assessed using the Schedules for Clinical Assessment in Neuropsychiatry and cannabis exposure measured by the World Health Organisation Alcohol, Smoking and Substance Involvement Screening Test (ASSIST). Cases reported higher lifetime and frequent cannabis use than controls in each setting. In Trinidad, cannabis use was associated with increased odds of psychotic disorder: lifetime cannabis use (adj. OR 1.58, 95% CI 0.99-2.53); frequent cannabis use (adj. OR 1.99, 95% CI 1.10-3.60); cannabis dependency (as measured by high ASSIST score) (adj. OR 4.70, 95% CI 1.77-12.47), early age of first use (adj. OR 1.83, 95% CI 1.03-3.27). Cannabis use in the other two settings was too rare to examine associations. In line with previous studies, we found associations between cannabis use and the occurrence and age of onset of psychoses in Trinidad. These findings have implications for strategies for prevention of psychosis.


Does methylmercury-induced hypercholesterolemia play a causal role in its neurotoxicity and cardiovascular disease?
Methylmercury (MeHg) is an environmental pollutant that biomagnifies throughout the aquatic food chain, thus representing a toxicological concern for humans subsiding on fish for their dietary intake. Although the developing brain is considered the critical target organ of MeHg toxicity, recent evidence indicates that the cardiovascular system may be the most sensitive in adults. However, data on the mechanisms mediating MeHg-induced cardiovascular toxicity are scarce. Based on the close relationship between cardiovascular disease and dyslipidemia, this study was designed to investigate the effects of long-term MeHg exposure on plasma lipid levels in mice, as well as their underlying mechanisms and potential relationships to MeHg-induced neurotoxicity. Our major finding was that long-term MeHg exposure induced dyslipidemia in rodents. Specifically, Swiss and C57BL/6 mice treated for 21 days with a drinking solution of MeHg (40 mg/l, ad libitum) diluted in tap water showed increased total and non-HDL plasma cholesterol levels. MeHg-induced hypercholesterolemia was also observed in low-density lipoprotein receptor knockout (LDLr⁻/⁻) mice, indicating that this effect was not related to decreased LDLr-mediated cholesterol transport from blood to other tissues. Although the hepatic synthesis of cholesterol was unchanged, significant signs of nephrotoxicity (glomerular shrinkage, tubular vacuolization, and changed urea levels) were observed in MeHg-exposed mice, indicating that the involvement of nephropathy in MeHg-induced lipid dyshomeostasis may not be ruled out. Notably, Probucol (a lipid-lowering drug) prevented the development of hypercholesterolemia when coadministered with MeHg. Finally, hypercholesterolemic LDLr⁻/⁻ mice were more susceptible to MeHg-induced cerebellar glial activation, suggesting that hypercholesterolemia in itself may pose a risk factor in MeHg-induced neurotoxicity. Overall, based on the strong and graded positive association between total as well as LDL cholesterol and risk of cardiovascular diseases, our data support the concept of MeHg-induced cardiovascular toxicity.


Revealing protein oligomerization and densities in situ using spatial intensity distribution analysis.
Measuring protein interactions is key to understanding cell signaling mechanisms, but quantitative analysis of these interactions in situ has remained a major challenge. Here, we present spatial intensity distribution analysis (SpIDA), an analysis technique for image data obtained using standard fluorescence microscopy. SpIDA directly measures fluorescent macromolecule densities and oligomerization states sampled within single images. The method is based on fitting intensity histograms calculated from images to obtain density maps of fluorescent molecules and their quantal brightness. Because spatial distributions are acquired by imaging, SpIDA can be applied to the analysis of images of chemically fixed tissue as well as live cells. However, the technique does not rely on spatial correlations, freeing it from biases caused by subcellular compartmentalization and heterogeneity within tissue samples. Analysis of computer-based simulations and immunocytochemically stained GABA(B) receptors in spinal cord samples shows that the approach yields accurate measurements over a broader range of densities than established procedures. SpIDA is applicable to sampling within small areas (6 μm(2)) and reveals the presence of monomers and dimers with single-dye labeling. Finally, using GFP-tagged receptor subunits, we show that SpIDA can resolve dynamic changes in receptor oligomerization in live cells. The advantages and greater versatility of SpIDA over current techniques open the door to quantificative studies of protein interactions in native tissue using standard fluorescence microscopy.


Enzyme Architecture: Modeling the Operation of a Hydrophobic Clamp in Catalysis by Triosephosphate Isomerase.
Triosephosphate isomerase (TIM) is a proficient catalyst of the reversible isomerization of dihydroxyacetone phosphate (DHAP) to d-glyceraldehyde phosphate (GAP), via general base catalysis by E165. Historically, this enzyme has been an extremely important model system for understanding the fundamentals of biological catalysis. TIM is activated through an energetically demanding conformational change, which helps position the side chains of two key hydrophobic residues (I170 and L230), over the carboxylate side chain of E165. This is critical both for creating a hydrophobic pocket for the catalytic base and for maintaining correct active site architecture. Truncation of these residues to alanine causes significant falloffs in TIM's catalytic activity, but experiments have failed to provide a full description of the action of this clamp in promoting substrate deprotonation. We perform here detailed empirical valence bond calculations of the TIM-catalyzed deprotonation of DHAP and GAP by both wild-type TIM and its I170A, L230A, and I170A/L230A mutants, obtaining exceptional quantitative agreement with experiment. Our calculations provide a linear free energy relationship, with slope 0.8, between the activation barriers and Gibbs free energies for these TIM-catalyzed reactions. We conclude that these clamping side chains minimize the Gibbs free energy for substrate deprotonation, and that the effects on reaction driving force are largely expressed at the transition state for proton transfer. Our combined analysis of previous experimental and current computational results allows us to provide an overview of the breakdown of ground-state and transition state effects in enzyme catalysis in unprecedented detail, providing a molecular description of the operation of a hydrophobic clamp in triosephosphate isomerase.


A new hereditary colorectal cancer network in the Middle East and eastern mediterranean countries to improve care for high-risk families.
Colorectal cancer (CRC) has a very high incidence in the western world. Data from registries in the Middle East showed that the incidence of CRC is relatively low in these countries. However, these data also showed that CRC incidence has increased substantially over the past three decades and that a high proportion of cases are diagnosed at an early age (<50 years). In view of these findings, more attention should be paid to prevention. Because of the often limited financial resources, focused screening of individuals with hereditary CRC, in particular those with Lynch syndrome, appears to be the most cost-effective strategy. During recent meetings of the Palestinian Society of Gastroenterology and the Mediterranean Task force for Cancer Control (MTCC) in Jericho, and the Patient's Friends Society of Jerusalem in Hebron the issue of hereditary CRC in the Middle East was discussed and the idea was conceived to establish a network on hereditary colorectal cancer (HCCN-ME) with the goal of improving care for high-risk groups in the Middle East and (Eastern) Mediterranean Countries.


Restoration impact of an uncontrolled phosphogypsum dump site on the seasonal distribution of abiotic variables, phytoplankton and zooplankton along the near shore of the south-western Mediterranean coast.
'In connection with the Taparura Project, we studied the distribution of phytoplankton and zooplankton communities in relation to environmental variables at 18 stations sampled during four coastal cruises conducted between October 2009 and July 2010 on the north coast of Sfax (Tunisia, western Mediterranean Sea). The inshore location was largely dominated by diatoms (66 %) represented essentially by members of the genera Navicula, Grammatophora, and Licmophora. Dinophyceae were numerically the second largest group and showed an enhanced species richness. Cyanobacteriae developed in association with an important proliferation of colonial Trichodesmium erythraeum, contributing 39.4 % of total phytoplankton abundances. The results suggest that phytoplankters are generally adapted to specific environmental conditions. Copepods were the most abundant zooplankton group (82 %) of total zooplankton. A total of 21 copepod species were identified in all stations, with an overwhelming abundance of Oithona similis in autumn and summer, Euterpina acutifrons in winter, and Oncaea conifera in spring. The phosphogypsum restoration had been acutely necessary allowing dominant zooplankton species to exploit a wide range of food resources including phytoplankton and thus improving water quality.


A conditional-lethal mutant of bacillus subtilis 168 with a thermosensitive glycerol-3-phosphate cytidylyltransferase, an enzyme specific for the synthesis of the major wall teichoic acid.
A biochemical analysis was undertaken of thermosensitive mutants of Bacillus subtilis 168 harbouring mutations in several tag genes, involved in the synthesis of the major wall teichoic acid, poly(glycerol phosphate), poly(groP). Incorporation of a pulse of [2-3H]glycerol into whole cells, following shift to the restrictive growth temperature, was used to assess synthesis of this polymer and to seek evidence of accumulation of a specific precursor. The rate of incorporation into poly(groP) was strongly decreased in all mutants; glycerol uptake was diminished by 80% or more for a strain harbouring mutation tagB1 (formerly tag-1) and one bearing tagD11 (formerly tag-11). The pool of CDP-glycerol (CDP-gro), a specific precursor of poly(groP), was increased, relative to the wild-type, for all mutations except tagD11, where the pool of CDP-gro was reduced. Cytoplasmic extracts, assayed at the permissive temperature for glycerol-3-phosphate cytidylyltransferase (gro-PCT), the enzyme synthesizing CDP-gro, revealed wild-type activities for all mutations except tagD11. Gro-PCT activity in the latter strain was 100-fold lower and, unlike that in all other mutant strains, highly thermolabile. This thermosensitivity suggests that tagD encodes gro-PCT. The identification, in a gene encoding a poly(groP)-specific enzyme, of a mutation conferring a thermosensitive growth phenotype renders explicit the conclusion that synthesis of this teichoic acid is essential for the growth of B. subtilis.


Breast and ovarian cancer risk perception after prophylactic salpingo-oophorectomy due to an inherited mutation in the BRCA1 or BRCA2 gene.
It is often recommended that women who carry a mutation in the BRCA1 or BRCA2 gene have their ovaries and fallopian tubes removed to reduce their risk of gynecologic cancer. The aim of this study was to evaluate women's perception of their risk of breast and ovarian cancer before and after prophylactic salpingo-oophorectomy. We surveyed 127 women who carry a BRCA1 or BRCA2 mutation and who underwent prophylactic salpingo-oophorectomy at the University Health Network, Toronto. Subjects were asked to estimate their risks of breast and ovarian cancer before and after surgery. Their perceived risks of cancers were then compared with published risks, based on their mutation status. BRCA1 carriers estimated their risk of breast cancer risk to be, on average, 69% before surgery and 41% after surgery. They estimated their risk of ovarian cancer to be 55% before surgery and 11% after surgery. BRCA2 carriers estimated their risk of breast cancer to be 69% prior to surgery and 45% after surgery and their perceived risk of ovarian cancer to be 43% before surgery and 8% after surgery. Compared with published risk figures, the perceived risk of ovarian cancer before prophylactic salpingo-oophorectomy was overestimated by 47% of BRCA1 mutation carriers and by 61% of BRCA2 mutation carriers. Most women who have undergone genetic counseling and subsequently choose prophylactic salpingo-oophorectomy accurately perceive their risk of breast cancer. However, in this study, many women overestimated their risk of ovarian cancer, particularly women who carry a BRCA2 mutation.


The effect of royal jelly on the growth of breast cancer in mice.
Due to various pharmacological properties, including antioxidative, anti-inflammatory and antibiotic properties, royal jelly (RJ) has been widely consumed in daily diets in numerous countries. In the present study, the effect of RJ on 4T1-bearing mice was investigated. The study was performed by feeding 4T1-bearing mice with RJ using either the prophylactic-therapeutic (PTRJ) or therapeutic (TRJ) method. The experimental results for the PTRJ group demonstrated that the weight of tumor was significantly reduced (RJ 0.5 and 1.5 g/kg); and in the serum, the levels of interleukin (IL)-2 (RJ 0.5 and 1.5 g/kg), interferon (IFN)-α, superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) were significantly elevated, but the concentrations of IL-4 (RJ 0.5 and 1.5 g/kg) and IL-10 (RJ 1.0 g/kg) were significantly decreased. In addition, the activities of T-AOC and glutathione reductase (GR) were significantly improved in the liver, whereas in the kidney, the activities of T-AOC and GR were significantly increased only under the dose of 0.5 g/kg. For the TRJ group, the antitumor effect of RJ was not significant; the change in IL-2, IFN-α, SOD and T-AOC levels in the serum, and the change in T-AOC and GR in liver were similar to those observed in the PTRJ groups. RJ treatment was demonstrated to reduce the development of breast tumor in mice, and simultaneously improve the antioxidant capacity of the serum, liver and kidney, particularly using the prophylactic-therapeutic method. These results corroborated the efficacy of RJ supplementation in diets. The results of the present study suggest that the antioxidant and immunomodulatory activities of RJ serve an important role on antitumor growth.


SGEF Is Regulated via TWEAK/Fn14/NF-κB Signaling and Promotes Survival by Modulation of the DNA Repair Response to Temozolomide.
Glioblastoma (GB) is the highest grade and most common form of primary adult brain tumors. Despite surgical removal followed by concomitant radiation and chemotherapy with the alkylating agent temozolomide, GB tumors develop treatment resistance and ultimately recur. Impaired response to treatment occurs rapidly, conferring a median survival of just fifteen months. Thus, it is necessary to identify the genetic and signaling mechanisms that promote tumor resistance to develop targeted therapies to combat this refractory disease. Previous observations indicated that SGEF (ARHGEF26), a RhoG-specific guanine nucleotide exchange factor (GEF), is overexpressed in GB tumors and plays a role in promoting TWEAK-Fn14-mediated glioma invasion. Here, further investigation revealed an important role for SGEF in glioma cell survival. SGEF expression is upregulated by TWEAK-Fn14 signaling via NF-κB activity while shRNA-mediated reduction of SGEF expression sensitizes glioma cells to temozolomide-induced apoptosis and suppresses colony formation following temozolomide treatment. Nuclear SGEF is activated following temozolomide exposure and complexes with the DNA damage repair (DDR) protein BRCA1. Moreover, BRCA1 phosphorylation in response to temozolomide treatment is hindered by SGEF knockdown. The role of SGEF in promoting chemotherapeutic resistance highlights a heretofore unappreciated driver, and suggests its candidacy for development of novel targeted therapeutics for temozolomide-refractory, invasive GB cells. SGEF, as a dual process modulator of cell survival and invasion, represents a novel target for treatment refractory glioblastoma.


Novel dye-doped cholesteric liquid crystal cone lasers with various birefringences and associated tunabilities of lasing feature and performance.
This study is the first to investigate novel cone lasers and the tunabilities of their lasing feature and performance based on dye-doped cholesteric liquid crystal (DDCLC) films with various LC birefringences (Δn). A unique conically-symmetric lasing ring with a low energy threshold occurs at a specific nonzero oblique angle (θ(ring)). The low energy threshold is comparable to those for common lasing signals occurring simultaneously at the short- and long-wavelength edges (SWE and LWE) of the CLC reflection band (CLCRB) for 0°. The lasing ring is induced by the enhancement in the density of photonic state for the fluorescence with a wavelength of λ(ring) based on an edge-overlapping effect, in which λ(ring) is just located at an edge-overlapping spectral position of the SWE of the CLCRB for 0° and the LWE of the CLCRB for θ(ring). The lasing feature (i.e., the lasing wavelengths of the three lasing signals and the emitted angle of the lasing ring) are tuned by varying Δn. The simulated relationship of an oblique angle with Δn, in which the SWE of the CLCRB for that oblique angle just overlaps the LWE of the CLCRB for 0°, can be obtained by calculating the dispersion relation of a planar CLC structure with various values of Δn based on Berreman's 4 × 4 matrix approach. The result of the calculation is highly consistent with the experimental data for the dependence of θ(ring) on Δn. Furthermore, the dependence of lasing performance (energy threshold and relative slope efficiency) on Δn for the three lasing signals is also measured, which findings can be used to qualitatively identify positive interaction or competition among the three lasing signals.


Understanding and optimizing species mixtures using functional-structural plant modelling.
Plant species mixtures improve productivity over monocultures by exploiting species complementarities for resource capture in time and space. Complementarity results in part from competition avoidance responses that maximize resource capture and growth of individual plants. Individual organs accommodate to local resource levels, e.g. with regard to nitrogen content and photosynthetic capacity or by size (e.g. shade avoidance). As a result, the resource acquisition in time and space is improved and performance of the community as a whole is increased. Modelling is needed to unravel the primary drivers and subsequent dynamics of complementary growth responses in mixtures. Here, we advocate using functional-structural plant (FSP) modelling to analyse the functioning of plant mixtures. In FSP modelling, crop performance is a result of the behaviour of the individual plants interacting through competitive and complementary resource acquisition. FSP models can integrate the interactions between structural and physiological plant responses to the local resource availability and strength of competition, which drive resource capture and growth of individuals in species mixtures. FSP models have the potential to accelerate mixed-species plant research, and thus support the development of knowledge that is needed to promote the use of mixtures towards sustainably increasing crop yields at acceptable input levels.


Platelet concentrates in spine fusion: meta-analysis of union rates and complications in controlled trials.
Platelet concentrates in spine fusion gained increasing popularity among spine surgeons. They avoid morbidity of bone harvest and promise good union rates without additional device-related adverse events. Therefore, they seem to be a safe and effective alternative to common bone substitutes. This meta-analysis assesses the available evidence for union rate and overall complications with the use of platelet concentrates in spine fusion. We conducted an online search for relevant controlled trials and extracted data on union rates, complications, and revision rates. These data were synthesized in a meta-analysis using fixed-effects odds ratios (OR). To assess covariates, meta-regression was performed as well. Our search produced 166 results, ten of which were eligible for inclusion. These studies report on a total of 763 patients (328 experimental, 435 controls) with a mean age of 50.3 ± 7.5 years. Mean follow-up was 1.9 ± 0.0.4 years. With the use of platelet concentrates, union rate decreased significantly, OR 0.53 (95 % CI 0.35-0.79, p = 0.002), compared with the control group. There was no statistically significant difference in complication rates OR 1.34 (95 % CI 0.62-2.90, p = 0.46) or in revision rates OR 3.0 (95 % CI 0.90-10.00, p = 0.74). Meta-regression showed no statistically significant influence of randomization, Jadad score, or assessment of fusion. The use of platelet concentrates in spine fusion shows significantly decreased union rates compared with the control group. However, complication and revision rates were not significantly increased. The current data do not recommend the use of platelet concentrate in spine fusion.


Exophilin-5 regulates allergic airway inflammation by controlling IL-33-mediated Th2 responses.
A common variant in the RAB27A gene in adults was recently found to be associated with the fractional exhaled nitric oxide level, a marker of eosinophilic airway inflammation. The small GTPase Rab27 is known to regulate intracellular vesicle traffic, although its role in allergic responses is unclear. We demonstrated that exophilin-5, a Rab27-binding protein, was predominantly expressed in both of the major IL-33 producers, lung epithelial cells, and the specialized IL-5 and IL-13 producers in the CD44hiCD62LloCXCR3lo pathogenic Th2 cell population in mice. Exophilin-5 deficiency increased stimulant-dependent damage and IL-33 secretion by lung epithelial cells. Moreover, it enhanced IL-5 and IL-13 production in response to TCR and IL-33 stimulation from a specific subset of pathogenic Th2 cells that expresses a high level of IL-33 receptor, which exacerbated allergic airway inflammation in a mouse model of asthma. Mechanistically, exophilin-5 regulates extracellular superoxide release, intracellular ROS production, and phosphoinositide 3-kinase activity by controlling intracellular trafficking of Nox2-containing vesicles, which seems to prevent the overactivation of pathogenic Th2 cells mediated by IL-33. This is the first report to our knowledge to establish the significance of the Rab27-related protein exophilin-5 in the development of allergic airway inflammation, and provides insights into the pathophysiology of asthma.


Hierarchy of Information Processing in the Brain: A Novel 'Intrinsic Ignition' Framework.
A general theory of brain function has to be able to explain local and non-local network computations over space and time. We propose a new framework to capture the key principles of how local activity influences global computation, i.e., describing the propagation of information and thus the broadness of communication driven by local activity. More specifically, we consider the diversity in space (nodes or brain regions) over time using the concept of intrinsic ignition, which are naturally occurring intrinsic perturbations reflecting the capability of a given brain area to propagate neuronal activity to other regions in a given brain state. Characterizing the profile of intrinsic ignition for a given brain state provides insight into the precise nature of hierarchical information processing. Combining this data-driven method with a causal whole-brain computational model can provide novel insights into the imbalance of brain states found in neuropsychiatric disorders.


Identification of a novel tetrameric structure for human apolipoprotein-D.
Apolipoprotein-D is a 25 kDa glycosylated member of the lipocalin family that folds into an eight-stranded β-barrel with a single adjacent α-helix. Apolipoprotein-D specifically binds a range of small hydrophobic ligands such as progesterone and arachidonic acid and has an antioxidant function that is in part due to the reduction of peroxidised lipids by methionine-93. Therefore, apolipoprotein-D plays multiple roles throughout the body and is protective in Alzheimer's disease, where apolipoprotein-D overexpression reduces the amyloid-β burden in Alzheimer's disease mouse models. Oligomerisation is a common feature of lipocalins that can influence ligand binding. The native structure of apolipoprotein-D, however, has not been conclusively defined. Apolipoprotein-D is generally described as a monomeric protein, although it dimerises when reducing peroxidised lipids. Here, we investigated the native structure of apolipoprotein-D derived from plasma, breast cyst fluid (BCF) and cerebrospinal fluid. In plasma and cerebrospinal fluid, apolipoprotein-D was present in high-molecular weight complexes, potentially in association with lipoproteins. In contrast, apolipoprotein-D in BCF formed distinct oligomeric species. We assessed apolipoprotein-D oligomerisation using native apolipoprotein-D purified from BCF and a suite of complementary methods, including multi-angle laser light scattering, analytical ultracentrifugation and small-angle X-ray scattering. Our analyses showed that apolipoprotein-D predominantly forms a ∼95 to ∼100 kDa tetramer. Small-angle X-ray scattering analysis confirmed these findings and provided a structural model for apolipoprotein-D tetramer. These data indicate apolipoprotein-D rarely exists as a free monomer under physiological conditions and provide insights into novel native structures of apolipoprotein-D and into oligomerisation behaviour in the lipocalin family.


A Rasch analysis of the Brief Pain Inventory Interference subscale reveals three dimensions and an age bias.
The Brief Pain Inventory is composed of two quantifiable scales: pain severity and pain interference. The reported factor structure of the interference subscale is not consistent in the extant literature, with no clear choice between a single- or two-factor structure. Here, we report on the results of Rasch-based analysis of the interference subscale using a large population-based ambulatory patient database (the Quebec Pain Registry). Observational cohort. A total of 1,000 responses were randomly drawn from a total database of 5,654 for this analysis. Both the original 7-item and an expanded 10-item version (Tyler 2002) of the interference subscale were evaluated. Rasch analysis revealed significant misfit of both versions of the scale, with the original 7-item version outperforming the expanded 10-item version. Analysis of dimensionality revealed that both versions showed improved model fit when considered two subscales (affective and physical interference) with the item on sleep interference removed or considered separately. Additionally, significant uniform differential item functioning was identified for 6 of the 7 original items when the sample was stratified by age above or below 55 years. The interference subscale achieved adequate model fit when considered as two separate subscales with age as a mediator of response, while interpreting the sleep interference item separately. A transformation matrix revealed that in all cases, ordinal-level change at the extreme ends of the scale appears to be more meaningful than does a similar change at the midpoints. The Interference subscale of the BPI should be interpreted as two separate subscales (Affective Interference, Physical Interference) with the sleep item removed or interpreted separately for optimal fit to the Rasch model. Implications for research and clinical use are discussed.


Adoptive transfer of zoledronate-expanded autologous Vγ9Vδ2 T-cells in patients with treatment-refractory non-small-cell lung cancer: a multicenter, open-label, single-arm, phase 2 study.
Not all non-small cell lung cancer (NSCLC) patients possess drug-targetable driver mutations, and response rates to immune checkpoint blockade therapies also remain unsatisfactory. Therefore, more effective treatments are still needed. Here, we report the results of a phase 2 clinical trial of adoptive cell therapy using zoledronate-expanded autologous Vγ9Vδ2 T-cells for treatment-refractory NSCLC. NSCLC patients who had undergone at least two regimens of standard chemotherapy for unresectable disease or had had at least one treatment including chemotherapy or radiation for recurrent disease after surgery were enrolled in this open-label, single-arm, multicenter, phase 2 study. After preliminary testing of Vγ9Vδ2 T-cell proliferation, autologous peripheral blood mononuclear cells were cultured with zoledronate and IL-2 to expand the Vγ9Vδ2 T-cells. Cultured cells (>1×109) were intravenously administered every 2 weeks for six injections. The primary endpoint of this study was progression-free survival (PFS), and secondary endpoints included overall survival (OS), best objective response rate (ORR), disease control rate (DCR), safety and immunomonitoring. Clinical efficacy was defined as median PFS significantly >4 months. Twenty-five patients (20 adenocarcinoma, 4 squamous cell carcinoma and 1 large cell carcinoma) were enrolled. Autologous Vγ9Vδ2 T-cell therapy was administered to all 25 patients, of which 16 completed the foreseen course of 6 injections of cultured cells. Median PFS was 95.0 days (95% CI 73.0 to 132.0 days); median OS was 418.0 days (179.0-479.0 days), and best overall responses were 1 partial response, 16 stable disease (SD) and 8 progressive disease. ORR and DCR were 4.0% (0.1%-20.4%) and 68.0% (46.5%-85.1%), respectively. Severe adverse events developed in nine patients, mostly associated with disease progression. In one patient, pneumonitis and inflammatory responses resulted from Vγ9Vδ2 T-cell infusions, together with the disappearance of a massive tumor. Although autologous Vγ9Vδ2 T-cell therapy was well tolerated and may have an acceptable DCR, this trial did not meet its primary efficacy endpoint. UMIN000006128.


Bonobos and chimpanzees remember familiar conspecifics for decades.
Recognition and memory of familiar conspecifics provides the foundation for complex sociality and is vital to navigating an unpredictable social world [Tibbetts and Dale, Trends Ecol. Evol. 22, 529-537 (2007)]. Human social memory incorporates content about interactions and relationships and can last for decades [Sherry and Schacter, Psychol. Rev. 94, 439-454 (1987)]. Long-term social memory likely played a key role throughout human evolution, as our ancestors increasingly built relationships that operated across distant space and time [Malone et al., Int. J. Primatol. 33, 1251-1277 (2012)]. Although individual recognition is widespread among animals and sometimes lasts for years, little is known about social memory in nonhuman apes and the shared evolutionary foundations of human social memory. In a preferential-looking eye-tracking task, we presented chimpanzees and bonobos (N = 26) with side-by-side images of a previous groupmate and a conspecific stranger of the same sex. Apes' attention was biased toward former groupmates, indicating long-term memory for past social partners. The strength of biases toward former groupmates was not impacted by the duration apart, and our results suggest that recognition may persist for at least 26 y beyond separation. We also found significant but weak evidence that, like humans, apes may remember the quality or content of these past relationships: apes' looking biases were stronger for individuals with whom they had more positive histories of social interaction. Long-lasting social memory likely provided key foundations for the evolution of human culture and sociality as they extended across time, space, and group boundaries.


Antecedents of basic psychological need satisfaction of pharmacy students: The role of peers, family, lecturers and workload.
Self-determination theory (SDT) provides a model to improve pharmacy students' well-being or functioning in their study context. According to SDT, students need a context that satisfies their needs for autonomy, relatedness and competence in order to function optimally. Contextual factors that could have an impact on a student's functioning are lecturers, family, peers and workload. To investigate whether there is a difference between the contributions family, lecturers, peers and workload make towards the satisfaction of pharmacy students' basic psychological needs within a university context. An electronic survey was administered amongst students registered with the North-West University's School of Pharmacy. Registered pharmacy students, 779, completed said electronic survey comprised of a questionnaire on demographics, BMPN (Balanced Measure of Psychological Needs) and self-developed ANPNS (Antecedents of Psychological Need-satisfaction Scale). Data derived from the afore-going was analysed with the aid of structural equation modelling (SEM). Structural equation modelling explained 46%, 25% and 30% respectively of the total group's variances in autonomy, competence and relatedness satisfaction, and 26% of the variance in psychological need frustration. Peers and family played a significant role in the satisfaction of students' need for autonomy, relatedness and competence, whilst workload seemingly hampered satisfaction with regards to relatedness and autonomy. Workload contributed towards frustration with regards to psychological need satisfaction. The role played by lecturers in satisfying pharmacy students' need for autonomy, relatedness and competence will also be highlighted. This study added to the body of knowledge regarding contextual factors and the impact those factors have on pharmacy students' need satisfaction by illustrating that not all factors (family, lecturers, peers and workload) can be considered equal. Lecturers ought to recognise the important role family and peers play in the emotional and mental wellbeing of students and utilise those factors in their teaching. The mechanism of basic psychological need satisfaction as described in Self-determination theory provide insight into pharmacy students' optimal functioning. Hence the influence of contextual factors, (lecturers, peers, family and workload) on the need satisfaction was investigated by means of a survey. The structural model explained 46%, 25% and 30% of the variances in autonomy, competence and relatedness satisfaction and 26% of the variance in psychological need frustration. Family and Peer support contributed the most to the variance explained of the variables. Lecturers should acknowledge this important role of family and peers and utilise this premise when they design learning encounters.


A comparative study of postoperative port-site pain after gallbladder retrieval from umbilical versus epigastric ports in laparoscopic cholecystectomy.
Gall bladder (GB) retrieval is an important cause for postoperative pain after laparoscopic cholecystectomy (LC). GB is usually extracted either from the epigastric or the umbilical port and there are limited data to decide the superiority of one over other in terms of postoperative pain. This study was designed to determine whether GB retrieval from the umbilical port was associated with less pain as compared to epigastric port in adult patients undergoing four ports elective LC. A total of 100 patients took part in the study and were randomly allocated into 2 groups. Postoperatively, port-site pain score was assessed at 1, 6, 12, and 24 h by visual analog scale (VAS) score both for the epigastric and umbilical ports in all the patients and the collected data were analyzed by using SPSS version 22. VAS score for postoperative pain at epigastric port at 1, 6, 12, and 24 h found to be higher as compared to umbilical port (6.640 ± 1.494 vs. 5.500 ± 1.176, 6.620 ± 1.549 vs. 5.320 ± 1.188, 6.100 ± 1.549 vs. 4.660 ± 1.232, 5.250 ± 1.459 vs. 3.970 ± 1.274, respectively) which was statistically significant (P value 0.001). But the time taken for retrieval of GB was significantly longer in the umbilical group (4.94 ± 1.56 vs. 3.24 ± 1.29). Umbilical port is better as compared to epigastric port for GB retrieval in patient undergoing elective four port LC in terms of postoperative port-site pain but it takes relatively longer time for the extraction.


Bladder cancer--genetic overview.
This article review the serial genetic changes which are responsible to the initiation and progression of bladder cancer. Knowledge of the exact genetic alteration has a direct implication on the development of knew more sensitive and specific tool for an early diagnosis and better prognosis calculations. Bladder cancer develop and progress through a series of genetic alterations. Understanding of the genetic mechanisms which lead to malignant transformation gave rise to the development of various genetic mechanisms which lead to malignant transformation gave rise to the development of various genetic tools providing better ability of early detection and more accurate prognosis prediction.


Prolactin-induced mouse mammary carcinomas model estrogen resistant luminal breast cancer.
Tumors that express estrogen receptor alpha (ERα+) comprise 75% of breast cancers in women. While treatments directed against this receptor have successfully lowered mortality rates, many primary tumors initially or later exhibit resistance. The paucity of murine models of this "luminal" tumor subtype has hindered studies of factors that promote their pathogenesis and modulate responsiveness to estrogen-directed therapeutics. Since epidemiologic studies closely link prolactin and the development of ERα+ tumors in women, we examined characteristics of the aggressive ERα+ and ERα- carcinomas which develop in response to mammary prolactin in a murine transgenic model (neu-related lipocalin- prolactin (NRL-PRL)). To evaluate their relationship to clinical tumors, we determined phenotypic relationships among these carcinomas, other murine models of breast cancer, and features of luminal tumors in women. We examined a panel of prolactin-induced tumors for characteristics relevant to clinical tumors: histotype, ERα/progesterone receptor (PR) expression and estrogen responsiveness, Activating Protein 1 (AP-1) components, and phosphorylation of signal transducer and activator of transcription 5 (Stat5), extracellular signal regulated kinase (ERK) 1/2 and AKT. We compared levels of transcripts in the ERα-associated "luminal" signature that defines this subtype of tumors in women and transcripts enriched in various mammary epithelial lineages to other well-studied genetically modified murine models of breast cancer. Finally, we used microarray analyses to compare prolactin-induced ERα+ and ERα- tumors, and examined responsiveness to estrogen and the anti-estrogen, Faslodex, in vivo. Prolactin-induced carcinomas were markedly diverse with respect to histotype, ERα/PR expression, and activated signaling cascades. They constituted a heterogeneous, but distinct group of murine mammary tumors, with molecular features of the luminal subtype of human breast cancer. In contrast to morphologically normal and hyperplastic structures in NRL-PRL females, carcinomas were insensitive to ERα-mediated signals. These tumors were distinct from mouse mammary tumor virus (MMTV)-neu tumors, and contained elevated transcripts for factors associated with luminal/alveolar expansion and differentiation, suggesting that they arose from physiologic targets of prolactin. These features were shared by ERα+ and ERα- tumors, suggesting a common origin, although the former exhibited transcript profiles reflecting greater differentiation. Our studies demonstrate that prolactin can promote diverse carcinomas in mice, many of which resemble luminal breast cancers, providing a novel experimental model to examine the pathogenesis, progression and treatment responsiveness of this tumor subtype.


Distinctive Paleo-Indian migration routes from Beringia marked by two rare mtDNA haplogroups.
It is widely accepted that the ancestors of Native Americans arrived in the New World via Beringia approximately 10 to 30 thousand years ago (kya). However, the arrival time(s), number of expansion events, and migration routes into the Western Hemisphere remain controversial because linguistic, archaeological, and genetic evidence have not yet provided coherent answers. Notably, most of the genetic evidence has been acquired from the analysis of the common pan-American mitochondrial DNA (mtDNA) haplogroups. In this study, we have instead identified and analyzed mtDNAs belonging to two rare Native American haplogroups named D4h3 and X2a. Phylogeographic analyses at the highest level of molecular resolution (69 entire mitochondrial genomes) reveal that two almost concomitant paths of migration from Beringia led to the Paleo-Indian dispersal approximately 15-17 kya. Haplogroup D4h3 spread into the Americas along the Pacific coast, whereas X2a entered through the ice-free corridor between the Laurentide and Cordilleran ice sheets. The examination of an additional 276 entire mtDNA sequences provides similar entry times for all common Native American haplogroups, thus indicating at least a dual origin for Paleo- Indians. A dual origin for the first Americans is a striking novelty from the genetic point of view, and it makes plausible a scenario positing that within a rather short period of time, there may have been several entries into the Americas from a dynamically changing Beringian source. Moreover, this implies that most probably more than one language family was carried along with the Paleo-Indians.


Platelet endothelial cell adhesion molecule-1 signaling inhibits the activation of human platelets.
Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) is a 130-kd transmembrane glycoprotein and a member of the growing family of receptors with immunoreceptor tyrosine-based inhibitory motifs (ITIMs). PECAM-1 is expressed on platelets, certain T cells, monocytes, neutrophils, and vascular endothelial cells and is involved in a range of cellular processes, though the role of PECAM-1 in platelets is unclear. Cross-linking of PECAM-1 results in phosphorylation of the ITIM allowing the recruitment of signaling proteins that bind by way of Src-homology domain 2 interactions. Proteins that have been implicated in the negative regulation of cellular activation by ITIM-bearing receptors include the tyrosine phosphatases SHP-1 and SHP-2. Tyrosine phosphorylation of immunoreceptor tyrosine-based activatory motif (ITAM)-bearing receptors such as the collagen receptor GPVI-Fc receptor gamma-chain complex on platelets leads to activation. Increasing evidence suggests that ITIM- and ITAM-containing receptors may act antagonistically when expressed on the same cell. In this study it is demonstrated that cross-linking PECAM-1 inhibits the aggregation and secretion of platelets in response to collagen and the GPVI-selective agonist convulxin. In these experiments thrombin-mediated platelet aggregation and secretion were also reduced, albeit to a lesser degree than for collagen, suggesting that PECAM-1 function may not be restricted to the inhibition of ITAM-containing receptor pathways. PECAM-1 activation also inhibited platelet protein tyrosine phosphorylation stimulated by convulxin and thrombin; this was accompanied by inhibition of the mobilization of calcium from intracellular stores. These data suggest that PECAM-1 may play a role in the regulation of platelet function in vivo.


Room-Temperature Cu-Catalyzed Amination of Aryl Bromides Enabled by DFT-Guided Ligand Design.
Ullmann-type C-N coupling reactions represent an important alternative to well-established Pd-catalyzed approaches due to the differing reactivity and the lower cost of Cu. While the design of anionic Cu ligands, particularly those by Ma, has enabled the coupling of various classes of aryl halides and alkyl amines, most methods require conditions that can limit their utility on complex substrates. Herein, we disclose the development of anionic N1,N2-diarylbenzene-1,2-diamine ligands that promote the Cu-catalyzed amination of aryl bromides under mild conditions. Guided by DFT calculations, these ligands were designed to (1) increase the electron density on Cu, thereby increasing the rate of oxidative addition of aryl bromides, and (2) stabilize the active anionic CuI complex via a π-interaction. Under optimized conditions, structurally diverse aryl and heteroaryl bromides and a broad range of alkyl amine nucleophiles, including pharmaceuticals bearing multiple functional groups, were efficiently coupled at room temperature. Combined computational and experimental studies support a mechanism of C-N bond formation that follows a catalytic cycle akin to the well-explored Pd-catalyzed variants. Modification of the ligand structure to include a naphthyl residue resulted in a lower energy barrier to oxidative addition, providing a 30-fold rate increase relative to what is seen with other ligands. Collectively, these results establish a new class of anionic ligands for Cu-catalyzed C-N couplings, which we anticipate may be extended to other Cu-catalyzed C-heteroatom and C-C bond-forming reactions.


Bedside Music Therapy for Women during Antepartum and Postpartum Hospitalization.
Stress and anxiety are prevalent during pregnancy and postpartum with adverse effects on mothers and newborns, yet women's psychological and emotional needs are often given a lower priority than their physical wellbeing. The purpose of this study was to assess feasibility of implementing a bedside music therapy intervention to alleviate stress and anxiety, provide emotional support, and facilitate mother-baby bonding for women during antepartum and postpartum hospitalization at a large urban medical center. Over 15 months, women on three units who were hospitalized during antepartum or postpartum were referred for music therapy and received a single bedside session from a credentialed music therapist (MT-BC), including tailored interventions and education in relaxation techniques. A retrospective analysis of postintervention feedback questionnaires and process notes was conducted to assess participant receptivity and satisfaction, and the feasibility of implementing the program on the units. Music therapy was provided to 223 postpartum and 97 antepartum patients. The program was found to be feasible and well received, including high satisfaction, positive effects on participants' relaxation and sense of connection with their baby, and enthusiastic reception from providers and staff. Qualitative feedback revealed salient themes including the effect of the intervention on mothers' mental, emotional and physical states, and the soothing effect of music on their newborns. Hospitals are in a unique position to provide support services and self-care education for women during their antepartum and postpartum hospitalization. Music therapy can be integrated successfully into inpatient care as a nurturing and patient-centered form of psychosocial support.


The significance of MDM2 SNP309 and p53 Arg72Pro in young women with breast cancer.
The p53 protein and its regulator MDM2 is central to tumorigenesis by directing cells to undergo cell cycle arrest and/or apoptosis in response to DNA damage or other stress signals. The genes encoding these proteins contain nucleotide variation (p53 codon 72, MDM2 SNP309) that influences cellular response. We examined the p53 codon 72 and MDM2 SNP309 to determine their implication with age of disease onset and risk of breast cancer in young women (<or=36 years). No risk of breast cancer was observed for the genotypes of p53 and MDM2, however, a tendency (P=0.15) towards increased risk of early onset breast cancer was observed in carriers of two or more Pro and/or G alleles. We further calculated the influence on age at diagnosis. Cases were grouped according to the number of G and Pro alleles (0, 1, 2 or 3-4) and age at diagnosis. A significant trend towards decreased age at diagnosis with increased number of risk alleles was found (P=0.013). Our results suggest that p53 codon 72 and MDM2 SNP309 may be implicated in early onset breast cancer.


Five drug regimens for treatment of acute toxoplasmosis in squirrel monkeys.
Five drug regimens for the treatment of acute toxoplasmosis were compared in a monkey model. Systemic disease that is almost always fatal in squirrel monkeys within 7-9 days was produced by oral inoculation of a brain suspension made from mice chronically infected with the Beverly strain of Toxoplasma gondii. All untreated controls died of toxoplasmosis (6/6) while treatment gave the following results: sulfamethoxazole, 0/3; spiramycin, 5/5; clindamycin/sulfadiazine (CLD/SLD), 0/4; pyrimethamine/sulfadiazine (PYR/SLD), 0/5; trimethoprim/sulfamethoxazole (TMP/SMZ), 0/4. Three of the five monkeys treated with CLD/SLD died during or shortly after the experiment from probable CLD toxicity. Sulfonamides alone or in combination with PYR or TMP were significantly more effective than spiramycin in treating toxoplasmosis in this model. The dose regimen used in this study did not allow us to determine if the addition of PYR or TMP changed the protection of sulfa alone.


Balancing the rates of new bone formation and polymer degradation enhances healing of weight-bearing allograft/polyurethane composites in rabbit femoral defects.
There is a compelling clinical need for bone grafts with initial bone-like mechanical properties that actively remodel for repair of weight-bearing bone defects, such as fractures of the tibial plateau and vertebrae. However, there is a paucity of studies investigating remodeling of weight-bearing bone grafts in preclinical models, and consequently there is limited understanding of the mechanisms by which these grafts remodel in vivo. In this study, we investigated the effects of the rates of new bone formation, matrix resorption, and polymer degradation on healing of settable weight-bearing polyurethane/allograft composites in a rabbit femoral condyle defect model. The grafts induced progressive healing in vivo, as evidenced by an increase in new bone formation, as well as a decrease in residual allograft and polymer from 6 to 12 weeks. However, the mismatch between the rates of autocatalytic polymer degradation and zero-order (independent of time) new bone formation resulted in incomplete healing in the interior of the composite. Augmentation of the grafts with recombinant human bone morphogenetic protein-2 not only increased the rate of new bone formation, but also altered the degradation mechanism of the polymer to approximate a zero-order process. The consequent matching of the rates of new bone formation and polymer degradation resulted in more extensive healing at later time points in all regions of the graft. These observations underscore the importance of balancing the rates of new bone formation and degradation to promote healing of settable weight-bearing bone grafts that maintain bone-like strength, while actively remodeling.


Interactions of the Bacillus subtilis DnaE polymerase with replisomal proteins modulate its activity and fidelity.
During Bacillus subtilis replication two replicative polymerases function at the replisome to collectively carry out genome replication. In a reconstituted in vitro replication assay, PolC is the main polymerase while the lagging strand DnaE polymerase briefly extends RNA primers synthesized by the primase DnaG prior to handing-off DNA synthesis to PolC. Here, we show in vivo that (i) the polymerase activity of DnaE is essential for both the initiation and elongation stages of DNA replication, (ii) its error rate varies inversely with PolC concentration, and (iii) its misincorporations are corrected by the mismatch repair system post-replication. We also found that the error rates in cells encoding mutator forms of both PolC and DnaE are significantly higher (up to 15-fold) than in PolC mutants. In vitro, we showed that (i) the polymerase activity of DnaE is considerably stimulated by DnaN, SSB and PolC, (ii) its error-prone activity is strongly inhibited by DnaN, and (iii) its errors are proofread by the 3' > 5' exonuclease activity of PolC in a stable template-DnaE-PolC complex. Collectively our data show that protein-protein interactions within the replisome modulate the activity and fidelity of DnaE, and confirm the prominent role of DnaE during B. subtilis replication.


Determinants of coronary collateral circulation in patients with coronary artery disease.
This study aims to identify possible determinants of coronary collaterals in patients with severe coronary artery disease. The current study has a retrospective cohort design. Seventy four patients with ≥90% stenosis or total occlusion of the left anterior descending artery (LAD) were enrolled; coronary collateral grades, high-sensitive C-reactive protein (hs-CRP), fibrinogen, protein C and S, lipids, uric acid levels and medications applied before coronary angiography were noted and compared. Multiple logistic regression analysis was used for the multivariate analyses of independent variables associated with the development of adequate coronary collateral vessels. The presence of coronary collaterals was significantly higher in males (p=0.018), with higher hs-CRP (p=0.023), prior statin use (p=0.022), and higher Gensini scores (p<0.001). In multiple logistic regression analysis, hs-CRP levels (OR=0.94, 95.0% CI=0.883-1.000, p=0.048), male gender (OR=4.73, 95.0% CI=1.441-15.539, p=0.010) and prior statin usage (OR=4.70, 95.0% CI=1.264-17.452, p=0.021) were identified as independent predictors of coronary collateral development. Male gender, prior statin usage, and higher hs-CRP levels are determinants of coronary collaterals in patients with coronary artery disease.


Single-crystal structures, optical absorptions, and electronic distributions of thorium oxychalcogenides ThOQ (Q = S, Se, Te).
The compounds ThOS, ThOSe, and ThOTe have been synthesized, and their structures have been determined by means of single-crystal X-ray diffraction methods. All three compounds adopt the PbFCl structure type in the tetragonal space group D(4h)(7) - P4/nmm. More precise crystallographic data have been obtained for ThOS and ThOSe, which had previously only been known from X-ray powder diffraction data. ThOS, ThOSe, and ThOTe are yellow-, orange-, and black-colored, respectively. From single-crystal optical absorption measurements the band gaps are 2.22, 1.65, and 1.45 eV, respectively. Optical band gaps, ionic charges, and densities of states were calculated for the three compounds with the use of Density Functional methods.


Identification of in vitro and in vivo disconnects using transcriptomic data.
Integrating transcriptomic experiments within drug development is increasingly advocated for the early detection of toxicity. This is partly to reduce costs related to drug failures in the late, and expensive phases of clinical trials. Such an approach has proven useful both in the study of toxicology and carcinogenicity. However, general lack of translation of in vitro findings to in vivo systems remains one of the bottle necks in drug development. This paper proposes a method for identifying disconnected genes between in vitro and in vivo toxicogenomic rat experiments. The analytical framework is based on the joint modeling of dose-dependent in vitro and in vivo data using a fractional polynomial framework and biclustering algorithm. Most disconnected genes identified belonged to known pathways, such as drug metabolism and oxidative stress due to reactive metabolites, bilirubin increase, glutathion depletion and phospholipidosis. We also identified compounds that were likely to induce disconnect in gene expression between in vitro and in vivo toxicogenomic rat experiments. These compounds include: sulindac and diclofenac (both linked to liver damage), naphtyl isothiocyanate (linked to hepatoxocity), indomethacin and naproxen (linked to gastrointestinal problem and damage of intestines). The results confirmed that there are important discrepancies between in vitro and in vivo toxicogenomic experiments. However, the contribution of this paper is to provide a tool to identify genes that are disconnected between the two systems. Pathway analysis of disconnected genes may improve our understanding of uncertainties in the mechanism of actions of drug candidates in humans, especially concerning the early detection of toxicity.


Hispolon inhibition of inflammatory apoptosis through reduction of iNOS/NO production via HO-1 induction in macrophages.
Phellinus linteus (Berkeley & Curtis), a well-known medical fungus, has long been used as a traditional medicine in Oriental countries to treat various diseases, and hispolon (HIS) is one of its bioactive components. HIS is known to possess potent antineoplastic and antiviral properties; however, its effect on inflammatory apoptosis is still undefined. RAW264.7 macrophages were incubated with HIS for 30 min followed by LPS, LTA, or PGN stimulation for 12h. The expression of indicated proteins AP-1 and NF-κB transcriptional activities was examined by Western blotting using specific antibodies. Levels of NO and ROS were examined by Griess reaction, and DCHF-DA staining via flow cytometric analysis, respectively. AP-1 and NF-κB transcriptional activities were detected by luciferase reporter assay. Knockdown of HO-1 protein expression was performed by transfection of macrophages with HO-1 siRNA. Pharmacological inhibitors including ROS scavenger NAC, JNK inhibitor SP600125, NF-κB inhibitor BAY117082 were applied for mechanism study. HIS showed concentration-dependent inhibition of LPS, LTA, and PGN-induced iNOS protein expressions and NO production by RAW264.7 macrophages. Accordingly, HIS protected RAW264.7 cells from LPS-, LTA-, and PGN-induced apoptosis. Increased HO-1 by HIS was detected at both protein and mRNA levels along with an increase in intracellular peroxide, and this was inhibited by the translational inhibitor, cycloheximide (CHX), the transcriptional inhibitor, actinomycin D (Act D), and the reactive oxygen species scavenger, N-acetylcysteine (NAC). A mechanistic study indicated that inhibition of c-Jun N-terminal kinase (JNK) protein phosphorylation, and activator protein (AP)-1 and nuclear factor (NF)-κB activation were involved in the anti-inflammatory actions of HIS in macrophages. A structure-activity relationship analysis showed that HIS expressed the most potent effect of inhibiting iNOS and apoptosis elicited by LPS, LTA, and PGN with a significant increase in HO-1 protein in macrophages. Evidence supporting HIS prevention of inflammatory apoptosis via blocking NO production and inducing HO-1 protein expression in macrophages is provided, and the hydroxyl at position C3 is a critical substitution for the anti-inflammatory actions of HIS.


Integrated research of a multi-wavelength method in anisotropic scattering flame on soot temperature and radiative coefficient reconstruction.
At present, the studies of scattering flame problems combined with multi-wavelength reconstruction technology are rather limited. In this paper, a multi-wavelength method combined with a collocation spectral method (CSM)-discrete ordinates method (DOM) forward method is developed for the simultaneous reconstruction of temperature and inhomogeneous radiative coefficient of an axisymmetric laminar ethylene diffusion flame. The scattering source term in the radiative transfer equation is solved by the forward solution method based on DOM, which couples a spatial scheme of CSM and the spherical rings arithmetic progression quadrature. The Tikhonov regularized method is employed to overcome the ill-posed matrix to obtain the global radiative source term. The boundary radiation intensity is input into the algorithm as a known value for inversion of temperature, absorption coefficient, and scattering coefficient. The retrieval results demonstrate that the temperature and the radiation parameters of the scattering flame can be well reconstructed for the flame with axisymmetric distribution, even for the flame with noisy data. In addition, the scattering coefficient is more difficult to rebuild than temperature. The inversion accuracy does not deteriorate with a slight increase in noise. Also, the addition of scattering terms to the proposed algorithm can improve the accuracy in reconstructing the radiation parameters. The developed method in this paper would be useful for multispectral algorithms, which could be used in later experiments based on hyperspectral techniques.


Invertebrate Biosecurity Challenges in High-Productivity Grassland: The New Zealand Example.
To protect productive grasslands from pests and diseases, effective pre- and at-border planning and interventions are necessary. Biosecurity failure inevitably requires expensive and difficult eradication, or long-term and often quite ineffective management strategies. This is compared to the early intervention more likely for sectors where there is public and political interest in plants of immediate economic and/or social value, and where associated pests are typically located above-ground on host plantings of relatively limited distribution. Here, biosecurity surveillance and responses can be readily designed. In contrast, pastures comprising plants of low inherent unit value create little, if any, esthetic interest. Yet, given the vast extent of pasture in New Zealand and the value of the associated industries, these plants are of immense economic importance. Compounding this is the invasibility of New Zealand's pastoral ecosystems through a lack of biotic resistance to incursion and invasion. Further, given the sheer area of pasture, intervention options are limited because of costs per unit area and the potential for pollution if pesticides are used. Biosecurity risk for pastoral products differs from, say, that of fruit where at least part of an invasive pathway can be recognized and risks assessed. The ability to do this via pastoral sector pathways is much reduced, since risk organisms more frequently arrive via hitchhiker pathways which are diffuse and varied. Added to this pasture pests within grassland ecosystems are typically cryptic, often with subterranean larval stages. Such characteristics make detection and response particularly difficult. The consequences of this threaten to add to the already-increasing stressors of production intensification and climate change. This review explores the unique challenges faced by pasture biosecurity and what may be done to confront existing difficulties. While there is no silver bullet, and limited opportunity pre- and at-border for improving pasture biosecurity, advancement may include increased and informed vigilance by farmers, pheromone traps and resistant plants to slow invasion. Increasingly, there is also the potential for more use of improved population dispersal models and surveillance strategies including unmanned aerial vehicles, as well as emerging techniques to determine invasive pest genomes and their geographical origins.


Genetic enhancement, human nature, and rights.
Authors such as Francis Fukuyama, the President's Council on Bioethics, and George Annas have argued that biotechnological interventions that aim to promote genetic enhancement pose a threat to human nature. This paper clarifies what conclusions these critics seek to establish, and then shows that there is no plausible account of human nature that will meet the conditions necessary to support this position. Appeals to human nature cannot establish a prohibition against the pursuit of genetic enhancement.


Circulating tumor microemboli diagnostics for patients with non-small-cell lung cancer.
Circulating tumor microemboli (CTM) are potentially important cancer biomarkers, but using them for cancer detection in early-stage disease has been assay limited. We examined CTM test performance using a sensitive detection platform to identify stage I non-small-cell lung cancer (NSCLC) patients undergoing imaging evaluation. First, we prospectively enrolled patients during 18F-FDG PET-CT imaging evaluation for lung cancer that underwent routine phlebotomy where CTM and circulating tumor cells (CTCs) were identified in blood using nuclear (DAPI), cytokeratin (CK), and CD45 immune-fluorescent antibodies followed by morphologic identification. Second, CTM and CTC data were integrated with patient (age, gender, smoking, and cancer history) and imaging (tumor diameter, location in lung, and maximum standard uptake value [SUVmax]) data to develop and test multiple logistic regression models using a case-control design in a training and test cohort followed by cross-validation in the entire group. We examined 104 patients with NSCLC, and the subgroup of 80 with stage I disease, and compared them to 25 patients with benign disease. Clinical and imaging data alone were moderately discriminating for all comers (Area under the Curve [AUC] = 0.77) and by stage I disease only (AUC = 0.77). However, the presence of CTM combined with clinical and imaging data was significantly discriminating for diagnostic accuracy in all NSCLC patients (AUC = 0.88, p value = 0.001) and for stage I patients alone (AUC = 0.87, p value = 0.002). CTM may add utility for lung cancer diagnosis during imaging evaluation using a sensitive detection platform.


A novel telomere elongation in an adriamycin-resistant stomach cancer cell line with decreased telomerase activity.
Actively dividing cells show progressive loss of telomeric DNA during successive rounds of replication due to end-replication problem. Telomere shortening has been proposed as a regulatory mechanism that controls the replicative capacity of primary cells before undergoing cellular senescence. In immortal cells including cancer, cellular senescence can be overcome by reactivation of telomerase or by a telomerase-independent mechanism for lengthening telomeres. In this work, we present a novel example of telomere elongation mechanism in a human stomach adenocarcinoma cell line which was selected for resistance to adriamycin. The resistant cell line (MKN/ADR) had long terminal restriction fragments (TRFs) of up to approximately 50 kb, while its parent cell line (MKN-45) had the TRFs, consisting of a smear extending from approximately 4 to approximately 25 kb. The very large TRFs in MKN/ADR cell line were proven to be telomeric by digestion with the exonuclease Bal31. When telomerase activity was examined using the PCR-based telomeric repeat amplification protocol (TRAP) assay, MKN/ADR cell line showed reduced activity to about 10% of that in MKN-45 cell line. The correlation between reduced telomerase activity and mRNA expression of telomerase subunits in MKN/ADR cell line was assessed by the reverse transcriptase-PCR analysis. The level of human telomerase reverse transcriptase (hTERT) mRNA was lower in MKN/ADR cell line than in MKN-45 cell line. This observation correlates with the finding that telomerase activity is reduced about 10-fold in MKN/ADR cell line. Reverse transcriptase-PCR analysis also revealed a close correlation between telomerase-associated protein (TP1) mRNA expression and telomerase activity in MKN/ADR cell line. In contrast, expression levels of human telomerase RNA (hTR) were identical in both MKN/ADR and MKN-45 cell lines. Taken together, these data suggest that telomeres in MKN/ADR cell line may be regulated through a novel mechanism other than telomerase. Although the basis for telomere elongation mechanism in MKN/ADR cell line is not yet understood, the occurrence of alternative mechanism for telomere elongation in drug-resistant cancer cells may have an important implication for use of telomerase inhibitors in human cancer treatment.


Vocational services associated with competitive employment in 18-25 year old cancer survivors.
Young adult cancer survivors report difficulties related to employment. This study investigated the association of vocational services on work in young cancer survivors unemployed prior to receipt of services. Administrative data obtained for years 2004 and 2005 from the Rehabilitation Services Administration (RSA) database was used in the analyses. A total of 368 cases aged 18-25 who were closed during the 2 years with a diagnosis of cancer were identified. All cancer survivors were unemployed at the time of application. Data on demographic characteristics, employment and vocational services were extracted and analyzed in relation to employment. Multivariate logistic regression was used to examine the relationship among services provided and work outcomes accounting for demographic characteristics. Cancer survivors represented 0.4% of the total population that received vocational services in the state-federal vocational rehabilitation system. Of the unemployed cancer survivors who received services, 190 (51.6%) achieved successful employment while 178 (48.4%) were not employed following receipt of vocational rehabilitation services. Gender (woman) (OR = 1.79; 95% CI: 1.16 to 2.76), vocational training (OR = 2.03; 95% CI: 1.03 to 4.00), miscellaneous training (OR = 4.01; 95% CI: 1.80 to 8.97), job search assistance (OR = 4.01; 95% CI: 1.80 to 8.97), job placement services (OR = 2.24; 95% CI: 1.11 to 4.52), on-the-job support (OR = 4.20; 95% CI: 1.66 to 10.63), and maintenance services (OR = 2.85; 95% CI: 1.38 to 5.90) were all related to an increased odds for employment. Provision of cash or medical benefits (e.g., Social Security Disability Insurance benefits) (OR = 0.43; 95% CI: 0.28 to 0.67) was associated with lower employment following vocational services. Very few young adult cancer survivors were involved in the state-federal rehabilitation program. Despite this, the provision of certain vocational rehabilitation services was related to increased employment in this group. Those who received job search assistance and on the job support were four times more likely to be employed following such services. While those in receipt of benefits were less likely to be employed, it is very likely that those receiving such benefits are the more severe cases. It is worth noting that the exact direction of these relationships can not be determined with the current design. Young adult cancer survivors who are seeking employment and can qualify for such services may benefit from certain services offered by state vocational rehabilitation agencies. This represents another service to consider when employment is a goal.


Mutations in myelodysplastic syndromes: Core abnormalities and CHIPping away at the edges.
The myelodysplastic syndromes (MDS) are a heterogeneous constellation of hematologic malignancies characterized by aberrant differentiation and clonal expansion of abnormal myeloid cells that initially manifest with ineffective hematopoiesis and consequent cytopenias. The prognosis of MDS is variable and depends on clinical and hematologic parameters, cytogenetic and molecular findings, as well as comorbidities. Gene sequencing studies have uncovered remarkable genomic complexity within MDS, based on the presence of recurrent and sometimes co-operating mutations in genes encoding proteins that play a role in numerous biologic pathways. Although the treatment of MDS is currently limited to the use of hypomethylating, immunomodulatory, or erythropoiesis-stimulating agents, improved understanding of the molecular underpinnings of its pathophysiology has led to the development of multiple targeted treatments that are poised to be added to the therapeutic armamentarium. This review will focus on the role of mutations in the pathogenesis, diagnosis, and prognosis of MDS and how the discovery of clonal hematopoiesis of indeterminate potential (CHIP) might impact the utility of detecting mutations in the diagnosis of MDS.


Insights into the chemical partitioning of trace metals in roadside and off-road agricultural soils along two major highways in Attica's region, Greece.
We report in this study the magnetic properties and partitioning patterns of selected trace metals (Pb, Zn, Cu, Cd, Ni) in roadside and off-road (>200m distance from the road edge) agricultural soils collected along two major highways in Greece. Sequential extractions revealed that the examined trace metals for the entire data set were predominantly found in the residual fraction, averaging 37% for Cd up to 80% for Cu. Due to the strong influence of lithogenic factors, trace metal pseudototal contents of the roadside soils did not differ significantly to those of the off-road soils. Magnetic susceptibility and frequency dependent magnetic susceptibility determinations showed a magnetic enhancement of soils; however, it was primarily related to geogenic factors and not to traffic-derived magnetic particles. These results highlight that in areas characterized by strong geogenic backgrounds, neither pseudototal trace metal contents nor magnetic properties determinations effectively capture traffic-related contamination of topsoils. The vehicular emission signal was traced by the increased acid-soluble and reducible trace metal contents of the roadside soils compared to their off-road counterparts. In the case of Cu and Zn, changes in the partitioning patterns were also observed between the roadside and off-road soils. Environmental risks associated with agricultural lands extending at the margins of the studied highways may arise from the elevated Ni contents (both pseudototal and potentially mobile), and future studies should investigate Ni levels in the edible parts of plants grown on these agricultural soils.


DNA methyl transferase 1 reduces expression of SRD5A2 in the aging adult prostate.
5-α Reductase type 2 (SRD5A2) is a critical enzyme for prostatic development and growth. Inhibition of SRD5A2 by finasteride is used commonly for the management of urinary obstruction caused by benign prostatic hyperplasia. Contrary to common belief, we have found that expression of SRD5A2 is variable and absent in one third of benign adult prostates. In human samples, absent SRD5A2 expression is associated with hypermethylation of the SRD5A2 promoter, and in vitro SRD5A2 promoter activity is suppressed by methylation. We show that methylation of SRD5A2 is regulated by DNA methyltransferase 1, and inflammatory mediators such as tumor necrosis factor α, NF-κB, and IL-6 regulate DNA methyltransferase 1 expression and thereby affect SRD5A2 promoter methylation and gene expression. Furthermore, we show that increasing age in mice and humans is associated with increased methylation of the SRD5A2 promoter and concomitantly decreased protein expression. Artificial induction of inflammation in prostate primary epithelial cells leads to hypermethylation of the SRD5A2 promoter and silencing of SRD5A2, whereas inhibition with tumor necrosis factor α inhibitor reactivates SRD5A2 expression. Therefore, expression of SRD5A2 is not static and ubiquitous in benign adult prostate tissues. Methylation and expression of SRD5A2 may be used as a gene signature to tailor therapies for more effective treatment of prostatic diseases.


Mechanism of the hypoglycemic effect of stevioside, a glycoside of Stevia rebaudiana.
We have studied the effects of stevioside on the glucose and insulin metabolism in 2 models of diabetes in rats, STZ-induced diabetic rats and NIDDM diabetic rats induced by feeding with fructose. Stevioside (0.5 mg/kg), lowered the blood glucose levels in STZ-induced diabetic rats, peaking at 90 min. Stevioside administered twice daily also demonstrated dose-dependent effects in lowering the glucose levels in both diabetic rat models. Stevioside reduced the rise in glucose during glucose tolerance testing in normal rats. Stevioside dose-dependently decreased protein levels of phosphoenol pyruvate carboxykinase (PEPCK) and PEPCK mRNA after 15 days of treatment. Stevioside also reduced insulin resistance in the diabetic animals as shown by the glucose lowering effects of tolbutamide. In conclusion, stevioside was able to regulate blood glucose levels by enhancing not only insulin secretion, but also insulin utilization in insulin-deficient rats; the latter was due to decreased PEPCK gene expression in rat liver by stevioside's action of slowing down gluconeogenesis. Further studies of this agent for the treatment of diabetes appear warranted.


A proteomics approach to the cell-surface interactome using the enzyme-mediated activation of radical sources reaction.
We previously reported a simple method to analyze the interaction of cell-surface molecules in living cells. This method termed enzyme-mediated activation of radical sources (EMARS) is featured by radical formation of the labeling reagent by horseradish peroxidase (HRP). Herein, we propose an approach to the cell-surface molecular interactome by using combination of this EMARS reaction and MS-based proteomics techniques. In the current study, we employed a novel labeling reagent, fluorescein-conjugated arylazide. The fluorescein-tagged proteins resulting from the EMARS reaction were directly detected in the electrophoresis gels with a fluorescence image analyzer. These products were also purified and concentrated by immunoaffinity chromatography with anti-fluorescein antibody-immobilized resins. The purified fluorescein-tagged proteins were subsequently subjected to an MS-based proteomics analysis. Analysis using HRP-conjugated cholera toxin subunit B, which recognizes a lipid raft marker, ganglioside GM1, revealed 30 membrane and secreted proteins that were candidates for the cell-surface molecules coclustering with GM1. The proposed approach will provide a clue to study functional molecular interactions in a variety of biological events on the cell surface.