Cdc7 is a potent anti-cancer target in pancreatic cancer due to abrogation of the DNA origin activation checkpoint.
Cdc7 is a serine/threonine kinase which is responsible for the 'firing' of replication origins leading to initiation of DNA replication. Inhibition or depletion of Cdc7 in normal cells triggers a DNA origin activation checkpoint causing a reversible G1 arrest. Here we investigate Cdc7 as a novel therapeutic target in pancreatic cancer. Cdc7 target validation was performed by immunoexpression profiling in a cohort of 73 patients with pancreatic adenocarcinoma including 24 controls. Secondly Cdc7 kinase was targeted in Capan-1 and PANC-1 pancreatic cancer cell line models using either an siRNA against Cdc7 or alternatively a small molecule inhibitor (SMI) of Cdc7 (PHA-767491). Cdc7 was significantly overexpressed in pancreatic adenocarcinoma compared to benign pancreatic tissue (median LI 34.3% vs. 1.3%; P<0.0001). Cdc7 knockdown using siRNA in Capan-1 and PANC-1 cells resulted in marked apoptotic cell death when compared with control cells. A prominent sub-G1 peak was seen on flow cytometry (sub-G1 51% vs. 3% and 45% vs. 0.7% in Capan-1 and PANC-1 cells, respectively). Annexin V labelling confirmed apoptosis in 64% vs. 11% and 75% vs. 8%, respectively. Western blotting showed cleavage of PARP-1 and caspase-3 and presence of γH2A.X. TUNEL assay showed strong staining in treated cells. These results were mirrored following Cdc7 kinase inhibition with PHA-767491. Our findings show that Cdc7 is a potent anti-cancer target in pancreatic adenocarcinoma and that Cdc7 immunoexpression levels might be used as a companion diagnostic to predict response to therapeutic siRNAs or SMIs directed against this kinase.


Factors Associated With False-Positive Recalls in Mammography Screening.
We aimed to identify factors associated with false-positive recalls in mammography screening compared with women who were not recalled and those who received true-positive recalls. We included 29,129 women, aged 40 to 74 years, who participated in the Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA) between 2011 and 2013 with follow-up until the end of 2017. Nonmammographic factors were collected from questionnaires, mammographic factors were generated from mammograms, and genotypes were determined using the OncoArray or an Illumina custom array. By the use of conditional and regular logistic regression models, we investigated the association between breast cancer risk factors and risk models and false-positive recalls. Women with a history of benign breast disease, high breast density, masses, microcalcifications, high Tyrer-Cuzick 10-year risk scores, KARMA 2-year risk scores, and polygenic risk scores were more likely to have mammography recalls, including both false-positive and true-positive recalls. Further analyses restricted to women who were recalled found that women with a history of benign breast disease and dense breasts had a similar risk of having false-positive and true-positive recalls, whereas women with masses, microcalcifications, high Tyrer-Cuzick 10-year risk scores, KARMA 2-year risk scores, and polygenic risk scores were more likely to have true-positive recalls than false-positive recalls. We found that risk factors associated with false-positive recalls were also likely, or even more likely, to be associated with true-positive recalls in mammography screening.


The minute virus of mice (MVM) nonstructural protein NS1 induces nicking of MVM DNA at a unique site of the right-end telomere in both hairpin and duplex conformations in vitro.
The right-end telomere of replicative form (RF) DNA of the autonomous parvovirus minute virus of mice (MVM) consists of a sequence that is self-complementary except for a three nucleotide loop around the axis of symmetry and an interior bulge of three unpaired nucleotides on one strand (designated the right-end 'bubble'). This right-end inverted repeat can exist in the form of a folded-back strand (hairpin conformation) or in an extended form, base-paired to a copy strand (duplex conformation). We recently reported that the right-end telomere is processed in an A9 cell extract supplemented with the MVM nonstructural protein NS1. This processing is shown here to result from the NS1-dependent nicking of the complementary strand at a unique position 21 nt inboard of the folded-back genomic 5' end. DNA species terminating in duplex or hairpin configurations, or in a mutated structure that has lost the right-end bulge, are all cleaved in the presence of NS1, indicating that features distinguishing these structures are not prerequisites for nicking under the in vitro conditions tested. Cleavage of the hairpin structure is followed by strand-displacement synthesis, generating the right-end duplex conformation, while processing of the duplex structure leads to the release of free right-end telomeres. In the majority of molecules, displacement synthesis at the right terminus stops a few nucleotides before reaching the end of the template strand, possibly due to NS1 which is covalently bound to this end. A fraction of the right-end duplex product undergoes melting and re-folding into hairpin structures (formation of a 'rabbit-ear' structure).


At the membranes of care: stories in narrative medicine.
Recognizing clinical medicine as a narrative undertaking fortified by learnable skills in understanding stories has helped doctors and teachers to face otherwise vexing problems in medical practice and education in the areas of professionalism, medical interviewing, reflective practice, patient-centered care, and self-awareness. The emerging practices of narrative medicine give clinicians fresh methods with which to make contact with patients and to come to understand their points of view. This essay provides a brief review of narrative theory regarding the structure of stories, suggesting that clinical texts contain and can reveal information in excess of their plots. Through close reading of the form and content of two clinical texts-an excerpt from a medical chart and a portion of an audiotaped interview with a medical student-and a reflection on a short section of a modernist novel, the author suggests ways to expand conventional medical routines of recognizing the meanings of patients' situations. The contributions of close reading and reflective writing to clinical practice may occur by increasing the capacities to perceive and then to represent the perceived, thereby making available to a writer that which otherwise might remain out of awareness. A clinical case is given to exemplify the consequences in practice of adopting the methods of narrative medicine. A metaphor of the activated cellular membrane is proposed as a figure for the effective clinician/patient contact.


Thermodynamic phase-field model for microstructure with multiple components and phases: the possibility of metastable phases.
A diffuse-interface model for microstructure with an arbitrary number of components and phases was developed from basic thermodynamic and kinetic principles and formalized within a variational framework. The model includes a composition gradient energy to capture solute trapping and is therefore suited for studying phenomena where the width of the interface plays an important role. Derivation of the inhomogeneous free energy functional from a Taylor expansion of homogeneous free energy reveals how the interfacial properties of each component and phase may be specified under a mass constraint. A diffusion potential for components was defined away from the dilute solution limit, and a multi-obstacle barrier function was used to constrain phase fractions. The model was used to simulate solidification via nucleation, premelting at phase boundaries and triple junctions, the intrinsic instability of small particles, and solutal melting resulting from differing diffusivities in solid and liquid. The shape of metastable free energy surfaces is found to play an important role in microstructure evolution and may explain why some systems premelt at phase boundaries and phase triple junctions, whereas others do not.


Surgical treatment of adult moyamoya disease with combined STA-MCA bypass and EDAS: demonstration of technique in video presentation.
The natural history of Moyamoya disease (MD) is variable. Moyamoya disease in children mostly presents with progressive ischemic complications and in adulthood it tends to present with hemorrhage. Surgical strategies depend on augmenting cerebral blood flow to the anterior cerebral circulation. Revascularization is the mainstay treatment for MD. We introduce a 31 year old female with a history of MD and leftsided revascularization as a child, who presented with headache, confusion, and worsening left sided weakness. Cranial computed tomography (CT) showed a right sided putaminal hemorrhage. Cerebral angiogram with selective external runs revealed MD, hypoplastic parietal branch of the superficial temporal artery (STA) on the right side and previous revascularization on the left side. Thus, our decision was made to perform a bypass with the frontal branch of the STA to an M3-M4 segment of the middle cerebral artery and an encephaloduroarteriomyosynangiosis with the parietal branch of the STA. The patient's postoperative course was uneventful. Postoperative CT angiogram confirmed patency of bypass. This technique provides immediate revascularization and seems to provide risk reduction for ischemic and hemorrhagic stroke. We review the natural history and surgical treatment of MD along with a case presentation in which surgical technique is demonstrated in video.


The American coneflower: a prophylactic role involving nonspecific immunity.
In humans, considerable circumstantial evidence exists that indicates soluble root extracts of the American coneflower, genus Echinacea, may act to ameliorate virus-mediated afflictions, such as the common cold, influenza, and even AIDS and virus-based tumors. This study was designed to quantify, in normal mice, Echinacea-mediated, quantitative, dynamic changes, with time on both mature and precursor cells, of all the hemopoietic and immune-cell lineages in the spleen and bone marrow. A specific, commercially prepared potent extract of Echinacea root was provided daily in the diet for either 1 week or 2 weeks with the aim of establishing a possible mechanism of action for this herb. The data revealed that natural-killer (NK) cells and monocytes, both mediators of nonspecific immunity and well-demonstrated killers of virus-containing cells, were numerically and significantly increased in both the bone marrow and the spleen as early as 1 week after beginning treatment with the dietary herb. In contrast to our observations with NK cells and monocytes, the sizes of all other hemopoietic and immune cell populations in these two organs remained at control levels even after 2 weeks of daily dietary Echinacea. The work has demonstrated the specific nature of Echinacea-derived phytochemicals in acting as stimulants of those cells responsible for nonspecific immunity, as the first line of defense against virus-infected/transformed cells. The observations that these cells were elevated in the bone marrow indicates that at least one mechanism of action of this herb, is to stimulate new cell production in situ. The significant elevation of these two fundamental immune-cell populations, in normal animals, suggests a prophylactic role for this herb.


Chemical strategies for controlling protein folding and elucidating the molecular mechanisms of amyloid formation and toxicity.
It has been more than a century since the first evidence linking the process of amyloid formation to the pathogenesis of Alzheimer's disease. During the last three decades in particular, increasing evidence from various sources (pathology, genetics, cell culture studies, biochemistry, and biophysics) continues to point to a central role for the pathogenesis of several incurable neurodegenerative and systemic diseases. This is in part driven by our improved understanding of the molecular mechanisms of protein misfolding and aggregation and the structural properties of the different aggregates in the amyloid pathway and the emergence of new tools and experimental approaches that permit better characterization of amyloid formation in vivo. Despite these advances, detailed mechanistic understanding of protein aggregation and amyloid formation in vitro and in vivo presents several challenges that remain to be addressed and several fundamental questions about the molecular and structural determinants of amyloid formation and toxicity and the mechanisms of amyloid-induced toxicity remain unanswered. To address this knowledge gap and technical challenges, there is a critical need for developing novel tools and experimental approaches that will not only permit the detection and monitoring of molecular events that underlie this process but also allow for the manipulation of these events in a spatial and temporal fashion both in and out of the cell. This review is primarily dedicated in highlighting recent results that illustrate how advances in chemistry and chemical biology have been and can be used to address some of the questions and technical challenges mentioned above. We believe that combining recent advances in the development of new fluorescent probes, imaging tools that enabled the visualization and tracking of molecular events with advances in organic synthesis, and novel approaches for protein synthesis and engineering provide unique opportunities to gain a molecular-level understanding of the process of amyloid formation. We hope that this review will stimulate further research in this area and catalyze increased collaboration at the interface of chemistry and biology to decipher the mechanisms and roles of protein folding, misfolding, and aggregation in health and disease.


Understanding cardiac extracellular matrix remodeling to develop biomarkers of myocardial infarction outcomes.
Cardiovascular Disease (CVD) is the most common cause of death in industrialized countries, and myocardial infarction (MI) is a major CVD with significant morbidity and mortality. Following MI, the left ventricle (LV) undergoes a wound healing response to ischemia that results in extracellular matrix (ECM) scar formation to replace necrotic myocytes. While ECM accumulation following MI is termed cardiac fibrosis, this is a generic term that does not differentiate between ECM accumulation that occurs in the infarct region to form a scar that is structurally necessary to preserve left ventricle (LV) wall integrity and ECM accumulation that increases LV wall stiffness to exacerbate dilation and stimulate the progression to heart failure. This review focuses on post-MI LV ECM remodeling, targeting the discussion on ECM biomarkers that could be useful for predicting MI outcomes.


Multicenter, randomized, prospective trial of early tracheostomy.
Determine the effect of early (days 3-5) or late (days 10-14) tracheostomy on intensive care unit length of stay (ICU LOS), frequency of pneumonia, and mortality, and evidence of short-term or long-term pharyngeal, laryngeal, or tracheal injury in head trauma, non-head trauma, and critically ill nontrauma patients. Randomized, prospective. Five Level I trauma centers. Data were obtained prospectively and included Acute Physiology and Chronic Health Evaluation III score (AIII), Glasgow Coma Scale score, Emergency Room Trauma Score, Injury Severity Score, Acute Injury Score, type of endotracheal tube or tracheostomy, level of positive end-expiratory pressure, and peak inspiratory pressure. Patients were to undergo laryngoscopy for detection of injury according to the Lindholm criteria at the time of endotracheal tube or tracheostomy removal and be reevaluated at 3 to 5 months after discharge. One hundred fifty-seven patients were entered, 127 to early randomization (3-5 days) and 28 to late randomization (10-14 days); however, only 112 patients with early and 14 with late randomization had completed data forms for the primary study goals. An additional 22 patients from the early entry groups were rerandomized late. Early randomization data: the AIII score was higher (p < 0.05) in the head trauma tracheostomy (65 +/- 4) than in the nontracheostomy group (51 +/- 4) and in the nontrauma tracheostomy (92 +/- 6) than in the nontracheostomy group (68 +/- 7), but was equivalent in the non-head trauma group. Glasgow Coma Scale score, Emergency Room Trauma Score, Injury Severity Score, Acute Injury Score, positive end-expiratory pressure, and peak inspiratory pressure were not significantly different in any of the groups. There were no significant differences in ICU LOS, frequency of pneumonia, or death in any of the groups after either early or late tracheostomy compared with continued endotracheal intubation. Only 83 patients underwent postextubation laryngoscopy. There were no significant differences between the groups; however, there were trends to more vocal cord ulceration and subglottic inflammation in the continued intubation group. No patient was seen in this study with late vocal cord or laryngeal stenosis; there were no tracheal-innominate artery fistulae. Seven of the patients with abnormal findings at extubation had normal 3- to 5-month postextubation laryngoscopy. Physician bias limited patient entry into the study. Although there were higher AIII scores in the head trauma early tracheostomy patients, there were no differences in the primary end points of ICU LOS, pneumonia, or death in any of the groups studied. Long-term endoscopic follow-up was poor, but no known late tracheal stenosis was seen.


Smoking and diabetes mellitus. Findings from 1988 Behavioral Risk Factor Surveillance System.
To examine the association between smoking and self-reported diabetes mellitus. The study was comprised of 3006 people greater than or equal to 18 yr of age with diabetes and 52,750 without diabetes. Twenty-six percent (SE 1.8) of the diabetic population were current smokers, 25.9% (SE 1.4) were former smokers, and 48.1% (SE 2) had never smoked. Similar percentages were found among the nondiabetic population. Compared to respondents without diabetes, the prevalence of current smoking was notably higher among respondents with diabetes who were between the ages of 18 and 34 yr (36.1%, SE 4.1), who had not graduated from high school (44.9%, SE 3.7), and who were men of African-American origin (54.8%, SE 5.8). Despite the excess risks, the overall prevalence of smoking in the diabetic population is comparable to that of the general population. Our finding of a higher prevalence of smoking among young people, people who had not graduated from high school, and African-American men with diabetes suggests that additional educational efforts should be targeted at these groups.


What's keeping people after stroke from walking outdoors to become physically active? A qualitative study, using an integrated biomedical and behavioral theory of functioning and disability.
In general people after stroke do not meet the recommendations for physical activity to conduct a healthy lifestyle. Programs to stimulate walking activity to increase physical activity are based on the available insights into barriers and facilitators to physical activity after stroke. However, these programs are not entirely successful. The purpose of this study was to comprehensively explore perceived barriers and facilitators to outdoor walking using a model of integrated biomedical and behavioral theory, the Physical Activity for people with a Disability model (PAD). Included were community dwelling respondents after stroke, classified ≥ 3 at the Functional Ambulation Categories (FAC), purposively sampled regarding the use of healthcare. The data was collected triangulating in a multi-methods approach, i.e. semi-structured, structured and focus-group interviews. A primarily deductive thematic content analysis using the PAD-model in a framework-analysis' approach was conducted after verbatim transcription. 36 respondents (FAC 3-5) participated in 16 semi-structured interviews, eight structured interviews and two focus-group interviews. The data from the interviews covered all domains of the PAD model. Intention, ability and opportunity determined outdoor walking activity. Personal factors determined the intention to walk outdoors, e.g. negative social influence, resulting from restrictive caregivers in the social environment, low self-efficacy influenced by physical environment, and also negative attitude towards physical activity. Walking ability was influenced by loss of balance and reduced walking distance and by impairments of motor control, cognition and aerobic capacity as well as fatigue. Opportunities arising from household responsibilities and lively social constructs facilitated outdoor walking. To stimulate outdoor walking activity, it seems important to influence the intention by addressing social influence, self-efficacy and attitude towards physical activity in the development of efficient interventions. At the same time, improvement of walking ability and creation of opportunity should be considered.


Role of antioxidant lycopene in cancer and heart disease.
Lycopene, a carotenoid without provitamin-A activity, is present in many fruits and vegetables; however, tomatoes and processed tomato products constitute the major source of lycopene in North American diet. Among the carotenoids, lycopene is a major component found in the serum and other tissues. Dietary intakes of tomatoes and tomato products containing lycopene have been shown to be associated with decreased risk of chronic diseases such as cancer and cardiovascular diseases in several recent studies. Serum and tissue lycopene levels have also been inversely related with the chronic disease risk. Although the antioxidant properties of lycopene are thought to be primarily responsible for its beneficial properties, evidence is accumulating to suggest other mechanisms such as modulation of intercellular gap junction communication, hormonal and immune system and metabolic pathways may also be involved. This review summarizes the background information about lycopene and presents the most current knowledge with respect to its role in human health and disease.


Homocysteine impairs coronary artery endothelial function by inhibiting tetrahydrobiopterin in patients with hyperhomocysteinemia.
Hyperhomocysteinemia (HHcy) has been associated with impaired vascular endothelial function. Our previous study demonstrated significantly higher secretion of the chemokine monocyte chemoattractant protein-1 from monocytes in response to lipopolysaccharide in patients with HHcy. In the present study, we investigated whether coronary endothelial function was damaged in patients with chronic HHcy (plasma level of homocysteine >15 μmol/l) and, if so, whether this impaired endothelial function is induced by the uncoupling of endothelial nitric oxide synthase (eNOS). When tetrahydrobiopterin levels are inadequate, eNOS is no longer coupled to l-arginine oxidation, which results in reactive oxygen species rather than nitric oxide production, thereby inducing vascular endothelial dysfunction. The 71 participants were divided into two groups, control (n = 50) and HHcy (n = 21). Quantification of coronary flow velocity reserve (CFVR) was after rest and after adenosine administration done by noninvasive Doppler echocardiography. Plasma levels of nitric oxide and tetrahydrobiopterin were significantly lower in patients with HHcy than in controls (99.54 ± 32.23 vs. 119.50 ± 37.68 μmol/l and 1.43 ± 0.46 vs. 1.73 ± 0.56 pmol/ml, all P < 0.05). Furthermore, CFVR was significantly lower in the HHcy than the control group (2.76 ± 0.49 vs. 3.09 ± 0.52, P < 0.05). In addition, plasma level of homocysteine was negatively correlated with CFVR. Chronic HHcy may contribute to coronary artery disease by inducing dysfunction of the coronary artery endothelium. The uncoupling of eNOS induced by HHcy in patients with chronic HHcy may explain this adverse effect in part.


Expression of Ly 1, Ly 2, Thy 1, and TL differentiation antigens on mouse T-cell tumors.
Transplanted lymphomas, most of thymic origin, induced in BALB/c mice with 1-ethyl-1-nitrosourea (ENU) and transplanted spontaneously occurring lymphomas of AKR mice were examined for the expression of the T-cell antigens Ly, TL, and Thy 1 by using three serological methods. Most (11 of 13) of the Thy 1+ and/or TL+ tumors, i.e., T-cell tumors, expressed high levels of either Ly 1 or Ly 2 antigen, but not both. Thus most thymic lymphocytic tumors expressed restricted Ly phenotypes comparable to phenotypes previously described for functional peripheral T cells. Because tumor phenotypes were stable over a number of transplant generations, they therefore appeared to be an intrinsic property of the specific tumors. The majority of the BALB/c lymphomas were Ly 1- 2+ and also positive with anti-TL antiserum. This predominant phenotype on the BALB/c tumors may be related to either the mode of tumor induction or to the mouse strain, but since the restricted Ly pattern was observed both in BALB/c and AKR tumors, the phenotypic restriction itself is not a consequence of either of these factors. Tumor induction by ENU per se is not responsible for Ly or TL ,ntigen expression since several non-T-cell BALB/ c tumors, also induced by ENU, did not express either Ly or TL antigens. Data presented here suggest that the target cell for leukemogenesis may be a partially differentiated thymus cell. The restricted expression of Ly antigens on differentiating thymus cells to either the (formula: see text), phenotype may occur before the loss of TL antigen.


Huntington's disease: current epidemiology and pharmacological management in UK primary care.
Recent debate suggests Huntington's disease (HD) may be more prevalent than previously reported. In addition, relatively little is known about current disease management. This study aims to provide epidemiological data and describe the pharmacological management of HD in the United Kingdom. A primary care research database was accessed to identify incident and prevalent HD cases between January 1, 2004, and December 31, 2008. Patients with Read codes denoting a definite diagnosis or possible diagnosis, and undiagnosed patients with a positive family history were identified. A subset of patients with a definite diagnosis and prescribed medication indicating symptom onset was also identified. Epidemiological data were estimated. Pharmacological prescriptions to HD patients from 2004 to 2008 were identified, and prescription frequencies were grouped according to the British National Formulary categories. HD incidence estimates ranged from 0.44 to 0.78 per 100,000 person-years, and HD prevalence ranged from 5.96 to 6.54 per 100,000 of the population. Forty-four percent of pharmacological prescriptions targeted the central nervous system. Nearly half of the HD patients were prescribed antidepressants, and over 40% were prescribed analgesics. Although prevalence estimates fell short of figures suggested in recent debate, it is feasible that the true prevalence may be much higher than previously reported. Pharmacological management appears to rely heavily on central nervous system drugs and nutrition support. Many of these drugs are prescribed to HD patients for reasons other than the medication's primary use. Further work is required to evaluate the impact of alternative management strategies, such as therapist intervention, counselling, and organisation support, on the patients' quality of life.


Surface integrity of polyethylene liners following trunnionosis of a dual modular neck total hip implant.
There has been a trend in the evolution of total hip arthroplasty towards increased modularity; with this increase in modularity come some potentially harmful consequences. Modularity at the neck shaft junction has been linked to corrosion, adverse reaction to metal debris and pseudotumour formation. The aim of this retrieval study is to assess whether the surface integrity of the polyethylene (PE) liner is affected by metal wear debris in a single implant design series of THA revised for trunnionosis. A retrieval analysis of thirty dual-taper modular neck hip prostheses was performed; the mean time from implantation to revision was 2.7 years (1.02-6.2). PE liners were analysed using a scanning electron microscope with an energy dispersive spectrometer to assess for metal particles embedded on the liner surface. Serum metal ion levels and inflammatory markers were also analysed. There were small numbers of metal particles present on the PE liners. The mean number of metal particles per liner was four and the particles varied in size from 0.5 µm to 122 µm mean 16 µm. All patients had elevated metal ion levels: cobalt 6.02 µg/l, chromium 1.22 µg/l, titanium 3.11 µg/l. The cobalt:chromium ratio was 7.55:1. Inflammatory markers were also marginally raised (ESR 17; CRP 10). These results suggest that retention of PE liners may be reasonable when performing isolated revision of the femoral component in cases of failure at the modular neck stem junction, especially when the inner diameter of the liner is already optimised for head size and stability.


Membrane-to-nucleus signaling links insulin-like growth factor-1- and stem cell factor-activated pathways.
Stem cell factor (mouse: Kitl, human: KITLG) and insulin-like growth factor-1 (IGF1), acting via KIT and IGF1 receptor (IGF1R), respectively, are critical for the development and integrity of several tissues. Autocrine/paracrine KITLG-KIT and IGF1-IGF1R signaling are also activated in several cancers including gastrointestinal stromal tumors (GIST), the most common sarcoma. In murine gastric muscles, IGF1 promotes Kitl-dependent development of interstitial cells of Cajal (ICC), the non-neoplastic counterpart of GIST, suggesting cooperation between these pathways. Here, we report a novel mechanism linking IGF1-IGF1R and KITLG-KIT signaling in both normal and neoplastic cells. In murine gastric muscles, the microenvironment for ICC and GIST, human hepatic stellate cells (LX-2), a model for cancer niches, and GIST cells, IGF1 stimulated Kitl/KITLG protein and mRNA expression and promoter activity by activating several signaling pathways including AKT-mediated glycogen synthase kinase-3β inhibition (GSK3i). GSK3i alone also stimulated Kitl/KITLG expression without activating mitogenic pathways. Both IGF1 and GSK3i induced chromatin-level changes favoring transcriptional activation at the Kitl promoter including increased histone H3/H4 acetylation and H3 lysine (K) 4 methylation, reduced H3K9 and H3K27 methylation and reduced occupancy by the H3K27 methyltransferase EZH2. By pharmacological or RNA interference-mediated inhibition of chromatin modifiers we demonstrated that these changes have the predicted impact on KITLG expression. KITLG knock-down and immunoneutralization inhibited the proliferation of GIST cells expressing wild-type KIT, signifying oncogenic autocrine/paracrine KITLG-KIT signaling. We conclude that membrane-to-nucleus signaling involving GSK3i establishes a previously unrecognized link between the IGF1-IGF1R and KITLG-KIT pathways, which is active in both physiologic and oncogenic contexts and can be exploited for therapeutic purposes.


Predicting Central Venous Pressure by Measuring Femoral Venous Diameter Using Ultrasonography.
The objective of this exploratory study was to find out the correlation of femoral vein diameter (FVD) to central venous pressure (CVP) measurements and to derive a prediction equation to help ascertain the fluid volume status in a critical patient. This was a single-centered prospective cohort study designed and conducted by the critical care department of Shifa International hospital in Islamabad, Pakistan. Patients were enrolled from the medical and surgical intensive care units. The inclusion criteria consisted of patients > 18 years of age, and an intrathoracic central venous catheterization (CVC) in place for producing CVP waveform through the transducer. Patients having contraindications to CVP placement and those unable to lie supine were excluded from the study. Critical Care fellows with sufficient training in performing venous ultrasonography measured the FVD. They were blinded to the CVP values of the same patients. The study included 108 patients. Among these 70/108 (64.8%) were males. Mean age was 53.85 (SD=16.74). The CVP and femoral vein diameter were measured in all patients. Mean CVP was 9.89 cmH2O (SD=3.46) and mean femoral vein diameter was 0.92 cm (SD=0.27). Multiple regression was used to generate a prediction model. FVD, age and sex of the patient were used as predictor variables to predict CVP diameter. The model was statistically significant with a p-value of < 0.000 and an F-value of 104.806. R-squared value for this model came out to be 0.744, thus the model was able to explain about 74.4% of the variance in the values observed for CVP. When controlled for age and sex, FVD was found highly correlated with CVP diameter with a p-value of < 0.000. A regression equation was derived that can be used to generate predicted values of CVP in millimeters of mercury with an R-square of 0.745 if FVD in centimeters is provided; CVP (cmH2O) = -0.039 + 10.718* FVD. FVD was found highly correlated to CVP measurements and it suggests an alternate non-invasive method of ascertaining the volume status in the critically ill.


FODMAP diet modulates visceral nociception by lipopolysaccharide-mediated intestinal inflammation and barrier dysfunction.
Foods high in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) exacerbate symptoms of irritable bowel syndrome (IBS); however, their mechanism of action is unknown. We hypothesized that a high-FODMAP (HFM) diet increases visceral nociception by inducing dysbiosis and that the FODMAP-altered gut microbial community leads to intestinal pathology. We fed rats an HFM and showed that HFM increases rat fecal Gram-negative bacteria, elevates lipopolysaccharides (LPS), and induces intestinal pathology, as indicated by inflammation, barrier dysfunction, and visceral hypersensitivity (VH). These manifestations were prevented by antibiotics and reversed by low-FODMAP (LFM) diet. Additionally, intracolonic administration of LPS or fecal supernatant (FS) from HFM-fed rats caused intestinal barrier dysfunction and VH, which were blocked by the LPS antagonist LPS-RS or by TLR4 knockdown. Fecal LPS was higher in IBS patients than in healthy subjects (HS), and IBS patients on a 4-week LFM diet had improved IBS symptoms and reduced fecal LPS levels. Intracolonic administration of FS from IBS patients, but not FS from HS or LFM-treated IBS patients, induced VH in rats, which was ameliorated by LPS-RS. Our findings indicate that HFM-associated gut dysbiosis and elevated fecal LPS levels induce intestinal pathology, thereby modulating visceral nociception and IBS symptomatology, and might provide an explanation for the success of LFM diet in IBS patients.


Myopia and glaucoma: sorting out the difference.
The aim of the present review was to summarize the evidence implicating the association between myopia and glaucoma, the possible underlying mechanisms for this relation, and the controversies surrounding detection of glaucomatous changes in coexisting myopia. Numerous studies have shown that increasing categories of myopia are associated with a higher risk for optic neuropathy and glaucoma-like visual field defects. Recently, some high-resolution imaging modalities have been developed that aid further detection of the microanatomical changes of the optic nerve head and thus may provide a new insight to explain the association between myopia and glaucoma. Although the highly myopic eye usually shows many structural and functional defects that are difficult to distinguish from those caused by glaucoma, some new methods have been introduced to better differentiate between these changes. The interaction of myopia with glaucoma risk remains complex, largely because of the retinal and nerve fiber layer damage that occurs in myopia alone. Whether to treat for glaucoma relies on the suspicion level of the clinician who must consider other risk factors for vision loss. Ultimately, it is the progression of glaucoma-like findings that determines whether a myopic patient has glaucoma.


Computed crystal energy landscapes for understanding and predicting organic crystal structures and polymorphism.
The phenomenon of polymorphism, the ability of a molecule to adopt more than one crystal structure, is a well-established property of crystalline solids. The possible variations in physical properties between polymorphs make the reliable reproduction of a crystalline form essential for all research using organic materials, as well as quality control in manufacture. Thus, the last two decades have seen both an increase in interest in polymorphism and the availability of the computer power needed to make the computational prediction of organic crystal structures a practical possibility. In the past decade, researchers have made considerable improvements in the theoretical basis for calculating the sets of structures that are within the energy range of possible polymorphism, called crystal energy landscapes. It is common to find that a molecule has a wide variety of ways of packing with lattice energy within a few kilojoules per mole of the most stable structure. However, as we develop methods to search for and characterize "all" solid forms, it is also now usual for polymorphs and solvates to be found. Thus, the computed crystal energy landscape reflects and to an increasing extent "predicts" the emerging complexity of the solid state observed for many organic molecules. This Account will discuss the ways in which the calculation of the crystal energy landscape of a molecule can be used as a complementary technique to solid form screening for polymorphs. Current methods can predict the known crystal structure, even under "blind test" conditions, but such successes are generally restricted to those structures that are the most stable over a wide range of thermodynamic conditions. The other low-energy structures can be alternative polymorphs, which have sometimes been found in later experimental studies. Examining the computed structures reveals the various compromises between close packing, hydrogen bonding, and pi-pi stacking that can result in energetically feasible structures. Indeed, we have observed that systems with many almost equi-energetic structures that contain a common interchangeable motif correlate with a tendency to disorder and problems with control of the crystallization product. Thus, contrasting the computed crystal energy landscape with the known crystal structures of a given molecule provides a valuable complement to solid form screening, and the examination of the low-energy structures often leads to a rationalization of the forms found.


Effects of post-learning REM sleep deprivation on hippocampal plasticity-related genes and microRNA in mice.
Sleep is essential for memory consolidation that stabilizes a memory trace. Memory consolidation includes waves of new gene expression and protein synthesis. Recently, microRNAs (miRNAs) have emerged as critical regulators of memory processes. Previous studies demonstrated that rapid eye movement (REM) sleep deprivation (REM SD) during specific time windows after training in the Morris water maze (MWM) task impairs memory consolidation. Here, we showed that the post-learning REM sleep, extending from 3 to 6 h after last training, is critical for spatial learning in the MWM task. Further, we found that the REM SD after training significantly changes the hippocampal expression of brain-derived neurotrophic factor (BDNF) mRNA; however, it causes minimal difference in the hippocampal expressions of calcium-calmodulin-dependent protein kinase II (CAMKII) and cAMP response-element-binding (CREB). In addition, it considerably affected the hippocampal expressions of miR-132, miR-182, and miR-124. In conclusion, after the MWM task, the post-learning REM sleep during specific time windows can modulate spatial memory consolidation, and its deprivation can impact the hippocampal transcriptional processes including memory-related miRNAs and mRNAs.


Second malignancies in early stage laryngeal carcinoma patients treated with radiotherapy.
A retrospective review of 240 patients with T1/T2 squamous cell carcinomas of the larynx was performed. Seventy-two per cent had glottic primaries, 27 per cent had supraglottic tumours and one per cent had subglottic disease. Sixty-nine per cent presented with T1 disease and 31 per cent had T2 staged tumours. All patients were treated with definitive radiotherapy between 1973 and 1997. With a median follow-up of 68 months, 68 patients (28 per cent) have developed 72 other cancers. Ten of 68 presented with synchronous primaries (15 per cent). Thirty per cent of glottic patients and 25 per cent of the supraglottic/subglottic patients developed second cancers. The most frequent second malignancy was lung cancer: 28/72 (39 per cent). Fifteen patients developed second head and neck cancers (21 per cent). Other second primary sites included oesophagus (eight), prostate (six), colorectal (five), breast (two) and others (eight). The median time from radiotherapy until the development of a second cancer was 31 months. The Kaplan-Meier survival estimate at five years was significantly less for those patients developing second cancers (55 per cent) compared to those not developing second malignancies (70 per cent), (p<0.05). The median survival from the development of a second cancer was 14 months. More died as a result of a second cancer (41 patients) than their primary laryngeal cancer (40 patients). Second cancers are common and deadly in patients with early stage laryngeal carcinoma.


Left ventricular lead electrical delay predicts response to cardiac resynchronization therapy.
Intracardiac electrograms can be used to guide left ventricular (LV) lead placement during implantation of cardiac resynchronization therapy (CRT) devices. Although attempts often are made to ensure that the LV lead is positioned at a site of maximal electrical delay, information on whether this is useful in predicting the acute hemodynamic response and long-term clinical outcome to CRT is limited. The purpose of this study was to assess the ability of intracardiac (electrogram) measurements made during LV lead placement in patients undergoing CRT for predicting acute hemodynamic response and long-term clinical outcome to CRT. Seventy-one subjects with standard indications for CRT underwent electrogram measurements and echocardiograms performed in the acute phase of this study. The LV lead electrical delay was measured intraoperatively from the onset of the surface ECG QRS complex to the onset of the sensed electrogram on the LV lead, as a percentage of the baseline QRS interval. Echocardiographic assessment of the hemodynamic response to CRT was measured as an intra-individual percentage change in dP/dt over baseline (DeltadP/dt, derived from the mitral regurgitation Doppler profile) with CRT on and off. dP/dt was measurable in 48 subjects, and acute responders to CRT were defined as those with DeltadP/dt >or=25%. Long-term response was measured as a combined endpoint of hospitalization for heart failure and/or all cause mortality at 12 months. Time to the primary endpoint was estimated by the Kaplan-Meier method, with comparisons made using the log rank test. LV lead electrical delay correlated weakly with DeltadP/dt of the combined group (n = 48, r = 0.311, P = .029) but was strongly correlated with DeltadP/dt in the nonischemic subgroup (n = 20, r = 0.48, P = .027). LV lead electrical delay (%) was significantly longer in acute responders (69.6 +/- 23.9 vs 31.95 +/- 11.57, P = .002) among patients with nonischemic cardiomyopathy. A reduced LV lead electrical delay (<50% of the QRS duration) was associated with worse clinical outcome within the entire cohort (hazard ratio: 2.7, 95% confidence interval: 1.17-6.68, P = .032) as well as when stratified into ischemic and nonischemic subgroups. Measuring LV lead electrical delay is useful during CRT device implantation because it may help predict hemodynamic response and long-term clinical outcome.


Future climate scenarios for a coastal productive planktonic food web resulting in microplankton phenology changes and decreased trophic transfer efficiency.
We studied the effects of future climate change scenarios on plankton communities of a Norwegian fjord using a mesocosm approach. After the spring bloom, natural plankton were enclosed and treated in duplicates with inorganic nutrients elevated to pre-bloom conditions (N, P, Si; eutrophication), lowering of 0.4 pH units (acidification), and rising 3°C temperature (warming). All nutrient-amended treatments resulted in phytoplankton blooms dominated by chain-forming diatoms, and reached 13-16 μg chlorophyll (chl) a l-1. In the control mesocosms, chl a remained below 1 μg l-1. Acidification and warming had contrasting effects on the phenology and bloom-dynamics of autotrophic and heterotrophic microplankton. Bacillariophyceae, prymnesiophyceae, cryptophyta, and Protoperidinium spp. peaked earlier at higher temperature and lower pH. Chlorophyta showed lower peak abundances with acidification, but higher peak abundances with increased temperature. The peak magnitude of autotrophic dinophyceae and ciliates was, on the other hand, lowered with combined warming and acidification. Over time, the plankton communities shifted from autotrophic phytoplankton blooms to a more heterotrophic system in all mesocosms, especially in the control unaltered mesocosms. The development of mass balance and proportion of heterotrophic/autotrophic biomass predict a shift towards a more autotrophic community and less-efficient food web transfer when temperature, nutrients and acidification are combined in a future climate-change scenario. We suggest that this result may be related to a lower food quality for microzooplankton under acidification and warming scenarios and to an increase of catabolic processes compared to anabolic ones at higher temperatures.


Temporal and reciprocal relationship between IADL/ADL disability and depressive symptoms in late life.
A strong association between functional disability and depressive symptoms in older people has frequently been reported. Some studies attribute this association to the disabling effects of depression, others to the depressogenic effects of physical health-related disability. The authors examined the reciprocal effects between depressive symptoms and functional disability and their temporal character in a community-based cohort of 753 older people with physical limitations who were assessed at yearly intervals. They compared structural equation models that differed in terms of direction and speed of effects between patient-reported disability in instrumental and basic activities of daily living (IADL/ADLs) and depressive symptoms. The association between disability and depression could be separated into three components: (a) a strong contemporaneous effect of change in disability on depressive symptoms, (b) a weaker 1-year lagged effect of change in depressive symptoms on disability (probably indirect through physical health), and (c) a weak correlation between the trait (or stable) components of depression and disability. IADL/ADL disability and depressive symptoms are thus mutually reinforcing over time. Compensatory forces like effective treatment and age-related adaptation may protect elders against this potential downward trend. To improve quality of life in elderly adults, treatment should target disability when it is new and depression when it is persistent.


E-cigarette advertising exposure among South African adults in 2017: findings from a nationally representative cross-sectional survey.
In South Africa, the Control of Tobacco and Electronic Delivery Systems Bill seeks to regulate e-cigarettes as tobacco products, including their advertising, promotion and sponsorship. Population data on e-cigarette advertising in South Africa are needed to inform public health programs, practice and policy. We examined self-reported e-cigarette advertising exposure during 2017. DESIGN: Cross-sectional. Household-based survey. 3063 individuals who participated in the 2017 South African Social Attitudes survey, a nationally representative, in-person survey of the non-institutionalised civilian adult population aged ≥16 years EXPOSURE: 'In the past 12 months, have you seen advertisements or promotions for e-cigarettes (including e-shisha, e-pipe) on any of the following media: newspapers/magazines, billboards, in the malls or any other source?' Beliefs and attitudes regarding e-cigarettes. Participants' mean age was 37.7 years. Overall, 20.1% reported exposure to e-cigarette advertisements. By age, exposure was most prevalent among those aged 16-19 years (24.6%). Top sources of exposure among those exposed were stores, 40.7%; malls, 30.9%; and television, 32.5%. Of those aware of e-cigarettes, 61.2% believed 'e-cigarette advertisements and promotion may make adolescents think of smoking traditional cigarettes'; 62.7% believed that 'e-cigarette advertisements and promotions may make ex-smokers think of starting smoking cigarettes again'; and 59.5% supported the statement that 'e-cigarette smoking should be banned indoors just as traditional cigarette smoking'. Notably, teens aged 16-19 reported the lowest prevalence (49.0%) of those believing that 'e-cigarette advertisements and promotion may make adolescents think of smoking traditional cigarettes', whereas this percentage was highest among those aged 55-64 years (73.2%). Comprehensive regulatory efforts are needed to address e-cigarette advertising, marketing and sponsorship in order to protect public health. The urgent enactment of the new tobacco control legislation, The Control of Tobacco Products and Electronic Delivery Systems Bill, can help reduce youth exposure to e-cigarette advertising in South Africa.


Morphological descriptions and morphometric discriminant function analysis reveal an additional four groups of Scylla spp.
There are four species of mud crabs within the genus Scylla, and most of them live sympatrically in the equatorial region. Apart from a report in Japan about the finding of a natural Scylla hybrid more than a decade ago after the division of genus Scylla into four species by Keenan, Davie & Mann (1998), no subsequent sighting was found. Thus, this study investigates the possible natural occurrence of potential hybridization among Scylla species in the wild. A total of 76,211 individuals from mud crab landing sites around the Malacca Straits, South China Sea and Sulu Sea were screened. In addition to the four-purebred species, four groups (SH 1, n = 2, 627; SH 2, n = 136; SH 3, n = 1; SH 4, n = 2) with intermediate characteristics were found, mostly at Sulu Sea. Discriminant Function Analysis revealed that all Scylla species, including SH 1 - 4, are distinguishable via their morphometric ratios. The most powerful discriminant ratios for each character and the top five discriminant ratios of males and females were suggested. The carapace width of SH 1 males and females were significantly smaller than pure species. Based on the discriminant ratios and the description of morphological characters, we hypothesize that the additional four groups of Scylla with intermediate characteristics could be presumed hybrids. Future work at the molecular level is urgently needed to validate this postulate.


Teratological evaluation of FD&C Red no. 2 -a collaborative government-industry study. II. FDA's study.
Because of recent studies indicating possible embryolethality and teratogenicity of FD&C Red No. 2, and ad hoc committee was convened by the Food and Drug Administration to consider these questions. The committee suggested a collaborative study by three laboratories [Food and Drug Administration (FDA), Industrial Bio-Test Laboratories (IBT), and National Center for Toxicological Research (NCTR)] in which Red No. 2 was given at 200 mg/kg body weight, by gavage during days 0-19, 6-15, or 7-9 of gestation. FD&C Red No. 2 was also given at the same dose level via water bottle. Appropriate controls were utilized. FDA used Osborne-Mendel strain rats, IBT used Charles River, and NCTR used both strains. No significant increases in skeletal or visceral abnormalities were seen. No significant increase in resorptions was seen in the Osborne-Mendel strain, but the Charles River strain at IBT showed a significant increase in litters with two or more resorptions after dams had been given 200 mg/kg at 0-19 days of gestation. The NCTR study on the Charles River strain also showed an increase in the same parameter for the same dose level and in addition showed a significant increase in the percentage of resorptions per litter. It was concluded that because of the inherent variation and the absence of an increase in abnormalities or other indications of embryotoxicity, there is reason to doubt that this effect is either biologically significant or reproducible.


DNA methyltransferase induced by PBCV-1 virus infection of a Chlorella-like green alga.
A DNA methyltransferase was isolated from a eucaryotic, Chlorella-like green alga infected with the virus PBCV-1. The enzyme recognized the sequence GATC and methylated deoxyadenosine solely in GATC sequences. Host DNA, which contains GATC sequences, but not PBCV-1 DNA, which contains GmATC sequences, was a good substrate for the enzyme in vitro. The DNA methyltransferase activity was first detected about 1 h after viral infection; PBCV-1 DNA synthesis and host DNA degradation also began at about this time. The appearance of the DNA methyltransferase activity required de novo protein synthesis, and the enzyme was probably virus encoded. Methylation of DNAs with the PBCV-1-induced methyltransferase conferred resistance of the DNAs to a PBCV-1-induced restriction endonuclease enzyme described previously (Y. Xia, D. E. Burbank, L. Uher, D. Rabussay, and J. L. Van Etten, Mol. Cell. Biol. 6:1430-1439). We propose that the PBCV-1-induced methyltransferase protects viral DNA from the PBCV-1-induced restriction endonuclease and is part of a virus-induced restriction and modification system in PBCV-1-infected Chlorella cells.


AMP kinase activation increases glucose uptake, decreases apoptosis, and improves pregnancy outcome in embryos exposed to high IGF-I concentrations.
Women with polycystic ovarian syndrome are at increased risk of miscarriage. Although evidence exists that metformin reduces this risk, the mechanism is unknown. This study tests the hypothesis that AMP kinase (AMPK) activation with metformin directly improves insulin signaling within the blastocyst, leading to improved pregnancy outcomes. Murine embryos were exposed to 200 nmol/l IGF-I, similar to the concentrations that can occur during polycystic ovary syndrome (PCOS). Resulting blastocysts were compared with embryos cocultured with excess IGF-I plus metformin and embryos cultured in control medium for the following: AMPK phosphorylation, insulin-stimulated glucose uptake, and apoptosis. Study and control blastocysts were also transferred into control animals. On embryonic day (E) 14.5, resulting fetuses were examined for size and rates of fetal implantation and resorption. Compared with control blastocysts, blastocysts exposed to high concentrations of IGF-I showed a decrease in AMPK activation and insulin-stimulated glucose uptake and an increase in the number of apoptotic nuclei. Blastocysts cocultured in metformin and excess IGF-I performed as well as controls in all studies. 5-Aminoimidazole-4-carboxamide 1-beta-d-ribofuranoside, another AMPK activator, also prevented the effects of excess IGF-I on blastocysts. Implantation rates and fetal size at day 14.5 were significantly lower among IGF-I-exposed embryos transferred into control mothers compared with control embryos transferred into control mothers. Both of these parameters were reversed by co-incubation with metformin and IGF-I before transfer. Activation of embryonic AMPK may be the mechanism responsible for the improved pregnancy outcomes seen in PCOS patients taking metformin.


Producer nutritional quality controls ecosystem trophic structure.
Trophic structure, or the distribution of biomass among producers and consumers, determines key ecosystem values, such as the abundance of infectious, harvestable or conservation target species, and the storage and cycling of carbon and nutrients. There has been much debate on what controls ecosystem trophic structure, yet the answer is still elusive. Here we show that the nutritional quality of primary producers controls the trophic structure of ecosystems. By increasing the efficiency of trophic transfer, higher producer nutritional quality results in steeper ecosystem trophic structure, and those changes are more pronounced in terrestrial than in aquatic ecosystems probably due to the more stringent nutritional limitation of terrestrial herbivores. These results explain why ecosystems composed of highly nutritional primary producers feature high consumer productivity, fast energy recycling, and reduced carbon accumulation. Anthropogenic changes in producer nutritional quality, via changes in trophic structure, may alter the values and functions of ecosystems, and those alterations may be more important in terrestrial ecosystems.


Relaxation of coronary artery smooth muscle cells.
The effect of adenosine and nitroglycerine on single smooth muscle cells isolated from the right coronary artery of the pig is reported. Trypan Blue exclusion and electron microscopy revealed that the cells used in this study were structurally intact. These cells were 79.2 +/- 1.6 microns long. Within 1 min of exposure to solutions containing norepinephrine, carbachol and high KCl, the cells contracted by 20-30%. The concentrations required for half maximal contraction for norepinephrine, carbachol and KCl were 0.1 to 1 nM, 0.01 to 0.1 nM and 15 to 25 mM, respectively. Adenosine and nitroglycerine inhibited the contractions caused by high (30 mM) K+ and also relaxed the cells previously contracted by high K+. Thus adenosine and nitroglycerine relax by acting directly on the smooth muscle cells.


Modulations of cell cycle checkpoints during HCV associated disease.
Impaired proliferation of hepatocytes has been reported in chronic Hepatitis C virus infection. Considering the fundamental role played by cell cycle proteins in controlling cell proliferation, altered regulation of these proteins could significantly contribute to HCV disease progression and subsequent hepatocellular carcinoma (HCC). This study aimed to identify the alterations in cell cycle genes expression with respect to early and advanced disease of chronic HCV infection. Using freshly frozen liver biopsies, mRNA levels of 84 cell cycle genes in pooled RNA samples from patients with early or advanced fibrosis of chronic HCV infection were studied. To associate mRNA levels with respective protein levels, four genes (p27, p15, KNTC1 and MAD2L1) with significant changes in mRNA levels (> 2-fold, p-value < 0.05) were selected, and their protein expressions were examined in the liver biopsies of 38 chronic hepatitis C patients. In the early fibrosis group, increased mRNA levels of cell proliferation genes as well as cell cycle inhibitor genes were observed. In the advanced fibrosis group, DNA damage response genes were up-regulated while those associated with chromosomal stability were down-regulated. Increased expression of CDK inhibitor protein p27 was consistent with its mRNA level detected in early group while the same was found to be negatively associated with liver fibrosis. CDK inhibitor protein p15 was highly expressed in both early and advanced group, but showed no correlation with fibrosis. Among the mitotic checkpoint regulators, expression of KNTC1 was significantly reduced in advanced group while MAD2L1 showed a non-significant decrease. Collectively these results are suggestive of a disrupted cell cycle regulation in HCV-infected liver. The information presented here highlights the potential of identified proteins as predictive factors to identify patients with high risk of cell transformation and HCC development.


A Conceptual Model to Describe the Decline of European Blackberry (Rubus anglocandicans), A Weed of National Significance in Australia.
Human activities have had an adverse impact on ecosystems on a global scale and have caused an unprecedented redispersal of organisms, with both plants and pathogens moving from their regions of origin to other parts of the world. Invasive plants are a potential threat to ecosystems globally, and their management costs tens of billions of dollars per annum. Rubus anglocandicans (European blackberry) is a serious invasive species in Australia. Herbicide and cultural control methods are generally inefficient or require multiple applications. Therefore, a biological control program using stem and leaf rust strains is the main option in Australia. However, biological control using rusts has been patchy, as host factors, climate, and weather can alter the impact of the rust at different locations. In 2007, Yeoh and Fontanini noticed that blackberry plants on the banks of the Donnelly and Warren rivers in the southwest of Western Australia were dying in areas that were being regularly monitored for the impact of rust as a biological control agent. The symptoms on blackberry became known as the disease "blackberry decline". Continuous and intensive investigations are required to discover the different biotic and abiotic components associated with specific declines in plant populations. The only agent so far introduced to Australia for the biological control of blackberry is the rust Phragmidium violaceum.


Amyloid burden and sleep blood pressure in amnestic mild cognitive impairment.
To determine whether cortical β-amyloid (Aβ) deposition is associated with circadian blood pressure (BP) profiles and dynamic cerebral blood flow (CBF) regulation in patients with amnestic mild cognitive impairment (aMCI). Forty participants with aMCI were included in this study. Cortical Aβ depositions were measured by (18)F-florbetapir PET and expressed as the standardized uptake value ratio (SUVR) relative to the cerebellum. Circadian BP profiles were measured by 24-hour ambulatory monitoring during awake and sleep periods. The dipping status of sleep BP (i.e., the percent changes from the awake BP) was calculated and dichotomized into the dipper (≥10%) and nondipper (<10%) groups. Dynamic CBF regulation was assessed by a transfer function analysis between beat-to-beat changes in BP and CBF velocity measured from the middle cerebral artery during a repeated sit-stand maneuver. Age was positively correlated with a greater Aβ deposition in the posterior cingulate, precuneus, and mean cortex. Accounting for the age effect, attenuated reductions in sleep systolic BP were associated with higher levels of posterior cingulate SUVR. Consistently, the nondippers exhibited a higher SUVR in the posterior cingulate than the dippers. Transfer function gain between changes in BP and CBF velocity was diminished in the nondippers, and moreover those individuals with a lower gain exhibited a higher SUVR in the posterior cingulate. Attenuated reductions in sleep BP are associated with a greater Aβ burden in the posterior cingulate and altered dynamic CBF regulation in patients with aMCI.


The role of astrocytes in CNS tumors: pre-clinical models and novel imaging approaches.
Brain metastasis is a significant clinical problem, yet the mechanisms governing tumor cell extravasation across the blood-brain barrier (BBB) and CNS colonization are unclear. Astrocytes are increasingly implicated in the pathogenesis of brain metastasis but in vitro work suggests both tumoricidal and tumor-promoting roles for astrocyte-derived molecules. Also, the involvement of astrogliosis in primary brain tumor progression is under much investigation. However, translation of in vitro findings into in vivo and clinical settings has not been realized. Increasingly sophisticated resources, such as transgenic models and imaging technologies aimed at astrocyte-specific markers, will enable better characterization of astrocyte function in CNS tumors. Techniques such as bioluminescence and in vivo fluorescent cell labeling have potential for understanding the real-time responses of astrocytes to tumor burden. Transgenic models targeting signaling pathways involved in the astrocytic response also hold great promise, allowing translation of in vitro mechanistic findings into pre-clinical models. The challenging nature of in vivo CNS work has slowed progress in this area. Nonetheless, there has been a surge of interest in generating pre-clinical models, yielding insights into cell extravasation across the BBB, as well as immune cell recruitment to the parenchyma. While the function of astrocytes in the tumor microenvironment is still unknown, the relationship between astrogliosis and tumor growth is evident. Here, we review the role of astrogliosis in both primary and secondary brain tumors and outline the potential for the use of novel imaging modalities in research and clinical settings. These imaging approaches have the potential to enhance our understanding of the local host response to tumor progression in the brain, as well as providing new, more sensitive diagnostic imaging methods.


Changes in Serum Electrolytes, Urea, and Creatinine in Aloe Vera-treated Rats.
This study was carried out to investigate the effect of Aloe vera extract (AvE) on serum electrolytes, urea, and creatinine as indices of renal function in Sprague-Dawley rats. Twelve male Sprague-Dawley rats weighing between 80 and 130 g were used. Rats were divided into two groups: The control and the test groups (n=6). The test group received 1 ml of AvE daily for 28 days. Both the groups fed on standard rat chow and water ad libitum. The results showed a decrease in serum levels of sodium, and potassium, but an increase in the serum levels of bicarbonate, urea, and creatinine in the test group. The changes seen were, however, statistically insignificant, except for the serum levels of sodium and creatinine (P<0.05). It is thus concluded that AvE impairs renal handling of electrolytes with consequent hyponatremia and hypercreatinemia. However, this might be of therapeutic value in conditions associated with hypernatremia.


Hypothetical Preclinical Alzheimer Disease Groups and Longitudinal Cognitive Change.
Clinical trials testing treatments for Alzheimer disease (AD) are increasingly focused on cognitively normal individuals in the preclinical phase of the disease. To optimize observing a treatment effect, such trials need to enroll cognitively normal individuals likely to show cognitive decline over the duration of the trial. To identify which group of cognitively normal individuals shows the greatest cognitive decline over time based on their cerebrospinal fluid biomarker profile. In this cohort study, cognitively normal participants were classified into 1 of the following 4 hypothetical preclinical AD groups using baseline cerebrospinal fluid levels of Aβ and tau or Aβ and phosphorylated tau (p-tau): stage 0 (high Aβ and low tau), stage 1 (low Aβ and low tau), stage 2 (low Aβ and high tau), and suspected non-AD pathology (SNAP) (high Aβ and high tau). The data presented herein were collected between August 1995 and August 2014. An a priori cognitive composite score based on the following 4 tests previously shown to predict progression from normal cognition to symptom onset of mild cognitive impairment or dementia: Paired Associates immediate recall, Logical Memory delayed recall, Boston Naming, and Digit-Symbol Substitution. Linear mixed-effects models were used to compare the cognitive composite scores across the 4 groups over time, adjusting for baseline age, sex, education, and their interactions with time. Two hundred twenty-two cognitively normal participants were included in the analyses (mean follow-up, 11.0 years [range, 0-18.3 years] and mean baseline age, 56.9 years [range, 22.1-85.8 years]). Of these, 102 were stage 0, 46 were stage 1, 28 were stage 2, and 46 were SNAP. Individuals in stage 2 (low Aβ and high tau [or p-tau]) had lower baseline cognitive scores and a greater decline in the cognitive composite score relative to the other 3 groups (β ≤ -0.06 for all and P ≤ .001 for the rate of decline for all). Individuals in stage 0, stage 1, and SNAP did not differ from one another in cognitive performance at baseline or over time (11.0 years) and showed practice-related improvement in performance. The APOE ε4 genotype was not associated with baseline cognitive composite score or the rate of change in the cognitive composite score. These results suggest that, to optimize observing a treatment effect, clinical trials enrolling cognitively normal individuals should selectively recruit participants with abnormal levels of both amyloid and tau (ie, stage 2) because this group would be expected to show the greatest cognitive decline over time if untreated.


Compressive stress induces collective migration through cytoskeletal remodelling in nasal polyp epithelium.
Nasal polyps in the nasal cavity and mucous discharge inside the maxillary sinus exhibit compressive stress on the nasal mucosal epithelium. However, there have been only a few studies on how compressive stress impacts the human nasal mucosal epithelium. We investigated the effect of compressive stress on collective migration, junctional proteins, transepithelial electri- cal resistance, epithelial permeability, and gene expression in well-differentiated normal human nasal epithelial (NHNE) cells and human nasal polyp epithelial (HNPE) cells. NHNE cells barely showed collective migration at compressive stress up to 150 mmH20. However, HNPE cells showed much greater degree of collective migration at a lower compressive stress of 100 mmH20. The cell migration of HNPE cells sub- jected to 100 mmH2O compression was significantly decreased at day 3 and was recovered to the status prior to the compressive stress by day 7, indicating that HNPE cells are relatively more sensitive to mechanical pressure than NHNE cells. Compressive stress also increased transepithelial electrical resistance and decreased epithelial permeability, indicating that the compressive stress disturbed the structural organization rather than physical interactions between cells. In addition, we found that compressive stress induced gene expressions relevant to airway inflammation and tissue remodelling in HNPE cells. Taken together, these findings demonstrate that compressive stress on nasal polyp epithelium is capable of inducing collective migration and induce increased expression of genes related to airway inflammation, innate immunity, and polyp remo- delling, even in the absence of inflammatory mediators.


Angular and fibrous particles in lung are markers of job categories.
The lung concentration of angular and fibrous particles has been measured when cases are stratified into their job categories; 21 miners (metallic mines such as gold, zinc and copper), 18 iron foundrymen, 22 non-iron foundrymen, four welders, three sand-blast workers, four construction workers, three technicians and professionals, seven workers in other trades excluding welding. Twelve asbestos miners representing a positive exposure to asbestos and 20 people representing a background population were added to the previous groups. Particles, both angular and fibrous, were extracted from lung parenchyma by a bleach digestion method, mounted on copper microscopic grids by a carbon replica technique and analyzed by transmission electron microscopy (TEM) and energy dispersive spectroscopy (EDS). Quartz concentration was also determined by X-ray diffraction (XRD) on a silver membrane filter after the extraction from the lung parenchyma. (1) The highest concentrations of quartz were found in mines (metallic mines), iron foundrymen and sand-blast workers. Notable amounts quartz were found in welders and professionals. (2) The highest concentrations of short fibres were found in non-iron foundrymen, asbestos miners and construction workers. (3) The highest concentrations of long fibres were found in non-iron foundry men and asbestos miners. (4) The highest concentrations of ferruginous bodies were found in non-iron foundrymen and asbestos miners. (5) The non-iron foundrymen were exposed to ceramic fibres and asbestos fibres. The results of the study may not be representative of the broad spectrum of workers in the industrial activities in which they have been involved. However, the detailed composition of the retained particles of our workers is explained both qualitatively and quantitatively by their work histories. Finally, the broad range of particle types identified in the lungs of these workers illustrate the complexity or trying to determine disease origins in these occupational settings.


Legislation of direct-to-consumer genetic testing in Europe: a fragmented regulatory landscape.
Despite the increasing availability of direct-to-consumer (DTC) genetic testing, it is currently unclear how such services are regulated in Europe, due to the lack of EU or national legislation specifically addressing this issue. In this article, we provide an overview of laws that could potentially impact the regulation of DTC genetic testing in 26 European countries, namely Austria, Belgium, Cyprus, the Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, the Netherlands and the United Kingdom. Emphasis is placed on provisions relating to medical supervision, genetic counselling and informed consent. Our results indicate that currently there is a wide spectrum of laws regarding genetic testing in Europe. There are countries (e.g. France and Germany) which essentially ban DTC genetic testing, while in others (e.g. Luxembourg and Poland) DTC genetic testing may only be restricted by general laws, usually regarding health care services and patients' rights.


Association of Sitting Time With Mortality and Cardiovascular Events in High-Income, Middle-Income, and Low-Income Countries.
High amounts of sitting time are associated with increased risks of cardiovascular disease (CVD) and mortality in high-income countries, but it is unknown whether risks also increase in low- and middle-income countries. To investigate the association of sitting time with mortality and major CVD in countries at different economic levels using data from the Prospective Urban Rural Epidemiology study. This population-based cohort study included participants aged 35 to 70 years recruited from January 1, 2003, and followed up until August 31, 2021, in 21 high-income, middle-income, and low-income countries with a median follow-up of 11.1 years. Daily sitting time measured using the International Physical Activity Questionnaire. The composite of all-cause mortality and major CVD (defined as cardiovascular death, myocardial infarction, stroke, or heart failure). Of 105 677 participants, 61 925 (58.6%) were women, and the mean (SD) age was 50.4 (9.6) years. During a median follow-up of 11.1 (IQR, 8.6-12.2) years, 6233 deaths and 5696 major cardiovascular events (2349 myocardial infarctions, 2966 strokes, 671 heart failure, and 1792 cardiovascular deaths) were documented. Compared with the reference group (<4 hours per day of sitting), higher sitting time (≥8 hours per day) was associated with an increased risk of the composite outcome (hazard ratio [HR], 1.19; 95% CI, 1.11-1.28; Pfor trend < .001), all-cause mortality (HR, 1.20; 95% CI, 1.10-1.31; Pfor trend < .001), and major CVD (HR, 1.21; 95% CI, 1.10-1.34; Pfor trend < .001). When stratified by country income levels, the association of sitting time with the composite outcome was stronger in low-income and lower-middle-income countries (≥8 hours per day: HR, 1.29; 95% CI, 1.16-1.44) compared with high-income and upper-middle-income countries (HR, 1.08; 95% CI, 0.98-1.19; P for interaction = .02). Compared with those who reported sitting time less than 4 hours per day and high physical activity level, participants who sat for 8 or more hours per day experienced a 17% to 50% higher associated risk of the composite outcome across physical activity levels; and the risk was attenuated along with increased physical activity levels. High amounts of sitting time were associated with increased risk of all-cause mortality and CVD in economically diverse settings, especially in low-income and lower-middle-income countries. Reducing sedentary time along with increasing physical activity might be an important strategy for easing the global burden of premature deaths and CVD.


Reliable quantification of rhinovirus species C using real-time PCR.
Rhinovirus C (RV-C) is an important respiratory pathogen of children, but little is known about its contribution to disease severity, though viral load appears to be important. Difficulty in RV-C cultivation and target sequence variation has precluded the development of a PCR based quantification method. The aim of this study was to develop and validate reverse transcription quantitative PCR (RT-qPCR) assays for a broad range of circulating RV-C genotypes in nasopharyngeal aspirates (NPAs). Four assays were designed to quantify a 296bp region located within the 5' untranslated region (UTR) of RV-C types. These assays were based on in silico analysis of available RV-C sequences. Probes were designed to provide 100% homology to the corresponding RV-C genotypes. The linear dynamic range of each of the four assays spanned eight orders of magnitude (10(4)-10(11) copies/mL). The limit of detection for assays 1-4 was estimated to be 1147 copies/mL, 765 copies/mL, 1138 copies/mL and 1470 copies/mL respectively. Each assay demonstrated a strong linear relationship (r(2)=>0.995) and amplification efficiency greater than 95%. Repeatability and reproducibility of the method were shown to be high, with coefficients of variations lower than 8% and 15% respectively.


Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant Hypocalcemia Type 1: Prevalence in a Large Healthcare Population.
The calcium-sensing receptor (CaSR) regulates serum calcium concentrations. CASR loss- or gain-of-function mutations cause familial hypocalciuric hypercalcemia type 1 (FHH1) or autosomal-dominant hypocalcemia type 1 (ADH1), respectively, but the population prevalence of FHH1 or ADH1 is unknown. Rare CASR variants were identified in whole-exome sequences from 51,289 de-identified individuals in the DiscovEHR cohort derived from a single US healthcare system. We integrated bioinformatics pathogenicity triage, mean serum Ca concentrations, and mode of inheritance to identify potential FHH1 or ADH1 variants, and we used a Sequence Kernel Association Test (SKAT) to identify rare variant-associated diseases. We identified predicted heterozygous loss-of-function CASR variants (6 different nonsense/frameshift variants and 12 different missense variants) in 38 unrelated individuals, 21 of whom were hypercalcemic. Missense CASR variants were identified in two unrelated hypocalcemic individuals. Functional studies showed that all hypercalcemia-associated missense variants impaired heterologous expression, plasma membrane targeting, and/or signaling, whereas hypocalcemia-associated missense variants increased expression, plasma membrane targeting, and/or signaling. Thus, 38 individuals with a genetic diagnosis of FHH1 and two individuals with a genetic diagnosis of ADH1 were identified in the 51,289 cohort, giving a prevalence in this population of 74.1 per 100,000 for FHH1 and 3.9 per 100,000 for ADH1. SKAT combining all nonsense, frameshift, and missense loss-of-function variants revealed associations with cardiovascular, neurological, and other diseases. In conclusion, FHH1 is a common cause of hypercalcemia, with prevalence similar to that of primary hyperparathyroidism, and is associated with altered disease risks, whereas ADH1 is a major cause of non-surgical hypoparathyroidism.


Instantaneous correlation of excitation and inhibition during ongoing and sensory-evoked activities.
Temporal and quantitative relations between excitatory and inhibitory inputs in the cortex are central to its activity, yet they remain poorly understood. In particular, a controversy exists regarding the extent of correlation between cortical excitation and inhibition. Using simultaneous intracellular recordings in pairs of nearby neurons in vivo, we found that excitatory and inhibitory inputs are continuously synchronized and correlated in strength during spontaneous and sensory-evoked activities in the rat somatosensory cortex.


Comparison of the effects of propofol and halothane on acute myocardial ischaemia and myocardial reperfusion injury.
The effects of two blood concentrations of propofol on acute severe regional myocardial ischaemia (15-minute occlusion of the LAD coronary artery) and 2-hour reperfusion were studied in 10 pigs. Results were contrasted with the effect of 0.8% halothane (N = 5). Results indicate that during acute ischaemia, regional myocardial function of the segment supplied by the LAD artery was not protected against the effects of ischaemia in the propofol or halothane groups. During reperfusion, animals subjected to halothane demonstrated significantly fewer reperfusion arrhythmias and segmental function was less stunned than in either propofol group. There was no difference in heart performance between the propofol groups. Results indicate that the proposed anti-oxidant effect of propofol is not sufficient to protect the animal heart from reperfusion injury.


Noncovalent inhibitors reveal BTK gatekeeper and auto-inhibitory residues that control its transforming activity.
Inhibition of Bruton tyrosine kinase (BTK) is a breakthrough therapy for certain B cell lymphomas and B cell chronic lymphatic leukemia. Covalent BTK inhibitors (e.g., ibrutinib) bind to cysteine C481, and mutations of this residue confer clinical resistance. This has led to the development of noncovalent BTK inhibitors that do not require binding to cysteine C481. These new compounds are now entering clinical trials. In a systematic BTK mutagenesis screen, we identify residues that are critical for the activity of noncovalent inhibitors. These include a gatekeeper residue (T474) and mutations in the kinase domain. Strikingly, co-occurrence of gatekeeper and kinase domain lesions (L512M, E513G, F517L, L547P) in cis results in a 10- to 15-fold gain of BTK kinase activity and de novo transforming potential in vitro and in vivo. Computational BTK structure analyses reveal how these lesions disrupt an intramolecular mechanism that attenuates BTK activation. Our findings anticipate clinical resistance mechanisms to a new class of noncovalent BTK inhibitors and reveal intramolecular mechanisms that constrain BTK's transforming potential.


Mechanism-of-injury approach to evaluating patients with blast-related polytrauma.
Civilians and military personnel alike are increasingly being exposed to explosives in war zones and other regions of political conflict and, consequently, they are suffering associated blast-related polytrauma (multiple complex injuries). Although acute, emergency-based medical care for patients with blast-related trauma has been well described, postacute clinical management--which is of greatest interest to primary care physicians and rehabilitation specialists--has not been well discussed or researched. The authors offer a description of the common injuries seen in patients with blast-related polytrauma, as well as a conceptual model of a potential evaluation and treatment strategy in the postacute setting. Although medical evaluation of a patient typically proceeds in a sequential manner based on primary symptoms, the authors advocate a parallel approach to patient evaluation based on mechanism (cause) of injury. Such an approach relies on knowledge of the typical physical and psychological sequelae associated with a particular mechanism of injury to guide patient assessment and treatment. The authors highlight the mechanism-of-injury approach used with patients who have blast-related polytrauma at the Veterans Health Administration's (VHA) Veterans Affairs Medical Center in Tampa, Fla, site of one of the VHA's four Polytrauma Rehabilitation Centers.


Planning schistosomiasis control: investigation of alternative sampling strategies for Schistosoma mansoni to target mass drug administration of praziquantel in East Africa.
In schistosomiasis control, there is a need to geographically target treatment to populations at high risk of morbidity. This paper evaluates alternative sampling strategies for surveys of Schistosoma mansoni to target mass drug administration in Kenya and Ethiopia. Two main designs are considered: lot quality assurance sampling (LQAS) of children from all schools; and a geostatistical design that samples a subset of schools and uses semi-variogram analysis and spatial interpolation to predict prevalence in the remaining unsurveyed schools. Computerized simulations are used to investigate the performance of sampling strategies in correctly classifying schools according to treatment needs and their cost-effectiveness in identifying high prevalence schools. LQAS performs better than geostatistical sampling in correctly classifying schools, but at a cost with a higher cost per high prevalence school correctly classified. It is suggested that the optimal surveying strategy for S. mansoni needs to take into account the goals of the control programme and the financial and drug resources available.


Requisite role of vasohibin-2 in spontaneous gastric cancer formation and accumulation of cancer-associated fibroblasts.
The vasohibin (VASH) family consists of two genes, VASH1 and VASH2. VASH1 is mainly expressed in vascular endothelial cells and suppresses angiogenesis in an autocrine manner, whereas VASH2 is mainly expressed in cancer cells and exhibits pro-angiogenic activity. Employing adenomatous polyposis coli gene mutant mice, we recently reported on the role of Vash2 in the spontaneous formation of intestinal tumors. In this study, we used K19-Wnt1/C2mE (Gan) mice and examined the role of Vash2 in spontaneous gastric cancer formation. Gan mice spontaneously develop gastric tumors by activation of Wnt and prostaglandin E2 signaling pathways in gastric mucosa after 30 weeks of age. Expression of Vash2 mRNA was significantly increased in gastric tumor tissues compared with normal stomach tissues. When Gan mice were crossed with the Vash2-deficient (Vash2LacZ/LacZ ) strain, gastric cancer formation was significantly suppressed in Vash2LacZ/LacZ Gan mice. Normal composition of gastric mucosa was partially maintained in Vash2LacZ/LacZ Gan mice. Knockout of Vash2 caused minimal reduction of tumor angiogenesis but a significant decrease in cancer-associated fibroblasts (CAF) in tumor stroma. DNA microarray analysis and real-time RT-PCR showed that mRNA levels of epiregulin (Ereg) and interleukin-11 (Il11) were significantly downregulated in gastric tumors of Vash2LacZ/LacZ Gan mice. Furthermore, conditioned medium of gastric cancer cells stimulated migration of and α-smooth muscle actin expression in fibroblasts, whereas conditioned medium of VASH2 knockdown cells attenuated these effects in vitro. These results suggest that VASH2 plays an important role in gastric tumor progression via the accumulation of CAF accompanying upregulation of EREG and IL-11 expression.


The TLR3 Agonist Inhibit Drug Efflux and Sequentially Consolidates Low-Dose Cisplatin-Based Chemoimmunotherapy while Reducing Side Effects.
The traditional maximum dose density chemotherapy renders the tumor patients not only the tumor remission but the chemotherapy resistance and more adverse side effects. According to the widely positive expression of Toll-like receptor (TLR)-3 in oral squamous cell carcinoma (OSCC) patients (n = 166), we here provided an alternative strategy involved the orderly treatment of TLR3 agonist polyinosine-polycytidylic acid (PIC) and low-dose cisplatin. The optimal dose of cisplatin, the novel role of PIC and the side effects of the combined chemotherapy were determined in vitro and in distinct human tumor models in vivo The results in vitro indicated that preculture with PIC downregulated drug transporters (e.g., P-gp and MRP-1) and increased the cytoplasmic residence of cisplatin, and dramatically strengthened the low-dose cisplatin-induced cell death in TLR3- and caspase-3-dependent manner. Meanwhile, the spleen immunocytes were activated but the immunosuppressive cancer-associated fibroblasts (CAF) were dampened. These findings were confirmed in human tumor models in vivo Pretreatment with PIC promoted the low-dose cisplatin residence for tumor regression with decreased myeloid-suppressive cells (MDSC), tumor-associated macrophages (TAM) and CAFs, and alleviated adverse side effects in the OSCC model, which was further enhanced by the Cetuximab safely. This strategy also repressed the progression of melanoma and lymphoma. Moreover, TLR3 negatively manipulated the inflammation-related long noncoding RNA lnc-IL7R, which was upregulated during this chemotherapy. Knockdown of lnc-IL7R improved the chemotherapy sensitivity. Overall, this study provided preclinically new instructions for the PIC/cisplatin utilization to target tumor microenvironment and strengthen the low-dose cisplatin-based chemotherapy with reduced side effects. Mol Cancer Ther; 16(6); 1068-79. ©2017 AACR.


Single-trial classification of neural responses evoked in rapid serial visual presentation: effects of stimulus onset asynchrony and stimulus repetition.
Rapid serial visual presentation (RSVP) tasks, in which participants are presented with a continuous sequence of images in one location, have been used in combination with electroencephalography (EEG) in a variety of Brain-Machine Interface (BMI) applications. The RSVP task is advantageous because it can be performed at a high temporal rate. The rate of the RSVP sequence is controlled by the stimulus onset asynchrony (SOA) between subsequent stimuli. When used within the context of a BMI, an RSVP task with short SOA could increase the information throughput of the system while also allowing for stimulus repetitions. However, reducing the SOA also increases the perceptual degradation caused by presenting two stimuli in close succession, and it decreases the target-to-target interval (TTI), which can increase the cognitive demands of the task. These negative consequences of decreasing the SOA could affect on the EEG signal measured in the task and degrade the performance of the BMI. Here we systematically investigate the effects of SOA and stimulus repetition (r) on single-trial target detection in an RSVP task. Ten healthy volunteers participated in an RSVP task in four conditions that varied in SOA and repetitions (SOA=500 ms, r=1; SOA=250 ms, r=2; SOA=166 ms, r=3; and SOA=100 ms, r=5) while processing time across conditions was controlled. There were two key results: First, when controlling for the number of repetitions, single-trial performance increases when the SOA decreases. Second, when the repetitions were combined, the best performance (AUC=0.967) was obtained with the shortest SOA (100 ms). These results suggest that shortening the SOA in an RSVP task has the benefit of increasing the performance relative to longer SOAs, and it also allows a higher number of repetitions of the stimuli in a limited amount of time.


On the role of the multiple regulatory elements involved in the activation of the Escherichia coli malEp promoter.
Activation of malEp and malKp, two divergent promoters from Escherichia coli, depends on the synergistic action of MalT and CRP. The reaction involves a common regulatory region located in between and comprising multiple binding elements for both regulatory proteins. The binding of MalT and CRP to this region is known to result in the formation of a higher-order structure that is responsible for malKp activation. This paper presents genetic data which together with previous results, provide compelling evidence that this higher-order structure is also responsible for malEp activation. The role(s) that this structure or elements thereof play in the activation of malEp is analysed by monitoring both the occupancy of the proximal MalT sites (sites 1 and 2) and the activity of different malEp variants in strains containing increasing amounts of active MalT. A truncated malEp promoter comprising only MalT sites 1 and 2 forms a minimal MalT-dependent promoter whose activity is limited by the occupancy of these sites. One role of the higher-order structure formed by MalT and CRP when bound to the entire regulatory region is to ensure high occupation of MalT sites 1 and 2, but it is not its only function. Some elements of this structure, namely the CRP site 1, located at -76.5, and the distal MalT sites, seem to play a direct role in malEp activation besides their participation in the assembly of the higher-order structure.


Physical Health Conditions Among a Population-Based Cohort of Vietnam-Era Women Veterans: Agreement Between Self-Report and Medical Records.
Little is known about medical morbidity among women Vietnam-era veterans, or the long-term physical health problems associated with their service. This study assessed agreement comparing data on physical health conditions from self-report and medical records from a population-based cohort of women Vietnam-era Veterans from the Health of Vietnam Era Women's Study (HealthViEWS). Women Vietnam-era veterans (n = 4219) self-completed a survey and interview on common medical conditions. A subsample (n = 900) were contacted to provide permission to obtain medical records from as many as three of their providers. Medical record reviews were conducted using a standardized checklist. Agreement and kappa (agreement beyond chance) were calculated for physical health condition groups. Of the 900, 449 had medical records returned, and of those, 412 had complete surveys/interviews. The most commonly reported conditions based on self-report or medical record review included hypertension, hyperlipidemia, or arthritis. Kappa scores between self-reported conditions and medical record documentation were 0.75-0.91 for hypertension, diabetes, most cancers, and neurological conditions, but lower (k = 0.29-0.55) for cardiovascular diseases, musculoskeletal, and gastrointestinal conditions. Generally, agreement did not significantly vary by different sociodemographic groups. There was relatively high agreement for physical health conditions when self-report was compared with medical record review. As more women are increasingly represented in the military and more veterans in general seek care outside the Veterans Health Administration, accurate measurement of physical health conditions among population-based samples is crucial.


A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by activation of the type I interferon (IFN) pathway. Here we convincingly replicate association of the IFN regulatory factor 5 (IRF5) rs2004640 T allele with SLE in four independent case-control cohorts (P = 4.4 x 10(-16)) and by family-based transmission disequilibrium test analysis (P = 0.0006). The rs2004640 T allele creates a 5' donor splice site in an alternate exon 1 of IRF5, allowing expression of several unique IRF5 isoforms. We also identify an independent cis-acting variant associated with elevated expression of IRF5 and linked to the exon 1B splice site. Haplotypes carrying the variant associated with elevated expression and lacking the exon 1B donor site do not confer risk of SLE. Thus, a common IRF5 haplotype driving elevated expression of multiple unique isoforms of IRF5 is an important genetic risk factor for SLE, establishing a causal role for type I IFN pathway genes in human autoimmunity.


A pilot study of the relation between humor styles and the past-positive and past-negative time perspectives.
Those who use self-enhancing and affiliative humor styles tend to recall positive experiences with their parents and primary caretakers, whereas those who use the self-defeating humor style tend to recall negative experiences with them. Considering the importance of experiences with parents and primary caretakers for life satisfaction and happiness, it was hypothesized that the affiliative and self-enhancing humor styles would be positively correlated with past-positive experiences and negatively correlated with past-negative experiences, and that the self-defeating humor style would be positively correlated with past-negative experiences and negatively correlated with past-positive experiences. The Humor Styles Questionnaire and the Past-Positive and Past-Negative subscales of the Zimbardo Time Perspective Inventory were administered to 114 undergraduates. The hypotheses were partially supported despite the retrospective nature of the Past-Positive and Past-Negative Subscales and the correlational nature of the study, indicating further research is needed.