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Recent theories and neural models of co-speech gesture have extensively considered its cognitive role in language comprehension but have ignored the emotional function. We investigated the integration of speech and co-speech gestures in memory for verbal information with different emotional connotations (either positive, negative, or neutral). In a surprise cued-recall task, gesture boosted memory for speech with all three emotional valences. Interestingly, gesture was more likely to become integrated into memory of neutrally and positively valenced speech than negatively valenced speech. The results suggest that gesture-speech integration is modulated by emotional valence of speech, which has implications for the emotional function of gesture in language comprehension.

Tumor myeloid suppressor cells impede response to T cell checkpoint immunotherapy. Immunoglobulin-like transcript 3 (ILT3, gene name, LILRB4) expressed on dendritic cells (DCs) promotes antigen-specific tolerance. Circulating monocytic MDSCs that express ILT3 have been linked to clinical outcomes and a soluble form of ILT3 is elevated in certain cancers. We find that LILRB4 expression is correlated with Gene Expression Profile of T-cell inflamed tumor microenvironment shown to be significantly associated with response to the anti-PD1 antibody pembrolizumab across several tumor types. A potent and selective anti-ILT3 mAb effectively antagonized IL-10 polarization of DCs and enabled T cell priming. In an MLR assay anti-ILT3 combined with pembrolizumab afforded greater CD8+ T cell activation compared to either agent alone. Anti-ILT3 antibodies impaired the acquisition of a suppressive phenotype of monocytes co-cultured with SK-MEL-5 cancer cells, accompanied by a reduction in surface detection of peptidase inhibitor 16, a cis interaction candidate for ILT3. Growth of myeloid cell-abundant SK-MEL-5 tumors was abrogated by ILT3 blockade and remodeling of the immune tumor microenvironment was evident by CyTOF. These data support the testing of anti-ILT3 antibodies for the treatment of a wide range of solid tumors replete with myeloid cells.

BACKGROUND: Prognostic models for malignant pleural mesothelioma (MPM) have been limited to demographics, symptoms, and laboratory values. We hypothesize higher accuracy using both tumor and patient characteristics. The Mesothelioma Prognostic Test (MPT) and molecular subtype based on Claudin-15 to Vimentin (C/V) expression ratio are molecular signatures associated with survival. Tumor volume (TV) has improved performance compared to clinical staging, while neutrophil-to-lymphocyte ratio (NLR) is prognostic for MPM. METHODS: Tumor specimens and clinical data were collected prospectively from patients who underwent extrapleural pneumonectomy (EPP) or pleurectomy and decortication (PD) during 2007–2014. MPT and C/V ratio were determined by RT-qPCR, while TV was assessed from pre-operative scans. Risk groups were derived from combinations of adverse factors based on the Cox model. Predictive accuracy was assessed using Harrell’s c-index. RESULTS: MPT, molecular subtype, TV, and NLR were independently prognostic in EPP patients (N=191), suggesting equal weighting in a final three-group model (c=0.644). In the PD cohort (N=193), MPT poor risk combined with TV>200 cc was associated with triple the risk compared to other subgroups (hazard ratio=2.94, 95% CI: 1.70–5.09, p

Lung cancer is the leading cause of cancer deaths. Tumor heterogeneity, which hampers development of targeted therapies, was herein deconvoluted via single cell RNA sequencing in aggressive human adenocarcinomas (carrying Kras-mutations) and comparable murine model. We identified a tumor-specific, mutant-KRAS-associated subpopulation which is conserved in both human and murine lung cancer. We previously reported a key role for the oncogene BMI-1 in adenocarcinomas. We therefore investigated the effects of in vivo PTC596 treatment, which affects BMI-1 activity, in our murine model. Post-treatment, MRI analysis showed decreased tumor size, while single cell transcriptomics concomitantly detected near complete ablation of the mutant-KRAS-associated subpopulation, signifying the presence of a pharmacologically targetable, tumor-associated subpopulation. Our findings therefore hold promise for the development of a targeted therapy for KRAS-mutant adenocarcinomas., Maroni, Bassal, Krishnan et al. characterise human non-small cell lung cancer (NSCLC) carrying Kras-mutations by single-cell RNA sequencing. They identify a tumour-specific population that is conserved in mice and responds to the drug, PTC596, which is currently in clinical trials and may offer a potential avenue for treating aggressive NSCLC expressing mutated Kras.

This paper summarises the results obtained from the doping control analyses performed during the Summer XXXI Olympic Games (August 3-21, 2016) and the XV Paralympic Games (September 7-18, 2016). The analyses of all doping control samples were performed at the Brazilian Doping Control Laboratory (LBCD), a World Anti-Doping Agency (WADA)-accredited laboratory located in Rio de Janeiro, Brazil. A new facility at Rio de Janeiro Federal University (UFRJ) was built and fully operated by over 700 professionals, including Brazilian and international scientists, administrative staff, and volunteers. For the Olympic Games, 4913 samples were analysed. In 29 specimens, the presence of a prohibited substance was confirmed, resulting in adverse analytical findings (AAFs). For the Paralympic Games, 1687 samples were analysed, 12 of which were reported as AAFs. For both events, 82.8% of the samples were urine, and 17.2% were blood samples. In total, more than 31 000 analytical procedures were conducted. New WADA technical documents were fully implemented; consequently, state-of-the-art analytical toxicology instrumentation and strategies were applied during the Games, including different types of mass spectrometry (MS) analysers, peptide, and protein detection strategies, endogenous steroid profile measurements, and blood analysis. This enormous investment yielded one of the largest Olympic legacies in Brazil and South America. Copyright © 2017 John Wiley & Sons, Ltd.

In 2015-2016, news stories from Charleston, South Carolina, and the University of Missouri, among others, motivated and inspired many people to organize against assaults on the Black community generally and Black students in particular. Similarly, Black students at Robert E. Lee High School in Virginia have come together around what they perceive as racist symbolism and inequitable educational policies and practices. The Black student leaders at Robert E. Lee High School have presented their school principal with a list of demands. Meanwhile, the school’s football and basketball teams, The Rebels, are threatening to go on strike until students’ demands are addressed. This case study could be used in educational leadership graduate programs as well as curriculum and instruction coursework, especially in courses that emphasize social justice and ethical decision making. Particularly relevant courses might include School-Community Relations, Organizational Culture, Politics of Education, Contemporary Issues in Education, Visionary Planning and Strategies, and Schools as Learning Communities. In addition, this case study aligns with Standards 1, 2, 4, 5, and 6 of the Interstate School Leaders Licensure Consortium (ISLLC) Standards and can be integrated in leadership preparation programs accordingly. This case might also be used in school district–sponsored professional development workshops for current and/or aspiring administrators.

The preface of Educators on Diversity, Social Justice, and Schooling: A Reader, an edited volume, opens with two important reminders: 1) the “ … need for teacher educators to reflect on schooling p...

Erythropoiesis-stimulating agents (ESAs) have been used in horses for doping purposes to increase the performance of these animals in endurance sports. Currently, enzyme-linked immunosorbent assay (ELISA) and mass spectrometry methods are used to detect ESA abuse in equines. However, the sarcosyl polyacrylamide gel-electrophoresis (SAR-PAGE) technique could also be used, since its application in human doping control is well established and has proven to be more sensitive. In this work, the SAR-PAGE method was used to detect recombinant human erythropoietin (rHuEPO), novel erythropoiesis stimulating protein (NESP), continuous erythropoietin receptor activator (CERA), and fusion protein of erythropoietin with human immunoglobulin heavy chain Fc region (EPO-Fc) in horse blood and urine. The purification technique for human blood using MAIIA kits worked well for horse samples. The major challenge was horse urine immunopurification, which proved difficult due to filter clogging, but heating and cooling of the horse urine followed by filtration in 30-kDa molecular weight cut-off filters solved this problem. The limits of detection (LODs) of 1.3, 1.6, 6.6, and 13.3 pg/mL for rHuEPO, NESP, CERA, and EPO-Fc, respectively, obtained in spiked urine and 40, 100, 80, and 400 pg/mL for rHuEPO, NESP, CERA, and EPO-Fc, respectively, acquired in spiked blood are lower than the LODs reported in the literature using liquid chromatography-mass spectrometry (LC-MS) methods. In addition, the presence of ESAs was detected up to 9 days after the administration of microdoses of Hemax (rHuEPO), NESP, and CERA in horse blood and urine. SAR-PAGE may be implemented in the routine analysis of horse doping control laboratories for screening and confirmation of ESA abuse, mainly due to its high sensitivity for both matrices compared to published mass spectrometric methods.

Background Patients with adenomatous polyposis may be at increased risk for developing thyroid cancer (TC). However, screening guidelines for TC in these patients are not well established. Methods Patients with a diagnosis of familial adenomatous polyposis, attenuated familial adenomatous polyposis, and gene mutation-negative adenomatous polyposis enrolled in our Hereditary Colorectal Cancer Family Registry were eligible for a screening thyroid ultrasound (US). Findings were reviewed by the study endocrinologist and intervention and/or follow-up determined. Results Fifty patients underwent screening thyroid US. Thirty-four (68%) patients had abnormal findings on US, including 27 (79%) with thyroid nodules. In 7 patients, US-detected thyroid nodules met established criteria for fine-needle aspiration. Of the 6 patients who underwent fine-needle aspiration, 2 (4%) were diagnosed with papillary TC. Both of these patients were female. Conclusions A large proportion of adenomatous polyposis patients will have abnormal results on thyroid US, including suspicious-appearing thyroid nodules that when biopsied are malignant. Female patients have an apparently greater risk of developing TC. Polyposis patients, especially women, should be offered participation in a thyroid US screening program.

Purpose Despite hazardous exposures to cancer-causing agents in the line of duty, the main health and safety concerns of active firefighters have yet to be studied. We compare the perceptions of health and cancer risks between rookie and experienced firefighters. Methods Focus groups were used to investigate potential risk of job exposures, and broad-based concerns regarding work and health. An 18-item demographic survey was also administered. Five focus group sessions were conducted with a total of 57 firefighters. Results Our findings indicate that both rookie and experienced firefighters have a “high risk, high reward” mindset and identify injury, chronic disease, and stress as main health concerns. Experienced firefighters reported a shift in firefighter culture related to health. Conclusion The perception of health and cancer risk of rookie and experienced firefighters differ in the prioritization of their concerns, however both groups equally report occupational cancer risk as their main health concern.

BACKGROUND Serrated polyposis syndrome is a rare syndrome associated with an increased risk for colorectal cancer. The World Health Organization criteria were established to standardize the diagnosis and management of patients afflicted with serrated polyposis. Although useful, the criteria may not be ideal for the initial screening of at-risk populations. OBJECTIVE The aim of this study was to examine the use of a minimal cutoff point of serrated lesions to increase the yield of serrated polyposis cases. DESIGN This was a retrospective review of colonoscopy and pathology reports to identify patients who met the World Health Organization criteria for serrated polyposis. SETTING This study was conducted at a tertiary cancer care referral center. PATIENTS Five hundred patients who had at least 2 pathologically confirmed hyperplastic polyps and/or sessile serrated adenomas/polyps diagnosed between 1999 and 2009 were assessed. MAIN OUTCOME MEASURES The primary outcome measure was the number of serrated polyposis cases. RESULTS Forty of the 500 (8%) patients met the World Health Organization criteria for serrated polyposis syndrome. Patients underwent a median of 4 colonoscopies (range, 1-23) before satisfying the criteria, and only 1 (3%) patient met the criteria for diagnosis during the initial colonoscopy. All 16 patients with a history of colorectal cancer were only diagnosed with serrated polyposis either at the time of their cancer diagnosis or during postoperative colonoscopies. Only 5 of the 40 (13%) patients were enrolled in our institutional Hereditary Colorectal Cancer Family Registry before our study for prospective serrated lesion tracking and colorectal cancer screening. LIMITATIONS This tool requires validation in a prospective setting. CONCLUSIONS The cutoff point of at least 2 pathologically confirmed serrated lesions can serve as a screening tool for identifying patients meeting the World Health Organization criteria for serrated polyposis syndrome who would otherwise go undetected.

Cribriform-morular variant (CMV) is a rare subtype of papillary thyroid carcinoma (PTC) that is associated with familial adenomatous polyposis (FAP). Given the high likelihood for multi-organ malignancies in FAP patients, this study explores the yield of diagnosing occult FAP among CMV-PTC patients. Institutional database was searched in order to identify patients with pathologically-confirmed CMV-PTC from 2000 to 2012. Medical records were reviewed, and clinical and pathological features were analyzed. Eleven cases of CMV were identified from 6,901 patients with PTC, for a prevalence of 0.16 %. All 11 patients were female. The median age at CMV-PTC diagnosis was 36 years (range 18-46). Two patients had pre-existing FAP at the time of PTC diagnosis. The other nine patients were referred for colonoscopy and/or genetic testing. Six patients underwent colonoscopy and one (17 %) was diagnosed with FAP based on polyposis phenotype and genetic testing. The mean age of patients at the time of CMV-PTC diagnosis was younger in the FAP group (23 years, range 18-34) than in the sporadic group (37 years, range 25-46). All three patients with FAP-associated CMV-PTC had multicentric tumors, while all five sporadic patients did not. Our study found that approximately one-sixth of patients with CMV-PTC may have occult FAP. Patients with FAP-associated CMV-PTC appear to be younger and more likely to have multicentric tumors than those with sporadic CMV-PTC. Due to the increased risk of malignancy in patients with FAP, patients with CMV-PTC should be referred for colonoscopy and/or genetic evaluation for FAP.

Approximately 5% of all breast cancers can be attributed to an inherited mutation in one of two cancer susceptibility genes, BRCA1 and BRCA2. We searched for genes that have the potential to distinguish healthy BRCA1 and BRCA2 mutation carriers from noncarriers based on differences in expression profiling. Using expression microarrays, we compared gene expression of irradiated lymphocytes from BRCA1 and BRCA2 mutation carriers versus control noncarriers. We identified 137 probe sets in BRCA1 carriers and 1,345 in BRCA2 carriers with differential gene expression. Gene Ontology analysis revealed that most of these genes relate to regulation pathways of DNA repair processes, cell-cycle regulation, and apoptosis. Real-time PCR was conducted on the 36 genes, which were most prominently differentially expressed in the microarray assay; 21 genes were shown to be significantly differentially expressed in BRCA1 and/or BRCA2 mutation carriers as compared with controls (P < 0.05). On the basis of a validation study with 40 mutation carriers and 17 noncarriers, a multiplex model that included six or more coincidental genes of 18 selected genes was constructed to predict the risk of carrying a mutation. The results using this model showed sensitivity 95% and specificity 88%. In summary, our study provides insight into the biologic effect of heterozygous mutations in BRCA1 and BRCA2 genes in response to ionizing irradiation-induced DNA damage. We also suggest a set of 18 genes that can serve as a prediction and screening tool for BRCA1 or BRCA2 mutational carriers by using easily obtained lymphocytes. Cancer Prev Res; 6(2); 82–90. ©2013 AACR.

Aim Haemoglobin (Hb) variability is associated with poor survival in patients with chronic kidney disease. Association of Hb variability after kidney transplantation with patients' and graft survival has not been adequetly studied. Methods This retrospective study used registry data to examine the association between Hb variability in the early post-transplant period (first 6 months) and graft survival after kidney transplantatin. Kaplan–Meier and Cox regression analyses were used for univariate and multivariate associations between mortality, death censored graft survival and the composite outcome of both, in 752 patients after kidney transplantation. Hb values were collected each month during the first 6 months after transplantation, and Hb variavility was calculated using the residual standard deviation method. Results The highest quartile of Hb variability was associated with inferior graft and patients' survival in univariate (hazard ratio (HR) 2.18; 95% confidence interval (CI) 1.51 to 3.13; P

Background: Various cytokines are increased in hemodialysis (HD) patients, and are considered prognostic markers. Metabolic acidosis is common among chronic HD patients and is associated with survival. The relationship between acidosis and cytokines in HD patients has not been fully explored. The study aim was to measure pro- and anti-inflammatory cytokines in HD patients, with relation to bicarbonate levels. Methods: Forty-seven stable HD patients were included (male/female 28/19, mean age 70.4 ± 14.5 years). Blood tests were taken before a midweek dialysis session. Cytokine secretion from peripheral blood mononuclear cells was measured. Results: Acidosis versus no acidosis (serum HCO3- 21.5 ± 0.2 vs. 24.9 ± 0.3 mEq/l, p < 0.001) was associated with decreased secretion of the anti-inflammatory interleukin-10 (IL-10, 1.16 ± 0.11 vs. 1.71 ± 0.20 ng/ml, p = 0.023). Patients with acidosis had higher parathyroid hormone (PTH), calcium-phosphate product, protein intake and transferrin. Higher IL-10 was associated with increased IL-6 secretion, higher bicarbonate, younger age and lower PTH. Conclusions: In stable chronic HD patients, a possible direct relation exists between metabolic acidosis and IL-10.

Purpose In an attempt to better understand the relationship between vascular access and inflammation we assessed the effect of vascular access on inflammatory markers changes during hemodialysis (HD) session. Methods Fifty HD patients were included: 23 patients with central venous catheters (CVC) and 27 patients with arteriovenous fistulas (AVF). Blood samples for high sensitivity C-reactive protein (hsCRP), Interleukin 6 (IL-6), and Tumor Necrosis Factor α (TNF α) were collected before and after HD session. The outcome was the change in the inflammatory markers during the dialysis. Results Predialysis hsCRP levels were high in 70% of patients, without differences between the groups. Predialysis values were also similar in the two groups for IL-6 and TNF α. There was no increase in hsCRP values following HD and no difference between the change from baseline values in the CVC and AVF groups (-0.01±0.09 mg/dL and -0.01±0.13 mg/dL, respectively [P=.95]). IL-6 values increased during the HD session in the AVF group and non-significantly decreased in the CVC group. The change from baseline values was statistically significantly greater in the AVF group compared to the CVC group (0.76±1.44 ng/mL and -0.52±1.66 ng/mL, respectively, P=.006). TNF α values were significantly decreased in the CVC group and were not changed in the AVF group. The decrease from baseline values was not different between the groups Conclusions Chronic inflammation is present in most HD patients. No increase in pro-inflammatory parameters was seen after a HD session in patients treated via CVC or AVF.

Summary Background and objectives Microalbuminuria predicts graft loss and death in the renal transplant population. Measurement of the urinary albumin-to-creatinine ratio (UACR) is recommended for its detection. There is uncertainty regarding the optimal UACR cutoff values. Few studies have examined the accuracy of UACR in the general population and none have been conducted in renal transplant recipients. The aim of this study is to determine the performance of UACR in the renal transplant population. Design, setting, participants & measurements Renal transplant recipients with a daily urinary albumin excretion rate of up to 300 mg accurately carried out a 24-hour urine collection and provided a morning urine sample for the measurement of albuminuria and UACR. The performance measures of UACR for the detection of microalbuminuria (30 to 300 mg/d) were calculated using different cutoffs. Results Median albuminuria was 23 mg/d, and median UACR was 17 mg/g. The area under the receiver-operating characteristic curve was 0.94 in men and 0.98 in women. The optimal cutoff was 21 mg/g in men and 24 mg/g in women. In men, the 30-, 17-, and 21-mg/g cutoffs provided a sensitivity of 0.79, 0.89, and 0.87. In women, the 30-, 25-, and 24-mg/g cutoffs provided a sensitivity of 0.90, 0.97, and 1.0. Conclusions These data show that in the renal transplant population, lower gender-specific cutoffs should be used for the detection of microalbuminuria than the recommended 30-mg/g cutoff. These data support the need for a reappraisal of the 30-mg/g cutoff for the detection of microalbuminuria.

Objective Rett syndrome is an X-linked dominant neurodevelopmental disorder caused by mutations in the MECP2 gene, and characterized by cognitive and communicative regression, loss of hand use, and midline hand stereotypies. Epilepsy is a core symptom, but literature is controversial regarding genotype–phenotype correlation. Analysis of data from a large cohort should overcome this shortcoming. Methods Data from the Rett Syndrome Networked Database on 1,248 female patients were included. Data on phenotypic and genotypic parameters, age of onset, severity of epilepsy, and type of seizures were collected. Statistical analysis was done using the IBM SPSS Version 21 software, logistic regression, and Kaplan-Meier survival curves. Results Epilepsy was present in 68.1% of the patients, with uncontrolled seizures in 32.6% of the patients with epilepsy. Mean age of onset of epilepsy was 4.68 ± (standard deviation) 3.5 years. Younger age of onset was correlated to severity of epilepsy (Spearman correlation r = 0.668, p < 0.01). Patients with late truncating deletions had lower prevalence of epilepsy. Compared to them, the p.R133C mutation, associated with a milder Rett phenotype, increased the risk for epilepsy (odds ratio [OR] 2.46, confidence interval [CI] 95% 1.3–4.66), but not for severe epilepsy. The p.R255X mutation conferred an increased risk for epilepsy (OR 2.07, CI 95% 1.2–3.59) as well as for severe epilepsy (OR 3.4, CI 95% 1.6–7.3). The p.T158M and p.C306C mutations relatively increased the risk for severe epilepsy (OR 3.09 and 2.69, CI 95% 1.48–6.4 and 1.19–6.05, respectively), but not for epilepsy occurrence. Significance Various mutations in the MECP2 gene have a different influence on epilepsy, unrelated to the severity of the general Rett phenotype. This might suggest a site-specific effect of MeCp2 on epileptic pathways. Further investigation of these mechanisms should promote better understanding of epileptogenesis in Rett syndrome.

Introduction Toll-like receptor 4 (TLR4) is an innate immune receptor expressed in immune cells and the heart. Activation of the immune system following myocardial ischemia causes the release of proinflammatory mediators that may negatively influence heart function. Aim The aim of this study is to determine whether TLR4 is activated in peripheral monocytes and heart tissue taken from patients with varying degrees of myocardial dysfunction caused by coronary artery diseases and scheduled for coronary artery bypass graft (CABG) surgery before 12 months following operation. Methods and Results Patients (n = 44) undergoing CABG surgery having left ventricular ejection fraction ≤ 45% (‘reduced EF’, n = 20) were compared to patients with preserved EF >45% (‘preserved EF’ group, n = 24). ‘Reduced EF’ patients exhibited increased TLR4 expression in monocytes (2.78±0.49 vs. 1.76±0.07 rMFI, p = 0.03). Plasma levels of C-reactive protein, microRNA miR-320a, brain natriuretic peptide (pro BNP) and NADPH oxidase (NOX4) were also significantly different between the ‘preserved EF’ and ‘reduced EF’groups. Elevated TLR4 gene expression levels in the right auricle correlated with those of EF (p

Elevated levels of chemokine receptor CCR9 expression in solid tumors may contribute to poor patient prognosis. In this study, we characterized a novel CCR9-mediated pathway that promotes pancreatic cancer cell invasion and drug resistance, indicating that CCR9 may play a critical role in cancer progression through activation of β-catenin. We noted that the CCL25/CCR9 axis in pancreatic cancer cells induced the activation of β-catenin, which enhanced cell proliferation, invasion, and drug resistance. CCR9-mediated activation of β-catenin and the resulting downstream effects were effectively inhibited by blockade of the PI3K/AKT pathway, but not by antagonism of Wnt. Importantly, we discovered that CCR9/CCL25 increased the lethal dose of gemcitabine, suggesting decreased efficacy of anti-cancer drugs with CCR9 signaling. Through in silico computational modeling, we identified candidate CCR9 antagonists and tested their effects on CCR9/β-catenin regulation of cell signaling and drug sensitivity. When combined with gemcitabine, it resulted in synergistic cytotoxicity. Our results show that CCR9/β-catenin signaling enhances pancreatic cancer invasiveness and chemoresistance, and may be a highly novel therapeutic target.

A meta-analysis was conducted to evaluate the effectiveness of client-clinician matching on the basis of race-ethnicity on overall functioning, service retention, and total number of sessions attended for African American and Caucasian American adult populations in mental health services. The analysis included 10 published and unpublished studies between 1991 and 2001. A random effects meta-analysis model showed no significant differences between client-clinician dyads matched racially-ethnically and those dyads not matched with respect to overall functioning, service retention, and total number of sessions attended. The finding was consistent for both African American and Caucasian American clients. Further implications of the findings are discussed. The authors also encourage more complete reporting of data suitable for quantitative research synthesis.

In patients infected with hepatitis C virus (HCV) genotype 1, sustained viral response (SVR) averages 10-40% depending on treatment regime. It has been proposed that high dose daily interferon (IFN) therapy early in therapy (induction dosing) may enhance SVR. In the present study we examined this issue and also assessed whether one could predict SVR and non-SVR, based on viral kinetics during the first month of induction therapy. End of treatment response and SVR was determined in 173 HCV infected patients who were treated with different induction doses of consensus interferon (CIFN) for one month followed by 11 months of standard 9 microg of CIFN thrice weekly (TIW). The second phase decline slope was calculated by log-linear regression on weekly measurements of serum HCV RNA during the first 7-28 days of treatment; rapid viral response (RVR) during the first month of induction dosing was defined as a decline of > 0.3 log copies/mL/week. Overall, SVR occurred in 11% of genotype 1 infected patients and 41% of patients with nongenotype 1. High dose induction therapy did not increase the rate of SVR, in either genotype 1 or genotype 2/3 infected patients. No patient without a RVR during the first month had SVR, while SVR occurred in 55% of the patients with RVR. RVR was the best predictor of SVR using multivariate analysis. These results indicate that induction dosing with CIFN does not improve SVR rates. They also suggest that early viral kinetics during the first month of therapy can predict non-SVR and thus save a patient a year long treatment which is fraught with side-effects and significant cost.

Background To compare the accuracy of different imaging modalities, alone and in combination in predicting findings at surgery after preoperative chemoradiation for locally advanced rectal cancer. Methods Following chemoradiation, tumors were reclassified on the basis of findings on pelvic computed tomography (CT) (94 patients), endorectal ultrasonography (EUS) (138 patients) alone or by both CT and EUS (80 patients). The ability of the imaging modalities, to predict the pathologic T status, N status, and TNM stage at surgery was evaluated and compared. Results Mean age of the patients was 64.5 years (range 28–88 years); 55% were male. CT and EUS combined had a positive predictive value of 20% for pathologic pT1 stage, 29% for pT1, 29% for pT2, and 58% for pT3. Predictive values for the operative TNM stage were 50% for stage I, 45% for stage II, and 31% for stage III. These values did not exceed those for each modality alone. Conclusion The performance of preoperative CT and EUS in predicting the T and TNM stage of rectal cancer at surgery is poor. Neither modality alone nor the two combined is sufficiently accurate to serve as the basis for decisions regarding treatment modification.

Background: Mitogen-activated protein (MAP) kinases (or extracellular signal regulated kinases; Erks) and stress-activated protein (SAP) kinases mediate cellular responses to a wide variety of signals. In the Erk MAP kinase pathway, activation of MAP kinases takes place in the cytoplasm and the activated enzyme moves to the nucleus. This translocation to the nucleus is essential to MAP kinase signalling because it enables the kinase to phosphorylate transcription factors. Whether components of the pathway mediated by the SAP kinase p38 change their cellular location on activation is not clear; we have therefore studied the cellular localisation of components of this pathway before and after stimulation. Results: The p38 SAP kinase substrate MAP-kinase-activated protein kinase-2 (MAPKAP kinase-2) contains a putative nuclear localisation signal which we show is functional and required for activation by a variety of stimuli. Following phosphorylation of MAPKAP kinase-2, nuclear p38 was exported to the cytoplasm in a complex with MAPKAP kinase-2. Export of MAPKAP kinase-2 required phosphorylation by p38 but did not appear to require the kinase activity of MAPKAP kinase-2. The p38 activators MKK3 and MKK6 were present in both the nucleus and the cytoplasm, consistent with a role in activating p38 in the nucleus. Conclusions: In the p38 SAP kinase pathway, MAPKAP kinase-2 serves both as an effector of p38 by phosphorylating substrates and as a determinant of cellular localisation of p38. Nuclear export of p38 and MAPKAP kinase-2 may permit them to phosphorylate substrates in the cytoplasm.

It has recently been recognized that cellular stresses activate certain members of the mitogen-activated protein kinase (MAPK) superfamily. One role of these “stress-activated” MAPKs is to increase the transactivating activity of the transcription factors c-Jun, Elk1, and ATF2. These findings may be particularly relevant to hearts that have been exposed to pathological stresses. Using the isolated perfused rat heart, we show that global ischemia does not activate the 42- and 44-kD extracellular signal–regulated (protein) kinase (ERK) subfamily of MAPKs but rather stimulates a 38-kD activator of MAPK-activated protein kinase-2 (MAPKAPK2). This activation is maintained during reperfusion. The molecular characteristics of this protein kinase suggest that it is a member of the p38/reactivating kinase (RK) group of stress-activated MAPKs. In contrast, stress-activated MAPKs of the c-Jun N-terminal kinase (JNK/SAPKs) subfamily are not activated by ischemia alone but are activated by reperfusion following ischemia. Furthermore, transfection of ventricular myocytes with activated protein kinases (MEKK1 and SEK1) that may be involved in the upstream activation of JNK/SAPKs induces increases in myocyte size and transcriptional changes typical of the hypertrophic response. We speculate that activation of multiple parallel MAPK pathways may be important in the responses of hearts to cellular stresses.

Haemoglobin (Hb) variability is associated with poor survival in patients with chronic kidney disease. Association of Hb variability after kidney transplantation with patients' and graft survival has not been adequetly studied.This retrospective study used registry data to examine the association between Hb variability in the early post-transplant period (first 6 months) and graft survival after kidney transplantatin. Kaplan-Meier and Cox regression analyses were used for univariate and multivariate associations between mortality, death censored graft survival and the composite outcome of both, in 752 patients after kidney transplantation. Hb values were collected each month during the first 6 months after transplantation, and Hb variavility was calculated using the residual standard deviation method.The highest quartile of Hb variability was associated with inferior graft and patients' survival in univariate (hazard ratio (HR) 2.18; 95% confidence interval (CI) 1.51 to 3.13; P 0.001) and multivariate models (HR 1.5; 95% CI 1.029 to 2.18; P = 0.035). This association was mainly due to increased death censored graft failure in the high variability group (HR 2.75; 95% CI 1.73 to 4.38; P 0.001) and (HR 1.67; 95% CI 1.023 to 2.74; P = 0.04) in the univariate and multivariate models, respectively. There was no association between Hb variability and the risk of death (HR 1.51; 95% CI 0.88 to 2.57; P = 0.132).High Hb variability is independently associated with inferior graft survival in patients after kidney transplantation.

Background We sought to evaluate the effect of intravenous (IV) iron supplementation on hemoglobin (Hb) levels and detect predictors for response. Methods This is a retrospective cohort study of 81 patients who were treated with IV iron post-transplant. We evaluated predictors of response to treatment defined as an increase in Hb value of more than 1 g/dL by linear regression analysis. Results Three months after treatment, the mean Hb level increased significantly from 9.8 ± 1.4 g/dL to 11.1 ± 1.6 g/dL (p

METHOD:: In this study we sought to characterize the relationship between several pharmacokinetic and pharmacodynamic parameters and virologic responses among HIV/hepatitis C virus genotype-1 co-infected patients receiving pegylated interferon-alpha-2b (peg-IFN2b) and ribavirin. We also tried to establish the underlying mechanisms that lead to poor sustained virologic responder rates observed with African-Americans against Caucasians and compared their results with those observed in a cohort of hepatitis C virus mono-infected patients. RESULTS:: Among our studied population, a viral decline of more than 1.0 log at day 3 combined with viral load of less than 5.0 log IU/ml at day 28 predicted sustained virologic responders with negative predictive value 100% and positive predictive value 100%. African-Americans had significantly (P < 0.01) slower hepatitis C virus viral kinetics as compared to Caucasians. However, peg-IFN2b concentrations and pharmacokinetic parameters, peg-IFN2bmax and peg-IFN2b half-life, were similar in both groups and did not predict sustained virologic responders. Nevertheless, the pharmacodynamic parameter EC50, estimated from nonlinear fitting of the viral kinetics together with peg-IFN2b concentration data, showed that HIV/ hepatitis C virus co-infected African-Americans have lower sensitivity to interferon-alpha thus giving rise to slower viral decline. The combined pharmacokinetic/pharmacodynamic parameter IFNmax/EC90 was an excellent predictor of sustained virologic responders, thus showing the importance of maintaining peg-IFN2b levels above EC90 to achieve successful treatment. CONCLUSION:: Further studies are needed to evaluate whether these pharmacodynamic predictions are a result of differential host response to peg-IFN2b or other viral factors conferring relative resistance to peg-IFN2b.

Time series reconstruction algorithms are widely used to create temporal profiles from data series. However, in many clinical fields, e.g., viral kinetics, the data is noisy and sparse, making it difficult to use standard algorithms. We developed PROFILASE, which combines advanced multi-objective genetic algorithm search with machine learning architecture to harvest experts’ decision-making considerations. Furthermore, PROFILASE implements additional scoring considerations, more biological in nature, thus further exploits domain expertise. We tested our system against a standard bottom-up algorithm by reconstruction of time series sparsely sampled with noise from simulated profiles. PROFILASE obtained RMS distance 2.5 fold lower (P\le0.0001) than the standard algorithm, 93% correct identification rate of segment number and 88% correct profile classification rate (versus 68%). The additional considerations were found to have a significant effect on the success of reconstruction. Finally, PROFILASE was generalized to evaluate additional considerations from different fields, thus allowing better understanding of other diseases.

It has recently been shown that upon initiation of interferon (IFN) treatment there is a biphasic decline in hepatitis C virus (HCV) RNA levels. In preliminary results, the rate of second phase viral decline has been shown to be an excellent predictor of treatment response. In this analysis, we determined whether the first phase viral kinetic parameters affected the rate of second phase viral decline. We also assessed whether first phase viral kinetic parameters could be used to predict treatment response within 24 h of initiating treatment. This study is a retrospective analysis of two completed studies from which detailed kinetic data were obtained in patients infected with genotype 1 HCV. In both studies, viral levels were measured frequently over the first 24 h, allowing the determination of IFNs effectiveness in blocking viral production and the viral load at the end of the first phase (v1). The second phase decline slope was calculated by log-linear regression on measurements of serum HCV RNA during days 2, 7 and 14. In study one, sustained viral response (SVR) rates were obtained, allowing the determination of the first phase's predictive power for SVR. Logistic regression and fisher exact tests were used to analyse data. In study one, no patient achieved SVR without an IFN effectiveness greater than 98% and a V1 less than 250 000 copies/mL. When V1 and IFN effectiveness were combined to predict SVR, a negative predictive value= 100%, positive predictive value=71% and accuracy of 95% was obtained after only 24 h of IFN treatment. Both studies illustrated strong correlations for both IFN effectiveness and V1 with the rate of 2nd phase slope (P < 0.001). V1 also correlated significantly with a calculation of infected cell loss (delta), which is a major determinant of the second phase viral decline. These results suggest that early viral kinetics may predict lack of response after only 24 h of treatment initiation and indicate a strong link between the degree of viral load reduction during the first phase, and the subsequent 2nd phase decline slope. This might be explained by a viral dynamics model assuming a jump-start of the immune response when viral loads are reduced below a threshold, subsequently giving rise to a faster 2nd phase decline slope.