Miracle-dz/UniFAR-FTUs huggingface dataset:
Using Quantitative Seroproteomics to Identify Antibody Biomarkers in Pancreatic Cancer

Serum samples from patients in a phase II pancreas cancer vaccine clinical trial were subjected to quantitative proteomics. Three highly induced proteins in the pancreas after vaccination became targets of antibodies. Patients harboring these antibodies had improved clinical outcomes. Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States. Less than 6% of patients survive beyond the fifth year due to inadequate early diagnostics and ineffective treatment options. Our laboratory has developed an allogeneic, granulocyte-macrophage colony-stimulating factor (GM-CSF)–secreting pancreatic cancer vaccine (GVAX) that has been tested in phase II clinical trials. Here, we employed a serum antibodies–based SILAC immunoprecipitation (SASI) approach to identify proteins that elicit an antibody response after vaccination. The SASI approach uses immunoprecipitation with patient-derived antibodies that is coupled to quantitative stable isotope–labeled amino acids in cell culture (SILAC). Using mass spectrometric analysis, we identified more than 150 different proteins that induce an antibody response after vaccination. The regulatory subunit 12A of protein phosphatase 1 (MYPT1 or PPP1R12A), regulatory subunit 8 of the 26S proteasome (PSMC5), and the transferrin receptor (TFRC) were shown to be pancreatic cancer–associated antigens recognized by postvaccination antibodies in the sera of patients with favorable disease-free survival after GVAX therapy. We further interrogated these proteins in over 80 GVAX-treated patients' pancreases and uniformly found a significant increase in the expression of MYPT1, PSMC5, and TFRC in neoplastic compared with non-neoplastic pancreatic ductal epithelium. We show that the novel SASI approach can identify antibody targets specifically expressed in patients with improved disease-free survival after cancer vaccine therapy. These targets need further validation to be considered as possible pancreatic cancer biomarkers. Cancer Immunol Res; 4(3); 225–33. ©2016 AACR.
Plasma Micro-RNA Alterations Appear Late in Pancreatic Cancer

Objectives: The aim of this research was to study whether plasma microRNAs (miRNA) can be used for early detection of pancreatic cancer (PC) by analyzing prediagnostic plasma samples collected before a PC diagnosis. Background: PC has a poor prognosis due to late presenting symptoms and early metastasis. Circulating miRNAs are altered in PC at diagnosis but have not been evaluated in a prediagnostic setting. Methods: We first performed an initial screen using a panel of 372 miRNAs in a retrospective case-control cohort that included early-stage PC patients and healthy controls. Significantly altered miRNAs at diagnosis were then measured in an early detection case-control cohort wherein plasma samples in the cases are collected before a PC diagnosis. Carbohydrate antigen 19–9 (Ca 19–9) levels were measured in all samples for comparison. Results: Our initial screen, including 23 stage I-II PC cases and 22 controls, revealed 15 candidate miRNAs that were differentially expressed in plasma samples at PC diagnosis. We combined all 15 miRNAs into a multivariate statistical model, which outperformed Ca 19–9 in receiver-operating characteristics analysis. However, none of the candidate miRNAs, individually or in combination, were significantly altered in prediagnostic plasma samples from 67 future PC patients compared with 132 matched controls. In comparison, Ca 19–9 levels were significantly higher in the cases at <5 years before diagnosis. Conclusion: Plasma miRNAs are altered in PC patients at diagnosis, but the candidate miRNAs found in this study appear late in the course of the disease and cannot be used for early detection of the disease.
Cognitive and anatomical correlates of anosognosia in amnestic mild cognitive impairment and early-stage Alzheimer's disease

ABSTRACT Background: Anosognosia is a common feature in Alzheimer's disease (AD). The brain substrates of anosognosia are not fully understood, and less is known about the cognitive substrates of anosognosia in prodromal and early stages of AD. Methods: Fourty-seven patients with amnestic-type mild cognitive impairment (aMCI) (n = 26) and early-stage AD (n = 21) were included, and Clinical Insight Rating Scale and Anosognosia Questionnaire for Dementia (AQ-D) were used to assess anosognosia. A detailed neuropsychological battery was administered; each patient underwent a structural magnetic resonance imaging (MRI). Correlation between anosognosia and performance in individual cognitive domains as well as correlation between anosognosia and cortical thickness values in regions of interest were assessed. Results: Performance of the anosognosic patients in Digit Ordering Test (DOT), Digit Span Backwards, and Clock Drawing Test (CDT) was significantly worse compared to non-anosognosic patients in the total study population and in the aMCI subgroup but not in AD group. AQ-D scores negatively correlated with Mini-Mental State Examination (MMSE), California Verbal Learning Test (CVLT), Digit Span Backwards and CDT scores in total group and MMSE, CVLT, DOT, and Digit Span Backwards scores in the aMCI group. No significant correlations were found between cortical thickness measurements and AQ-D scores in any of the patient populations. Conclusions: Anosognosia was associated with episodic memory, working memory, and executive functions in the total population and aMCI group, but no association was found in early-stage AD patients. Anosognosia in the early stages of AD may be related with non-structural changes such as hypoconnectivity rather than structural changes.
When False Recognition Meets Metacognition: The Distinctiveness Heuristic

Abstract We investigated the contribution of a distinctiveness heuristic to rejecting false memories. Individuals studied words, pictures, or both types of items and then completed a recognition test on which the studied items appeared once, whereas the new words appeared twice. Participants who had studied pictures were less likely to falsely recognize repeated new words than were participants who had studied words. We argue that studying pictures provides a basis for using a distinctiveness heuristic during the recognition test; participants infer from the absence of memory for expected picture information that a test item is “new. ” These experiments also investigated the influence of two variables—diagnosticity and metacognitive control—on the use of the distinctiveness heuristic. We examined the role of diagnostic information in eliciting the heuristic by varying the proportion of studied items that appeared as pictures. Compared to a word encoding condition, participants successfully rejected repeated new words after studying 50, 25, and 33% of the items as pictures in Experiments 1, 2, and 3, respectively. Thus, the distinctive information need not be completely diagnostic (i.e., perfectly predictive of an item's oldness) for participants to use the heuristic. We also show that the distinctiveness heuristic is under metacognitive control such that it can be turned on or off depending on participants' expectations about its usefulness for reducing memory errors.
Effectiveness of Osteopathic Manipulative Therapy for Managing Symptoms of Irritable Bowel Syndrome: A Systematic Review

Abstract Context: Irritable bowel syndrome (IBS) is a common and often lifelong functional gastrointestinal disorder. There is a scarcity of effective management options for IBS. Objective: To assess the effectiveness of osteopathic manipulative therapy (OMTh) for managing the symptoms of IBS. Data Sources: Articles without language or publication-date restriction were searched in PubMed, Embase, Cochrane Library, PEDro, OSTMED.DR, and Osteopathic Research Web. Search terms included irritable bowel syndrome, IBS, functional colonic disease, colon irritable, osteopath*, osteopathic manipulation, osteopathic medicine, clinical trial, and randomized clinical trial. Experts in the field of visceral osteopathy were also contacted to identify additional studies. Study Selection: The authors evaluated randomized controlled trials (RCTs) of OMTh for IBS in adults in whom IBS was diagnosed using Rome (I-III) criteria. If OMTh was not the sole intervention in the intervention group and if the same additional interventions were not applied to the control group, the study was excluded. Data Extraction: Citation identification, study selection, and data extraction were independently undertaken by 2 reviewers with a data extraction form from the Cochrane Collaboration. A consensus method was used to resolve disagreements concerning the assessment of the methodologic quality of the RCTs that were reviewed. Results: The search identified 10 studies that examined OMTh for patients with IBS; 5 studies (204 patients) met the inclusion criteria. All studies were assessed as having low risk of bias according to the Cochrane Collaboration criteria, although there was heterogeneity in the outcome measures and control interventions. Three studies used visual analog scales for abdominal pain, whereas others used the IBS severity score and the Functional Bowel Disorder Severity Index. A variety of secondary outcomes were used. All studies reported more pronounced short-term improvements with OMTh compared with sham therapy or standard care only. These differences remained statistically significant after variable lengths of follow-up in 3 studies. Conclusion: The present systematic review provides preliminary evidence that OMTh may be beneficial in the treatment of patients with IBS. However, caution is required in the interpretation of these findings because of the limited number of studies available and the small sample sizes.
ACTG A5353: A Pilot Study of Dolutegravir Plus Lamivudine for Initial Treatment of Human Immunodeficiency Virus-1 (HIV-1)–infected Participants With HIV-1 RNA <500000 Copies/mL

Background Limited data exist on initial human immunodeficiency virus type 1 (HIV-1) treatment with dolutegravir plus lamivudine. Methods A5353 is a phase 2, single-arm, pilot study of once-daily dolutegravir (50 mg) plus lamivudine (300 mg) in treatment-naive participants with HIV-1 RNA ≥1000 and <500000 copies/mL. Exclusion criteria included active hepatitis B or major protease, reverse transcriptase, or integrase resistance. The primary efficacy measure was the proportion with HIV-1 RNA <50 copies/mL (FDA [US Food and Drug Administration] Snapshot) at week 24. Virologic failure (VF) was confirmed HIV-1 RNA >400 copies/mL at week 16/20 or >200 copies/mL at or after week 24. Dolutegravir levels and drug resistance testing were performed at VF. Results One hundred and twenty participants (87% male, median age 30 years, 37 (31%) HIV-1 RNA >100000 copies/mL) initiated study treatment. Median entry HIV-1 RNA and CD4 count were 4.61 log10 copies/mL and 387 cells/mm3. Virologic efficacy at week 24 was 108/120 (90%, confidence interval [83%, 95%]), with comparable results in the >100000 copies/mL and ≤100000 copies/mL strata, that is, 89% (75%, 97%) and 90% (82%, 96%), respectively. Three participants with VF, had undetected plasma dolutegravir at ≥1 time points; the M184V and R263R/K mutations developed in 1 participant. Two participants experienced grade 3 possible/probable treatment-related adverse events; none discontinued treatment due to adverse events. Conclusions Dolutegravir plus lamivudine demonstrated efficacy in individuals with pretreatment HIV-1 RNA up to 500000 copies/mL in this pilot trial, but a participant developed resistance mutations. Clinical Trials Registration NCT02582684.
Impacts of decline harvest of country food on nutrient intake among Inuit in Arctic Canada: impact of climate change and possible adaptation plan

Background The pervasive food insecurity and the diet transition away from local, nutrient-rich country foods present a public health challenge among Inuit living in the Canadian Arctic. While environmental factors such as climate change decreased the accessibility and availability of many country food species, new species were introduced into regions where they were previously unavailable. An adaptation such as turning to alternate country food species can be a viable solution to substitute for the nutrients provided by the declined food species. The objective of this study was to estimate the impact on nutrient intake using hypothetical scenarios that current commonly harvested country foods were reduced by 50%, and were replaced with alternate or new species. Methods Data collected during the 2007–2008 Inuit Health Survey from 36 Canadian Arctic communities spanning Nunavut, the Inuvialuit Settlement Region and Nunatsiavut were used. Results A 50% decline in consumption of fish, whale, ringed seals and birds (the food that was reported to be in decline) resulted in a significant decrease in essential nutrient intake. Possible substitute foods were identified but some nutrients such as zinc and especially vitamin D were most often found lacking in the alternative diet. Conclusions If the alternative species are not available or feasible, more expensive and less nutritionally dense store-bought foods may be sought. Given the superior quality of country foods and their association with food security, and Inuit cultural health and personal identity, developing skills and awareness for adaptation, promoting regional sharing networks, forming a co-management agency and continuing nutritional monitoring may potentially preserve the nutritional integrity of Inuit diet, and in turn their health and cultural survival.
Bivalirudin anticoagulation for left ventricular assist device implantation on an extracorporeal life support system in patients with heparin-induced thrombocytopenia antibodies.

OBJECTIVES Heparin-induced thrombocytopenia (HIT) requires alternative anticoagulation strategies. We investigated outcomes in patients with HIT antibodies undergoing low-dose bivalirudin anticoagulation during left ventricular assist device implantation on an extracorporeal life support system (ECLS) and compared the results with non-HIT patients treated with heparin and receiving left ventricular assist device implantation with ECLS support. METHODS The institutional ventricular assist device database was searched for the period from March 2012 to March 2016. The primary end-point was the need for early (<7 days) surgical re-exploration due to persistent haemorrhage or cardiac tamponade postoperatively. The secondary clinical end-points were delayed chest closure, stroke, intracranial bleeding, re-thoracotomy >7 days and mortality up to 1 year. Unadjusted comparison was used for the entire groups. Because of non-random group assignment, propensity score matching was also performed to compare treatment effects. RESULTS Twenty-one patients were treated with bivalirudin and 36 patients with heparin. INTERMACS levels were lower, inotropic score was higher and the prevalence of mechanical ventilation and preoperative ECLS implants was also significantly higher in the heparin group than in the bivalirudin group (P-values <0.05). The primary end-point was reached by 19% in the bivalirudin group and 16.7% in the heparin group (bivalirudin group: odds ratio 1.18, 95% confidence interval 0.29-4.76; P = 0.820). The propensity score-matched groups also showed no difference in this regard (P = 0.455). All secondary clinical end-points were comparable between groups, both in the unadjusted analysis and in the propensity score-matched groups. CONCLUSIONS In patients with HIT antibodies, low-dose bivalirudin anticoagulation on ECLS support appears to be a feasible option for left ventricular assist device implantation.
Impact of carbapenem restriction on the antimicrobial susceptibility pattern of Pseudomonas aeruginosa isolates in the ICU

Background Rates of carbapenem-resistant Pseudomonas aeruginosa are increasing. Aggressive prevention strategies, including instituting antimicrobial stewardship programmes, are essential for combating antimicrobial resistance. Objectives We conducted this study to compare the antimicrobial susceptibility pattern of P. aeruginosa before and after carbapenem restriction. Methods We conducted a two-phase retrospective study in an adult ICU. The first phase was from May until July 2016 (before carbapenem restriction), whereas the second phase was from September until November 2016 (while implementing carbapenem restriction). The antimicrobial susceptibility pattern of P. aeruginosa was reviewed in August and December 2016. The measure of carbapenem-resistant P. aeruginosa was the proportion of resistant isolates (percentage resistant). The measure of antibacterial consumption in the study phases was DDDs/1000 patient days. Results The overall carbapenem consumption decreased significantly in the second phase, from 28.44 to 11.67 DDDs/1000 patient days (P = 0.012). The resistance of P. aeruginosa to imipenem and meropenem decreased significantly from 76.0% to 38.5% (P = 0.019) and from 74.1% to 30.0% (P = 0.012), respectively. Susceptibility of P. aeruginosa to other antibacterials was not affected by carbapenem restriction. Conclusions These data suggest that restricting carbapenems, even for a short duration, may be an effective strategy for managing the problem of carbapenem resistance in P. aeruginosa.
Characteristics and intestinal immunomodulating activities of water-soluble pectic polysaccharides from Chenpi with different storage periods.

BACKGROUND The traditional view considers that Chenpi (dried citrus peel) stored over the long-term has better health efficacies compared to fresh Chenpi, although the detailed mechanism responsible for this remains obscure. RESULTS The three water-soluble pectic polysaccharides (CPP1, CPP5 and CPP10) were obtained from 1-, 5- and 10-year Chenpi, respectively, and their physicochemical characteristics and intestinal immunomodulating activities were investigated and compared. The results obtained showed that CPP5 and CPP10 demonstrated a lower dynamic viscosity and degree of methylesterification, as well as a higher molecular heterogeneity, compared to CPP1. Monosaccharide composition analysis indicated that CPP1 was composed of arabinose, galacturonic acid and galactose, and a small amount of rhamnose; however, CPP5 and CPP10 consisted of arabinose, galacturonic acid, galactose, glucose and xylose, and a small amount of rhamnose. With the extension of storage period of Chenpi, the content of soluble conjugate phenolic acids increased in the pectic polysaccharide. Furthermore, it was confirmed that the pectic polysaccharides extracted from the 5-year and 10-year Chenpi could significantly enhance the proliferation of bone marrow cells via activating the Peyer's patch cells in vitro. CONCLUSION The present study demonstrates the differences in the pectic polysaccharides from Chenpi with different storage periods and also confirms that the pectic polysaccharides extracted from Chenpi stored over the long-term had more significant intestinal activities compared to that obtained from the fresh Chenpi. This phenomenon might partly explain why the Chenpi stored over the long-term has better healthcare effects. © 2018 Society of Chemical Industry.
Synchronization of multiple linear systems with communication delay

In this paper the problem of state and output synchronization of multi-agent systems with individual identical linear dynamics has been considered in the presence of constant and homogeneous communication delay. A linear synchronization protocol is introduced to perceive distributive control strategy which uses delayed information of states from the neighbouring agents. For marginally unstable dynamics of agents, maximum possible delay margin has been found. The delay margin depends both on the system matrix of the agent dynamics and network topology for directed graph whereas for undirected graph it depends only on the system matrix of the agents. However, for single-integrator and double-integrator agents, proposed protocol ensures synchronization with arbitrarily large bounded delay. A condition on coupling strength is derived for the proposed control methodology to tolerate delay less than the delay margin. It has been shown that the eigenvalues of the Laplacian matrix representing the communication topology are crucial in finding the condition for reaching synchronization. The idea of state synchronization is extended to output synchronization by the use of Luenberger observer. Finally, numerical simulations are provided to illustrate the results.
The Relationship Between Problem Size and Fixation Patterns During Addition, Subtraction, Multiplication, and Division

Eye-tracking methods have only rarely been used to examine the online cognitive processing that occurs during mental arithmetic on simple arithmetic problems, that is, addition and multiplication problems with single-digit operands (e.g., operands 2 through 9; 2 + 3, 6 x 8) and the inverse subtraction and division problems (e.g., 5 – 3; 48 ÷ 6). Participants (N = 109) solved arithmetic problems from one of the four operations while their eye movements were recorded. We found three unique fixation patterns. During addition and multiplication, participants allocated half of their fixations to the operator and one-quarter to each operand, independent of problem size. The pattern was similar on small subtraction and division problems. However, on large subtraction problems, fixations were distributed approximately evenly across the three stimulus components. On large division problems, over half of the fixations occurred on the left operand, with the rest distributed between the operation sign and the right operand. We discuss the relations between these eye tracking patterns and other research on the differences in processing across arithmetic operations.
Molecular mechanism of thermosensory function of human heat shock transcription factor Hsf1

The heat shock response is a universal homeostatic cell autonomous reaction of organisms to cope with adverse environmental conditions. In mammalian cells, this response is mediated by the heat shock transcription factor Hsf1, which is monomeric in unstressed cells and upon activation trimerizes, and binds to promoters of heat shock genes. To understand the basic principle of Hsf1 activation we analyzed temperature-induced alterations in the conformational dynamics of Hsf1 by hydrogen exchange mass spectrometry. We found a temperature-dependent unfolding of Hsf1 in the regulatory region happening concomitant to tighter packing in the trimerization region. The transition to the active DNA binding-competent state occurred highly cooperative and was concentration dependent. Surprisingly, Hsp90, known to inhibit Hsf1 activation, lowered the midpoint temperature of trimerization and reduced cooperativity of the process thus widening the response window. Based on our data we propose a kinetic model of Hsf1 trimerization. DOI: http://dx.doi. org/10.7554/eLife.11576. 001