Miracle-dz/UniFAR-FTUs huggingface dataset:
Immune microenvironmental shift along human colorectal adenoma–carcinoma sequence: is it relevant to tumor development, biomarkers and biotherapeutic targets?

Abstract Human colorectal carcinoma (CRC) is one of the leading cancers. Every year, the WHO estimates a total of 945,000 new CRC cases, with 492,000 deaths worldwide. Most CRCs arise from the main premalignant lesion, colorectal adenomas, and the progression of colorectal adenoma to CRCs may take a long-term time course. The development of human CRCs is not only determined by the adenomatous cells, but also by the interaction between adenomatous cells and host immune environment. In response to tumor initiation or invasion, many inflammatory cells and components will be inevitably activated and form an inflammatory microenvironment surrounding the CRC tumors. Accumulative evidence has revealed that inflammatory response plays a key role in the development of human CRCs by implicating in many aspects including in determining the microenvironmental immune function shift from immunosurveillance to immunosuppression and significantly influences the progression of precancerous lesions to cancers. In this review, the functional changes of immune microenvironment from precancerous stage (adenoma) to cancer stage are summarized, and their potential as predictive biomarkers and biotherapeutic significance in preventing the development of CRCs are discussed.
Targeting of Pseudomonas aeruginosa in the Bloodstream with Bispecific Monoclonal Antibodies1

We examined the ability of a bispecific mAb reagent, consisting of a mAb specific for the primate erythrocyte complement receptor cross-linked with an anti-bacterial mAb, to target bacteria in the bloodstream in an acute infusion model in monkeys. In vitro studies demonstrated a variable level of complement-mediated binding (immune adherence) of Pseudomonas aeruginosa (strain PAO1) to primate E in serum. In vivo experiments in animals depleted of complement revealed that binding of bacteria to E was <1% before administration of the bispecific reagent, but within 5 min of its infusion, >99% of the bacteria bound to E. In complement-replete monkeys, a variable fraction of infused bacteria bound to E. This finding may have significant implications in the interpretation of animal models and in the understanding of bacteremias in humans. Treatment of these complement-replete monkeys with the bispecific reagent led to >99% binding of bacteria to E. Twenty-four-hour survival studies were conducted; several clinical parameters, including the degree of lung damage, cytokine levels, and liver enzymes in the circulation, indicate that the bispecific mAb reagent provides a degree of protection against the bacterial challenge.
The cytoplasmic phosphoproteome of the Gram‐negative bacterium Campylobacter jejuni: Evidence for modification by unidentified protein kinases

We have undertaken a comprehensive analysis of cytoplasmic protein phosphorylation in Campylobacter jejuni by mass spectrometric identification of phosphoproteins and localization of the sites of modification by phosphopeptide analyses. Cell extracts, enriched for phosphoproteins using Fe(III) IMAC or commercial phosphoprotein purification kits, were analyzed by 1‐D and 2‐D SDS‐PAGE and subjected to mass fingerprinting by in‐gel tryptic digestion and MALDI‐TOF MS. Fifty‐eight phosphopeptides were identified from 1‐D gel bands by nano‐LC‐MS/MS and automated searching in a C. jejuni ORF database resulting in the unequivocal identification of 36 phosphoproteins of diverse function. In addition to elongation factors and chaperonins, which have been reported to be phosphorylated in other bacteria, the major phosphoproteins included bacterioferritin and superoxide dismutase. The sequences around the phosphorylated Ser and Thr residues are indicative of specific kinases being responsible for some of the modifications. However, many of the other identified proteins are enzymes that have phosphorylated substrates, including ATP, hence other modifications may arise from autophosphorylation. Comparative analyses of IMAC extracts from the Escherichia coli strain AD202 and Helicobacter pylori resulted in the identification of homologs of six of the C. jejuni phosphoproteins, though their overall phosphoproteome maps were distinctly different.
Thr2446 Is a Novel Mammalian Target of Rapamycin (mTOR) Phosphorylation Site Regulated by Nutrient Status*

The mammalian target of rapamycin (mTOR) is a key regulator of protein translation. Signaling via mTOR is increased by growth factors but decreased during nutrient deprivation. Previous studies have identified Ser2448 as a nutrient-regulated phosphorylation site located in the mTOR catalytic domain, insulin stimulates Ser2448 phosphorylation via protein kinase B (PKB), while Ser2448 phosphorylation is attenuated with amino acid starvation. Here we have identified Thr2446 as a novel nutrient-regulated phosphorylation site on mTOR. Thr2446 becomes phosphorylated when CHO-IR cells are nutrient-deprived, but phosphorylation is reduced by insulin stimulation. Nutrient deprivation activates AMP-activated protein kinase (AMPK). To test whether this could be involved in regulating phoshorylation of mTOR, we treated cultured murine myotubes with 5′-aminoimidazole-4-carboxamide ribonucleoside (AICAR) or dinitrophenol (DNP). Both treatments activated AMPK and also caused a concomitant increase in phosphorylation of Thr2446 and a parallel decrease in insulin's ability to phosphorylate p70 S6 kinase. In vitro kinase assays using peptides based on the sequence in amino acids 2440–2551 of mTOR found that PKB and AMPK are capable of phosphorylating sites in this region. However, phosphorylation by PKB is restricted when Thr2446 is mutated to an acidic residue mimicking phosphorylation. Conversely, AMP-kinase-induced phosphorylation is reduced when Ser2448 is phosphorylated. These data suggest differential phosphorylation Thr2446 and Ser2448 could act as a switch mechanism to integrate signals from nutrient status and growth factors to control the regulation of protein translation.
CD41 expression defines the onset of primitive and definitive hematopoiesis in the murine embryo

The platelet glycoprotein IIb (αIIb; CD41) constitutes the alpha subunit of a highly expressed platelet surface integrin protein. We demonstrate that CD41 serves as the earliest marker of primitive erythroid progenitor cells in the embryonic day 7 (E7.0) yolk sac and high-level expression identifies essentially all E8.25 yolk sac definitive hematopoietic progenitors. Some definitive hematopoietic progenitor cells in the fetal liver and bone marrow also express CD41. Hematopoietic stem cell competitive repopulating ability is present in CD41dim and CD41lo/- cells isolated from bone marrow and fetal liver cells, however, activity is enriched in the CD41lo/- cells. CD41bright yolk sac definitive progenitor cells co-express CD61 and bind fibrinogen, demonstrating receptor function. Thus, CD41 expression marks the onset of primitive and definitive hematopoiesis in the murine embryo and persists as a marker of some stem and progenitor cell populations in the fetal liver and adult marrow, suggesting novel roles for this integrin.
Length dependence of striated muscle force generation is controlled by phosphorylation of cTnI at serines 23/24

• An important mechanism in beat‐to‐beat optimization of heart performance is matching ventricular output with end‐diastolic volume, which is known as the Frank–Starling Relationship. • The cellular basis for this regulation involves myofilament length–tension relationships. • We previously showed two populations of length–tension relationships in mammalian left ventricular cardiac myocytes, one steep like fast‐twitch skeletal muscle fibres and the other shallow like slow‐twitch skeletal muscle fibres, and cardiac myocytes with shallow length–tension relationships shift to steep relationships by protein kinase A‐induced myofilament phosphorylation. • The current study investigated the molecular and amino acid residue mechanisms that control length–tension relationships. • The single muscle cell experiments demonstrated that cardiac troponin I phosphorylation at serines 23/24 control length–tension relationships in striated muscle. • This study provides: (i) a mechanism to explain a length dependence of force generation in striated muscle; and (ii) an important target to potentially treat heart disease associated with compromised Frank–Starling relationships.
Estimation of Stroke Volume and Stroke Volume Changes by Electrical Impedance Tomography

BACKGROUND: Electrical impedance tomography (EIT) is a noninvasive imaging method that identifies changes in air and blood volume based on thoracic impedance changes. Recently, there has been growing interest in EIT to measure stroke volume (SV). The objectives of this study are as follows: (1) to evaluate the ability of systolic impedance variations (&Dgr;Zsys) to track changes in SV in relation to a baseline condition; (2) to assess the relationship of &Dgr;Zsys and SV in experimental subjects; and (3) to identify the influence of body dimensions on the relationship between &Dgr;Zsys and SV. METHODS: Twelve Agroceres pigs were instrumented with transpulmonary thermodilution catheter and EIT and were mechanically ventilated in a random order using different settings of tidal volume (VT) and positive end-expiratory pressure (PEEP): VT 10 mL·kg−1 and PEEP 10 cm H2O, VT 10 mL·kg−1 and PEEP 5 cm H2O, VT 6 mL·kg−1 and PEEP 10 cm H2O, and VT 6 mL·kg−1 and PEEP 5 cm H2O. After baseline data collection, subjects were submitted to hemorrhagic shock and successive fluid challenges. RESULTS: A total of 204 paired measurements of SV and &Dgr;Zsys were obtained. The 4-quadrant plot showed acceptable trending ability with a concordance rate of 91.2%. Changes in &Dgr;Zsys after fluid challenges presented an area under the curve of 0.83 (95% confidence interval, 0.74–0.92) to evaluate SV changes. Conversely, the linear association between &Dgr;Zsys and SV was poor, with R2 from linear mixed model of 0.35. Adding information on body dimensions improved the linear association between &Dgr;Zsys and SV up to R2 from linear mixed model of 0.85. CONCLUSIONS: EIT showed good trending ability and is a promising hemodynamic monitoring tool. Measurements of absolute SV require that body dimensions be taken into account.
Changing patterns in causes of death in a cohort of injecting drug users, 1980-2001.

BACKGROUND High mortality among drug users has been widely recognized. This study investigates, in a large family practice of 10 000 patients in Edinburgh, Scotland, whether there has been a change in causes of mortality over time. Patients known to have ever injected drugs were recruited into a cohort study from 1980 until 2001. METHODS Death certificates and clinical notes were scrutinized and data relating to demographic features, drug use, and causes of death were recorded. RESULTS Of 667 patients, there were 153 deaths at follow-up (110 men and 43 women). Average annual mortality rate was 2.3%. Death rate peaked in the early to mid-1990s, reflecting the development of advanced human immunodeficiency virus (HIV) from the early epidemic in 1982-1984 and the onset of the effect of antiviral chemotherapy. Drug deaths and suicide were the same in both sexes but tended to occur in younger subjects. Principal cause of death was overdose in the early years and HIV/AIDS in later years. Toward the close of the study period, hepatitis C emerged as a cause of death. CONCLUSIONS Injecting drug users have a very high risk of mortality. Infectious diseases from nonsterile injecting are the most obvious preventable cause of death. Use of death certificate information alone is inaccurate in analyzing drug-related deaths and greatly underestimates the full impact of the HIV epidemic. This study provides some of the most convincing evidence so far that harm minimization, in its broadest sense, is effective in reducing drug-related mortality.
Reliability of Pharmacodynamic Analysis by Logistic Regression: A Computer Simulation Study

Background: Many pharmacologic studies record data as binary yes-or-no variables, and analysis is performed using logistic regression. This study investigates the accuracy of estimation of the drug concentration associated with a 50% probability of drug effect (C50) and the term describing the steepness of the concentration-effect relation (&ggr;). Methods: The authors developed a technique for simulating pharmacodynamic studies with binary yes-or-no responses. Simulations were conducted assuming either that each data point was derived from the same patient or that data were pooled from multiple patients in a population with log-normal distributions of C50 and &ggr;. Coefficients of variation were calculated. The authors also determined the percentage of simulations in which the 95% confidence intervals contained the true parameter value. Results: The coefficient of variation of parameter estimates decreased with increasing n and &ggr;. The 95% confidence intervals for C50 estimation contained the true parameter value in more than 90% of the simulations. However, the 95% confidence intervals of &ggr; did not contain the true value in a substantial number of simulations of data from multiple patients. Conclusion: The coefficient of variation of parameter estimates may be as large as 40–50% for small studies (n ≤ 20). The 95% confidence intervals of C50 almost always contain the true value, underscoring the need for always reporting confidence intervals. However, when data from multiple patients is naively pooled, the estimates of &ggr; may be biased, and the 95% confidence intervals may not contain the true value.
Small-dense LDL and LDL glycation in metabolic syndrome and in statin-treated and non-statin-treated type 2 diabetes

Small-dense LDL (SD-LDL) has been particularly implicated in atherosclerosis. It has previously been reported that in non-diabetic people SD-LDL is preferentially glycated. The distribution of glycated apolipoprotein B (glyc-apoB) in lipoproteins in metabolic syndrome (MS) and in type 2 diabetes has not previously been studied. Plasma apoB and glyc-apoB were determined in different apoB-containing lipoproteins including buoyant and SD-LDL in MS (n=18) and type 2 diabetes (DM) [n=48; 12 statin-untreated (DM−S) and 36 statin-treated (DM+S)]. Plasma glyc-apoB was 5.6 ± 0.9, 3.5 ± 0.5 and 4.0 ± 0.2 mg/dl in DM−S, DM+S and MS, respectively. The glycated proportion of SD-LDL-apoB was greater than buoyant LDL in all groups. SD-LDL contributed most to plasma glyc-apoB in DM−S, because SD-LDL-apoB was higher in DM−S than in MS and DM+S (p < 0.001). Plasma glyc-apoB correlated with SD-LDL-apoB (r=0.74, p < 0.0001 in diabetes and r=0.53, p < 0.001 in MS), but not with HbA1c. SD-LDL is preferentially glycated in type 2 diabetes and MS. Its concentration is a stronger determinant of plasma glycapoB than glycaemia. Statin-induced changes in its level may be important in decreasing apoB glycation in diabetes. These findings may explain the small effect of improving glycaemia relative to statin treatment in reducing atherosclerosis risk in type 2 diabetes and the increased risk in MS even before the onset of type 2 diabetes.
The dysfunctional innate immune response triggered by Toll‐like receptor activation is restored by TLR7/TLR8 and TLR9 ligands in cutaneous lichen planus

Lichen planus (LP) is a chronic inflammatory mucocutaneous disease. Toll‐like receptors (TLRs) bind numerous exogenous and endogenous antigens by recognizing conserved pathogen‐associated molecular patterns (PAMPs) and have the ability to induce the production of proinflammatory cytokines. Therefore, alterations in innate immunity could explain the inflammation and T‐cell autoreactivity leading to the development of LP disease.
Factors Influencing the Competitiveness of Cocoa Export of Ghana and Its Implication on Ghana’s Economy

This study examines the competitiveness of Ghana’s cocoa by assessing the performance and determinants of cocoa export from Ghana. Competitiveness of the country in cocoa exports was assessed using the Pearson's Correlation model and Linear Regression model using SPSS and STATA respectively. Time series data on Ghana’s cocoa production and exports and GDP from 2000 to 2014 were collected and analyzed using Pearson Correlation Statistics that were adopted in SPSS. The first analysis was to find the relationship between total cocoa products exports in US$ (including raw cocoa beans and processed cocoa products) and factors such as the real world prices of cocoa (US$/MT) between 2000 and 2014, the gross domestic product of Ghana, the amount of Cocoa beans produced (in tonnes) and processed cocoa exports. The outcome of the analyses revealed that Ghana has comparative advantage in the exportation of cocoa, that Ghana is highly competitive in exports of cocoa beans, total cocoa products and processed cocoa exports. In spite of improvements observed in the country’s export performance over the past three decades, there is potential for further improvement, based on the SPSS and STATA results. The study proceeds to propose measures eminent in ensuring robust cocoa production and consequential exports. Keywords ： Competitiveness, cocoa export, determinants, real world price, gross domestic price. DOI : 10.7176/JESD/10-6-05 Publication date :March 31 st 2019
Overwhelming infection with group B beta-hemolytic Streptococcus associated with circumcision.

The lack of valid medical indications has caused routine neonatal circumcision to fall into disrepute in recent years.1-3 However, despite the substantial arguments against continuation of this therapy, it still ranks as one of the most common surgical procedures.3,4 Significant infection is rarely solely attributed to circumcision because a clear-cut cause and effect relationship is difficult to establish. There have been reports5-7 of newborns who have been circumcised and then developed life-threatening infection within several days of this procedure. However, the fact that in these infants infection has occurred at an age when the incidence of infection is high due to other factors complicates interpretation of these reports.
Möbius syndrome redefined

Objective: To investigate the variable clinical picture of Möbius syndrome (MIM no. 157900) and to further understand the pathogenesis of the disorder. Methods: A standardized questionnaire was submitted to 37 Dutch patients with Möbius syndrome. All underwent standardized neurologic examination with special attention to cranial nerve functions, motor skills, and facial and limb anomalies. Results: Of 37 patients with facial paresis, 97% had bilateral and 3% had unilateral ocular abduction weakness. Further analysis showed isolated abducens nerve palsy in 9%, a conjugated horizontal gaze paresis in 48%, features of Duane retraction syndrome in 34%, and congenital fibrosis of the extraocular muscles in 9%. Other signs included lingual involvement (77%), dysfunction of palate and pharynx (56%), general motor disability (88%), poor coordination (83%), and respiratory abnormalities (19%). Conclusion: Möbius syndrome is more than a cranial nerve or nuclear developmental disorder. It is a syndrome of rhombencephalic maldevelopment involving predominantly motor nuclei and axons, as well as traversing long tracts. The authors also noted gaze palsies, Duane retraction syndrome, feeding and respiratory problems, and poor motor development, suggesting a regional developmental disorder.
Relationships Between Curing of the F Episome by Rifampin and by Acridine Orange in Escherichia coli

Subinhibitory doses of rifampin cured F+Escherichia coli cells from the episome. The target of the drug was transcription because E. coli mutants with a ribonucleic acid polymerase resistant to rifampin were not cured. The experimental conditions required for optimal curing with rifampin very closely resembled those required for curing with acridine orange. Mutants were found which are more resistant to curing by both acridine orange and rifampin. Probably the two drugs affect a common metabolic step, or alternatively they may inhibit the synthesis of a factor which is necessary for the replication of the episome.
Combination of drugs acting on the natriuretic system and the renin-angiotensin system in heart failure

Conventional diuretic agents are very effective agents in relieving volume overload and congestive symptoms in chronic heart failure (CHF). However, they are associated with activation of the renin-angiotensin system (RAS) and the sympathetic nervous system and a reduction in glomerular filtration rate, all of which have been associated with adverse outcomes in CHF. Therefore, there is an increasing interest in drugs that target the natriuretic system without neurohormonal activation and deterioration of renal function. In this review, we will discuss the underlying rationale and evidence behind currently pursued strategies that target the natriuretic system. This includes the administration of natriuretic peptides (NPs) and strategies that potentiate the NP system, such as neutral endopeptidase inhibition. We will also highlight some potentially important interactions of these strategies with drugs that target the RAS.
Therapies for multidrug resistant and extensively drug-resistant non-fermenting gram-negative bacteria causing nosocomial infections: a perilous journey toward ‘molecularly targeted’ therapy

ABSTRACT Introduction: Non-fermenting Gram-negative bacilli are at the center of the antimicrobial resistance epidemic. Acinetobacter baumannii and Pseudomonas aeruginosa are both designated with a threat level to human health of ‘serious’ by the Centers for Disease Control and Prevention. Two other major non-fermenting Gram-negative bacilli, Stenotrophomonas maltophilia and Burkholderia cepacia complex, while not as prevalent, have devastating effects on vulnerable populations, such as those with cystic fibrosis, as well as immunosuppressed or hospitalized patients. Areas covered: In this review, we summarize the clinical impact, presentations, and mechanisms of resistance of these four major groups of non-fermenting Gram-negative bacilli. We also describe available and promising novel therapeutic options and strategies, particularly combination antibiotic strategies, with a focus on multidrug resistant variants. Expert commentary: We finally advocate for a therapeutic approach that incorporates in vitro antibiotic susceptibility testing with molecular and genotypic characterization of mechanisms of resistance, as well as pharmacokinetics and pharmacodynamics (PK/PD) parameters. The goal is to begin to formulate a precision medicine approach to antimicrobial therapy: a clinical-decision making model that integrates bacterial phenotype, genotype and patient’s PK/PD to arrive at rationally-optimized combination antibiotic chemotherapy regimens tailored to individual clinical scenarios.