Background
Vincristine is a commonly used chemotherapeutic agent. It is associated with undesirable digestive side effects. However, the impact of vincristine on gastrointestinal structure and ...motility or its long‐term effects have not been deeply studied in animal models. This could be useful in order to develop therapeutic or preventive strategies for cancer patients. The aim of this study was to analyze such effects.
Methods
Rats received saline or vincristine (0.1 mg kg−1, ip) daily for 10 days. Evaluations were performed during treatment and 2‐6 weeks after. Somatic mechano‐sensitivity was assessed using von Frey hairs. Gastrointestinal motor function was studied by means of radiographic still images and colonic propulsion of fecal pellets using fluoroscopy videos. Histological assessment of the gut morphology and immunohistochemistry for HuC/D and nNOS were performed in whole‐mount myenteric plexus preparations.
Key Results
Peripheral sensitivity was increased in animals treated with vincristine and did not subside 2 weeks after treatment finalization. Vincristine treatment inhibited gastrointestinal motility although this was recovered to normal values with time. Damage in the digestive wall after vincristine treatment was greater in the ileum than in the colon. Villi shortening (in ileum) and large inflammatory nodules still remained 2 weeks after treatment finalization. Finally, the proportion of nNOS‐immunoreactive neurons was increased with vincristine and continued to be increased 2 weeks after treatment finalization.
Conclusions and Inferences
Vincristine alters gastrointestinal motility, peripheral sensitivity and mucosal architecture. Vincristine‐induced neuropathy (somatic and enteric), intestinal mucosa damage and inflammatory infiltrations are relatively long‐lasting.
The effects produced by vincristine repeatedly administered in rats are described. Although reduction in general gastrointestinal motility and colonic propulsion of fecal pellets seem to recover after treatment, vincristine‐induced neuropathy (somatic and enteric), intestinal mucosa damage and inflammatory infiltrations are relatively long‐lasting. Sequelae of chemotherapy should be more closely monitored.
Abstract
Tissue ischemia is a key risk factor in anastomotic leak (AL). Indocyanine green (ICG) is widely used in colorectal surgery to define the segments with the best vascularization. In an ...experimental model, we present a new system for quantifying ICG fluorescence intensity, the SERGREEN software. Controlled experimental study with eight pigs. In the initial control stage, ICG fluorescence intensity was analyzed at the level of two anastomoses, in the right and in the left colon. Control images of the two segments were taken after ICG administration. The images were processed with the SERGREEN program. Then, in the experimental ischemia stage, the inferior mesenteric artery was sectioned at the level of the anastomosis of the left colon. Fifteen minutes after the section, sequential images of the two anastomoses were taken every 30 min for the following 2 h. At the control stage, the mean scores were 134.2 (95% CI 116.3–152.2) for the right colon and 147 (95% CI 134.7–159.3) for the left colon (p = 0.174) (Scale RGB—Red, Green, Blue). The right colon remained stable throughout the experiment. In the left colon, intensity fell by 47.9 points with respect to the pre-ischemia value (p < 0.01). After the first post-ischemia determination, the values of the ischemic left colon remained stable throughout the experiment. The relative decrease in ICG fluorescence intensity of the ischemic left colon was 32.6%. The SERGREEN program quantifies ICG fluorescence intensity in normal and ischemic situations and detects differences between them. A reduction in ICG fluorescence intensity of 32.6% or more was correlated with complete tissue ischemia.
Fetal undernutrition is a risk factor for heart disease in both genders, despite the protection of women against hypertension development. Using a rat model of maternal undernutrition (MUN) we aimed ...to assess possible sex differences in the development of cardiac alterations and the implication of hypertension and cardiac oxidative stress.
Male and female offspring from rats fed ad libitum (control) or with 50% of the normal daily intake during the second half of gestation (MUN) were used. Heart weight/body weight ratio (HW/BW), hemodynamic parameters (anaesthetized rats) and plasma brain natriuretic peptide (BNP, ELISA) were assessed in 21-day, 6-month and 22-month old rats. Plasma testosterone (ELISA) and cardiac protein expression of enzymes related to reactive oxygen species synthesis (p22phox, xanthine-oxidase) and degradation (catalase, Cu/Zn-SOD, Mn-SOD, Ec-SOD) were evaluated in 21-day and 6-month old rats (Western Blot). Heart structure and function was studied at the age of 22 months (echocardiography).
At the age of 21 days MUN males exhibited significantly larger HW/BW and cardiac p22phox expression while females had reduced p22phox expression, compared to their respective sex-matched controls. At the age of 6-months, MUN males showed significantly larger blood pressure and cardiac xanthine-oxidase expression; MUN females were normotensive and had a lower cardiac expression of antioxidant enzymes, compared to their respective sex-matched controls. At the age of 22 months, both MUN males and females showed larger HW/BW and left ventricular mass and lower ejection fraction compared to sex-matched controls; only MUN males exhibited hypertension and a larger plasma BNP compared to aged male controls.
1) During perinatal life females exposed to fetal undernutrition are protected from cardiac alterations, but in ageing they exhibit ventricular hypertrophy and functional loss, like MUN males; 2) cardiac oxidative stress might be implicated in the observed heart alterations in both sexes and 3) the severity of cardiac damage might be greater in males due to hypertension.
Computational biology analyses the theoretical tertiary structure of proteins and identifies the 'topological' differences between RhD and RhCE. Our aim was to identify the theoretical structural ...differences between the four isoforms of RhCE and RhD using computational biological tools.
Physicochemical profile was determined by hydrophobicity and electrostatic potential analysis. Secondary and tertiary structures were generated using computational biology tools. The structures were evaluated and validated using Ramachandran algorithm, which calculates the single score, p-value and root mean square deviation (RMSD). Structures were overlaid on local refinement of 'RhAG-RhCE-ANK' (PBDID 7uzq) and RhAG to compare their spatial distribution within the membrane.
All proteins differed in surface area and electrostatic distance due to variations in hydrophobicity and electrostatic potential. The RMSD between RhD and RhCE was 0.46 ± 0.04 Å, and the comparison within RhCE was 0.57 ± 0.08 Å. The percentage of amino acids in the hydrophobic thickness was 50.24% for RhD while for RhCE it ranged between 73.08% and 76.68%. The RHAG hydrophobic thickness was 34.2 Å, and RhCE's hydrophobic thickness was 33.83 Å. We suggest that the C/c antigens differ exofacially at loops L1 and L2. For the E/e antigens, the difference lies in L6. By contrast, L4 is the same for all proteins except Rhce.
The physicochemical properties of Rh proteins made them different, although their genes are homologous. Using computational biology, we model structures with sufficient precision, similar to those obtained experimentally. An amino acid variation alters the folding of the tertiary structure and the interactions with other proteins, modifying the electrostatic environment, the spatial conformations and therefore the antigenic recognition.
•Sex and type of mechanical stimulation strongly influence visceral pain.•Responses to tonic stimuli are less intense compared to those to phasic stimuli.•Sex influences the responses to phasic but ...not to tonic stimulation.•Visceral pain behavior may depend on abdominal musculature composition features.•Estrogens modulate the different pathways activated by tonic and phasic stimuli.
Visceral pain may be influenced by many factors. The aim of this study was to analyze the impact of sex and quality of intracolonic mechanical stimulus on the behavioral manifestations of visceral pain in a preclinical model.
Male and female young adult Wistar rats were sedated, and a 5 cm long latex balloon was inserted into the colon. Sedation was reverted and behavior was recorded. The pressure of the intracolonic balloon was gradually increased using a sphygmomanometer. Visceral sensitivity was measured as abdominal contractions in response to mechanical intracolonic stimulation. Two different types of stimulation were used: tonic and phasic. Phasic stimulation consisted of repeating several times (3x) the same short stimulus (20 s) within a 5 min interval allowing a 1 min break between individual stimuli. For tonic stimulation the stimulus was maintained throughout the whole 5 min interval. Both phasic and tonic stimulation produced a pressure-dependent increase of abdominal contractions. The abdominal response was more intense under phasic than under tonic stimulation, but with differences depending on the sex of the animals: females exhibited more contractions than males and of similar duration at all pressures, whereas duration of contractions pressure-dependently increased in males. The duration of tonically stimulated contractions was lower and not sex- or pressure-dependent. In the rat, responses to colonic distension depend on the quality of the stimulus, which also produces sex-dependent differences that must be taken into account in the development of models of pathology and visceral pain treatments.
Background
Few reported studies compare drug survival in moderate‐to‐severe psoriasis vulgaris.
Objectives
To describe and compare drug survival of systemic drugs, including biologic agents ...(infliximab, etanercept, adalimumab and ustekinumab) and classical drugs (acitretin, ciclosporin and methotrexate) in moderate‐to‐severe psoriasis.
Methods
This was a multicenter, prospective, cohort study of patients receiving systemic therapies between 2008 and 2013 in 12 hospitals in Spain. Baseline data and drug discontinuation were collected. Drug survival is presented using Kaplan–Meier survival curves. We compared adjusted risk ratios of serious adverse events (AEs) with results of survival analysis for AEs.
Results
A total of 1956 patients were included for analysis (1240 exposed to biologics during follow‐up and 1076 to classic therapies). Median follow‐up time was 3.3 years (0.0–5.1 years). There were 2209 discontinuations out of 3640 therapy cycles started. The main reason for discontinuation was lack of efficacy (36.4%) and remission (27.2%). Biologics showed a higher drug survival than classics and the pattern of survival results for all outcomes (positive or negative) were very similar. Adjusted risk ratios of serious AEs did not agree with results of survival analysis.
Limitations
A limitation is that this is an observational study with potential selection bias.
Conclusion
Survival as a proxy measure of drug safety in psoriasis is inadequate.
The present study analyzed the volatile compounds emitted by Glycine max (cv. FT-Cristalina-RCH) soybean plants: healthy plants and plants damaged mechanically or by the Mexican soybean weevil ...Rhyssomatus nigerrimus. The SPME method was used to compare the volatile profile of soybean plants in four different conditions. The volatile profile of G. max plants infested by R. nigerrimus was qualitatively and quantitatively different from that of healthy and mechanically damaged plants. Emission of 59 compounds was detected in the four treatments. Of these compounds, 19 were identified by comparison of the Kovats index, mass spectrum and retention times with those of synthetic standards. An increase in concentration of the volatiles (Z)-3-hexenyl acetate and the compound 1-octen-3-ol was observed when the soybean plants were mechanically damaged. The compounds mostly produced by the soybean plant during infestation by male and female R. nigerrimus were 1-octen-3-ol, 6-methyl-5-hepten-2-one, (E)-β-ocimene, salicylaldehyde, unknown 10, linalool, methyl salicylate, (Z)-8-dodecenyl acetate (ester 5), ketone 2 and geranyl acetone. Behavioral effects of the identified compounds during the insect-plant interaction and their conspecifics are discussed.
Splicing alterations represent an actionable cancer hallmark. Splicing factor 3B subunit 1 (SF3B1) is a crucial splicing factor that can be targeted pharmacologically (e.g. pladienolide-B). Here, we ...show that SF3B1 is overexpressed (RNA/protein) in hepatocellular carcinoma (HCC) in two retrospective (n = 154 and n = 172 samples) and in five in silico cohorts (n > 900 samples, including TCGA) and that its expression is associated with tumor aggressiveness, oncogenic splicing variants expression (KLF6-SV1, BCL-XL) and decreased overall survival. In vitro, SF3B1 silencing reduced cell viability, proliferation and migration and its pharmacological blockade with pladienolide-B inhibited proliferation, migration, and formation of tumorspheres and colonies in liver cancer cell lines (HepG2, Hep3B, SNU-387), whereas its effects on normal-like hepatocyte-derived THLE-2 proliferation were negligible. Pladienolide-B also reduced the in vivo growth and the expression of tumor-markers in Hep3B-induced xenograft tumors. Moreover, SF3B1 silencing and/or blockade markedly modulated the activation of key signaling pathways (PDK1, GSK3b, ERK, JNK, AMPK) and the expression of cancer-associated genes (CDK4, CD24) and oncogenic SVs (KLF6-SV1). Therefore, the genetic and/or pharmacological inhibition of SF3B1 may represent a promising novel therapeutic strategy worth to be explored through randomized controlled trials.
Display omitted
•The splicing factor SF3B1 is overexpressed in HCC and associated to overall survival.•Genetic silencing of SF3B1 reduces oncogenic potential of HCC cell lines.•SF3B1 pharmacological blockade with pladienolide-B exerts inhibitory effects in HCC.•SF3B1 blockade by pladienolide-B reduces tumor growth in preclinical models.•SF3B1 modulates the expression of key oncogenic splicing variants.
In this work, a secure architecture to send data from an Internet of Things (IoT) device to a blockchain-based supply chain is presented. As is well known, blockchains can process critical ...information with high security, but the authenticity and accuracy of the stored and processed information depend primarily on the reliability of the information sources. When this information requires acquisition from uncontrolled environments, as is the normal situation in the real world, it may be, intentionally or unintentionally, erroneous. The entities that provide this external information, called Oracles, are critical to guarantee the quality and veracity of the information generated by them, thus affecting the subsequent blockchain-based applications. In the case of IoT devices, there are no effective single solutions in the literature for achieving a secure implementation of an Oracle that is capable of sending data generated by a sensor to a blockchain. In order to fill this gap, in this paper, we present a holistic solution that enables blockchains to verify a set of security requirements in order to accept information from an IoT Oracle. The proposed solution uses Hardware Security Modules (HSMs) to address the security requirements of integrity and device trustworthiness, as well as a novel Public Key Infrastructure (PKI) based on a blockchain for authenticity, traceability, and data freshness. The solution is then implemented on Ethereum and evaluated regarding the fulfillment of the security requirements and time response. The final design has some flexibility limitations that will be approached in future work.
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