Notes

Myelin plasticity modulates nerve organs circuitry required for learning as well as actions.
Breast cancer is the most common cancer among women and is considered a developed country disease. Moreover, is a heterogenous disease, existing different types and stages of breast cancer development, therefore, better understanding of cancer biology, helps to improve the development of therapies. The conventional treatments accessible after diagnosis, have the main goal of controlling the disease, by improving survival. In more advance stages the aim is to prolong life and symptom palliation care. Surgery, radiation therapy and chemotherapy are the main options available, which must be adapted to each person individually. However, patients are developing resistance to the conventional therapies. This resistance is due to alterations in important regulatory pathways such as PI3K/AKt/mTOR, this pathway contributes to trastuzumab resistance, a reference drug to treat breast cancer. Therefore, is proposed the repurposing of drugs, instead of developing drugs de novo, for example, to seek new medical treatments within the drugs available, to be used in breast cancer treatment. Providing safe and tolerable treatments to patients, and new insights to efficacy and efficiency of breast cancer treatments. The economic and social burden of cancer is enormous so it must be taken measures to relieve this burden and to ensure continued access to therapies to all patients. In this review we focus on how conventional therapies against breast cancer are leading to resistance, by reviewing those mechanisms and discussing the efficacy of repurposed drugs to fight breast cancer.A novel chalcone derivative, LQFM064, demonstrated antileishmanial activity against Leishmania (L.) amazonensis, with an IC50 value of ~10 μM for the promastigote form. Electron paramagnetic resonance (EPR) spectroscopy of a spin-labeled stearic acid incorporated in the plasma membrane of L. amazonensis promastigotes revealed that after 2 h of treatment with LQFM064, the parasite showed remarkable reductions in membrane fluidity. The features of the altered EPR spectra were similar to those reported for the erythrocyte membrane, which was suggested to be due to the cross-linking of oxidized hemoglobin with the cytoskeleton spectrin. In comparison to miltefosine (MIL), LQFM064 demonstrated a much lower hemolytic potential against both erythrocytes in PBS and whole blood, less cytotoxicity in J774.A1 macrophages and equivalent ability to kill parasites internalized in J774.A1 macrophages. Measurements of the IC50 values for assays with different cell concentrations enabled the estimation of the membrane-water partition coefficient (KM/W), as well as the concentrations of LQFM064 in membrane (cm50) and aqueous phase (cw50) that reduces the cell population by 50%. From the KM/W and cm50 values it was deduced that LQFM064 has a greater affinity than MIL for the parasite membrane, but the antiproliferative activity of both substances is exerted at a similar concentration in the plasma membrane.Cryptosporidium spp. are enteric protozoan parasites that infect a wide range of hosts including humans, and domestic and wild animals. The aim of this study was to molecularly characterize the Cryptosporidium spp. found in calf faeces in Japan. A total of 80 pre-weaned beef and dairy calves' diarrhoeic faecal specimens were collected from nine different prefectures in Japan. A nested polymerase chain reaction targeting the small subunit 18S rRNA and GP60 genes were used to detect the Cryptosporidium genotypes and subtypes. 83.8% (67 out of 80) of the specimens were positive for Cryptosporidium spp.; Cryptosporidium was found in both beef and dairy calves. Cryptosporidium parvum was the predominant species, detected in 77.5% (31/40) of beef calves and 80% (32/40) of dairy calves. Cryptosporidium bovis was also detected, 5.0% (2/40) of dairy calves, and C. ryanae was also found 2.5% (1/40) of dairy calves. One mixed-species infection, 2.5% (1/40) was detected in a beef calf having C. parvum, and C. ryanae. We detected the most common subtype of C. parvum (i.e., IIaA15G2R1), as well as other subtypes (i.e., IIaA14G3R1, IIaA14G2R1, and IIaA13G1R1) that have not previously been detected in calves in Japan. Our results demonstrate the widespread diversity of Cryptosporidium infection in calves in Japan.The present study was conducted to evaluate the effects of marine polysaccharides from seaweed Enteromorpha on growth performance, immune responses, intestinal morphology and microbial community in the banana shrimp Fenneropenaeus merguiensis. Two thousand and four hundred juvenile shrimps with an average body weight of 2.18 ± 0.06 g were fed for 42 d with diets containing different levels of Enteromorpha polysaccharides (EPS) 0 (control), 1, 2 and 3 g/kg as treatment groups, each of group was replicated three times with two hundred shrimps per replicate. Dietary supplementation of 1 g/kg EPS showed a consistent improvement in the final weight, weight gain, average daily gain rate (ADGR) and specific growth rate (SGR) (P less then 0.05), while showed a decrease in the feed conversion ratio (FCR) of shrimp (P less then 0.05). Besides, the total anti-oxidative capacity (T-AOC), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione S-transferase (GST), lysozyme (Lyz), alkaline phosphatase (ALhese findings revealed that dietary 1 g/kg EPS could improve growth performance, enhance nonspecific immunity and modulate intestinal function of banana shrimp F. merguiensis.The SARS-CoV-2 spike trimer is the primary antigen for several serology assays critical to determining the extent of SARS-CoV-2 exposure in the population. Until stable cell lines are developed to increase the titer of this secreted protein in mammalian cell culture, the low yield of spike protein produced from transient transfection of HEK293 cells will be a limiting factor for these assays. To improve the yield of spike protein and support the high demand for antigens in serology assays, we investigated several recombinant protein expression variables by altering the incubation temperature, harvest time, chromatography strategy, and final protein manipulation. Through this investigation, we developed a simplified and robust purification strategy that consistently yields 5 mg of protein per liter of expression culture for two commonly used forms of the SARS-CoV-2 spike protein. We show that these proteins form well-behaved stable trimers and are consistently functional in serology assays across multiple protein production lots.Despite the new treatment strategies within the last 30 years, peripheral nerve injury (PNI) is still a worldwide clinical problem. The incidence rate of PNIs is 1 in 1000 individuals per year. In this study, we designed a composite nanoplatform for dual therapy in peripheral nerve injury and investigated the in-vivo efficacy in rat sciatic nerve crush injury model. Alpha-lipoic acid (ALA) was loaded into poly lactic-co-glycolic acid (PLGA) electrospun nanofibers which would release the drug in a faster manner and atorvastatin (ATR) loaded chitosan (CH) nanoparticles were embedded into PLGA nanofibers to provide sustained release. Sciatic nerve crush was generated via Yasargil aneurism clip with a holding force of 50 g/cm2. Nanofiber formulations were administered to the injured nerve immediately after trauma. Functional recovery of operated rat hind limb was evaluated using the sciatic functional index (SFI), extensor postural thrust (EPT), withdrawal reflex latency (WRL) and Basso, Beattie, and Bresnahan (BBB) test up to one month in the post-operative period at different time intervals. In addition to functional recovery assessments, ultrastructural and biochemical analyses were carried out on regenerated nerve fibers. L-929 mouse fibroblast cell line and B35 neuroblastoma cell line were used to investigate the cytotoxicity of nanofibers before in-vivo experiments. The neuroprotection potential of these novel nanocomposite fiber formulations has been demonstrated after local implantation of composite nanofiber sheets incorporating ALA and ATR, which contributed to the recovery of the motor and sensory function and nerve regeneration in a rat sciatic nerve crush injury model.Drug-drug cocrystals (DDC) represent a unique subset of pharmaceutical materials offering distinct advantages in combination therapies, pharmacokinetics, and patient compliance. However, their structure-function relationships are rarely reported despite its central importance in successful medicine. A material-sparing approach consisting a molecular and structural perspective is reported to evaluate tabletability of a model DDC, metforminsalicylic acid, to its components metformin HCl (MET) and sodium salicylate (SAL). MET alone displayed a very poor tabletability, which could be attributed to its isotropic and stiff interaction topology. SAL displayed a highly anisotropic interaction topology with layers of strongly hydrogen-bonded salicylate molecules promoting deformation and tabletability. This is also confirmed by its low moduli. DDC yielded intermediate stiffness and elastic anisotropy material with an improved plastic flow and overall better tabletability. Overall, DDC is a promising therapeutic class requiring the physical-mechanical evaluation to assure their processability to enjoy their therapeutic advantages.The essence of Continuous Manufacturing (CM) resides in the fact that continuous process units are directly connected to each other forming a continuous process train. The thorough understanding of material flow in this train based on suitable sensors, including on-line process analytical technologies and other sensors, is key in understanding the time-domain behavior of the system and the process. This real-time monitoring correlated with the time domain material flow behavior could be used to close control-loops. In practical terms, the implementation of such a control strategy is only feasible, if the overlying control system knows precisely what material is when and where at all times. Consequently, thorough knowledge of the residence time distribution (RTD) of the material throughout the whole manufacturing network needs to be established early on in development. Once RTD is well understood, its constant observation could also be used for continuous process verification purposes hinging on the argument tsay). In the third step, it was then demonstrated that recurring low-level step testing during routine manufacturing could be used as a way to determine the current system health, as observed changes in RTD indicated blockages and accidental material hold-up in the line. While deliberate changes in API content during commercial production might seem counter intuitive, they would actually aid in ensuring the production of quality product in a better way, than running at constant process settings over an extended period of time without the constant assessment of system health.Here we investigated variations of endogenous descending modulation of nociception and therapeutic effects of intramuscular (i.m.) heating-needle stimulation in early stage of Parkinson's disease (PD) induced by unilateral microinjection of 3.5 μl of 2.5 μg/μl 6-hydroxydopamine into the rat striatum. Paw withdrawal reflexes to noxious mechanical and heat stimuli in PD rats with and without exposure to i.m. 5.8% saline induced muscle nociception were evaluated. Experimental PD had no influence on mechanical or heat sensitivity in the baseline condition, whereas descending facilitation was stronger and descending inhibition was weaker in PD rats than vehicle-treated or naive rats during muscle nociception (P less then 0.05). Striatal administration of 5 μg of dopamine failed to reverse the PD-associated changes in descending facilitation or inhibition, whereas dopamine in the thalamic mediodorsal (MD) nucleus and ventromedial (VM) nucleus significantly decreased the increase in descending facilitation and reversed the attenuation in descending inhibition, respectively (P less then 0.05). I.m. 43 °C of heating-needle stimulation had no effects on the enhanced descending facilitation in PD rats, but it markedly increased descending inhibition and reversed the increase in the number of apomorphine-induced body rotations (P less then 0.05), which effects were dose-dependently attenuated by raclopride, a dopamine 2 receptor antagonist, in the thalamic VM nucleus (P less then 0.05). The results indicate that the early-stage PD is associated with enhanced descending facilitation and weakened descending inhibition. From clinical perspective, 43 °C heat therapeutic regime promises to selectively enhance descending inhibition that is accompanied by improvement of motor dysfunction in PD.Hypoxic-ischemic encephalopathy (HIE) in neonates can lead to severe long-term disabilities including cerebral palsy and brain injury. The small molecule P7C3-A20 has been shown to exert neuroprotective effects in various disorders such as ischemic stroke and neurodegenerative diseases. However, it is unclear whether P7C3-A20 has therapeutic potential for the treatment of HIE, and the relationship between P7C3-A20 and neuronal apoptosis is unknown. To address these questions, the present study investigated whether P7C3-A20 reduces HI injury in vitro using a PC12 cell oxygen-glucose deprivation (OGD) model and in vivo in postnatal day 7 and 14 rats subjected to HI, along with the underlying mechanisms. We found that treatment with P7C3-A20 (40-100 µM) alleviated OGD-induced apoptosis in PC12 cells. In HI model rats, treatment with 5 or 10 mg/kg P7C3-A20 reduced infarct volume; reversed cell loss in the cortex and hippocampus and improved motor function without causing neurotoxicity. The neuroprotective effects were abrogated by treatment with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. These results demonstrate that P7C3-A20 exerts neuroprotection by activating PI3K/protein kinase B/glycogen synthase kinase 3β signaling and can potentially be used to prevent brain injury in neonates following HIE.Background The purpose of the study was to evaluate the feasibility and efficacy of the novel BeGraft covered stent for the treatment of abdominal penetrating aortic ulcer (PAU) or penetrating ulcer of the iliac arteries (PUIA). Methods This was a single-center observational study, including 24 consecutive patients undergoing endovascular surgery due to abdominal PAU or PUIA between June 2017 and September 2019. Demographics of patients, lesion characteristics, diameter, and length of the BeGraft stents, post-operative events were prospectively collected and retrospectively analyzed. Follow-up examinations were done at 1, 6, 12, and 24 months with clinical and hemodynamic evaluation. Outcome measures included technical success, peri-operative complications, and stent patency. Results 24 patients (13 male and 11 female), median age 67 years (range 42-81 years), were analyzed. Twenty patients were symptomatic, and four patients underwent elective surgery due to the size of PAU. A total of 54 BeGraft stents (26 aortic and 28 peripheral) were successfully delivered and deployed to cover 13 aortic and 13 common iliac artery ulcer lesions. The technical success rate was 100%. The average procedural time was 53.8±12.8 min. Complications included one case of the access-site pseudoaneurysm, which was successfully treated by thrombin injection. During a median follow-up of 20.5 months (range 6-33 months), all stents remained patent, without endoleak or ulcer recurrence. Conclusions BeGraft stents used during endovascular treatment of abdominal PAU and PUIA lesions are associated with favorable outcomes regarding technical success and patency. The primary use of BeGraft covered stents provides a valid option for patients with abdominal penetrating aortic ulcer. Long-term follow-up is required to confirm these promising results.Objectives In octogenarians with carotid stenosis, data supporting the decision to intervene and choice of intervention with either carotid endarterectomy (CEA) or stenting (CAS), has been conflicting. The purpose of this study was to compare the perioperative outcomes of CEA and CAS in octogenarians, and to identify patients at high risk for unfavorable outcomes. Methods The American College of Surgeons National Surgical Quality Improvement Program database (2011-2018) was queried for patients aged ≥ 80 years who underwent CAS or CEA. Propensity-scores were created for the odds of undergoing CAS. Patients were matched 11 based on propensity-score and outcomes were compared after matching. Multivariable logistic regression analyses were used to identify risk factors for unfavorable postoperative outcomes. Results In total, 15,858 and 527 patients who underwent CEA and CAS were identified. After matching, there was no difference between CEA and CAS in perioperative stoke (2.3% vs. 2.9%, P=.56), cardiac complications (2.3% vs. 2.3%, P=.99), mortality (1.1% vs. 1.7%, P=.44), length of stay (median (IQR) 2 (1- 4) vs 1 (1- 4) days; P=.13) and 30-day readmission (11.8% vs. 11.6%, P=.92). On multivariable analysis, the following were predictive for postoperative stroke urgent operation (OR 2.12, 95% CI, 1.68-2.69, PIII (OR 1.46, 95% CI, 1.15-1.86, P=.002). Urgent procedure (OR 2.86, 95% CI 2.11-3.87, P less then .001), COPD (OR 2.31, 95% CI 1.61-3.32, P less then .001), dependent functional status (OR 2.05, 95% CI 1.35-3.1, P less then .001), and age ≥ 85 years (OR 1.92, 95% CI 1.43-2.57, P less then .001) were predictive for 30-day mortality. Conclusions Outcomes of CEA and CAS were similar in octogenarians. Risk factors for worse intervention outcomes were identified, which may guide risk-benefit discussions and shared decision-making.Objectives Brachiocephalic arteriovenous fistulas (BCF) are commonly placed in outpatient settings. The impact of general (GA), regional (RA), or local (LA) anesthesia on perioperative recovery and fistula maturation/patency after outpatient BCF creations is unknown. We evaluated whether outcomes of outpatient BCF creations vary based on anesthesia modality. Methods The Vascular Quality Initiative (2011-2018) national database was queried for outpatient BCF creations. Anesthesia modalities included GA, RA, and LA. Perioperative, three-month, and one-year outcomes were compared between GA versus RA/LA anesthesia types. Results Among 3,527 outpatient BCF creations, anesthesia types were GA in 1,043 (29.6%), RA in 1,150 (32.6%), and LA in 1,334 (37.8%). Patients receiving GA were more often younger, obese, Medicaid recipients, without coronary artery disease, and treated in non-office-based settings (P less then .05 for all). GA compared with RA/LA cohorts were more often admitted postoperatively (5.3% vs 2.4%, ilar one-year access occlusion (HR 1.2, 95% CI .95-1.51, P=.13). Conclusion Compared with regional/local anesthesia use, general anesthesia use in patients undergoing outpatient BCF creations was associated with increased hospital admissions, decreased access utilization at three months, and similar one-year access occlusion and reintervention. Regional/local anesthesia is preferable to expedite recovery and access utilization.Objetive To compare contrast usage and radiation exposure during endovascular aneurysm repair (EVAR) using mobile C-arm imaging in a conventional operating room (OR) or fixed angiographic equipment in a hybrid OR. Methods Retrospective unicenter study from may 2016 to august 2019. All consecutives patients undergoing standard EVAR were included. Patients were divided into 2 groups. Group OR included EVARs performed in a conventional OR with a mobile C-arm (May 2016 to April 2018) and group HR included EVARs performed with a fixed angiographic equipment in a hybrid OR (May 2018 to August 2019). Data collected included patient demographics, aneurysm diameter, neck length, radiation dose median dose-area product (DAP), flouroscopy time, total operative time, contrast use and 30-day clinical outcomes. Results We included 77 patients, 42 and 35 patients in group OR and HR, respectively. There was no difference in age, body mass index, mean aneurysm and neck length between groups. Patients in group HR received less contrast volume (108.6 mls [±41.5] vs. 162.5 mls [±52.6], P less then 0.001*), but higher radiation dose (154 Gy.cm2 [±102.9] vs. 61.5Gy.cm2 [±42.4], P less then 0.001*). There were no differences in fluoroscopy time (20.4 min [±8.5] vs. 23.2 min [±12.4], P = 0.274) and total operative time (106.4 [±22.3] vs. 109.4 [±25.8] , P = 0.798). No difference was found in terms of 30-day complication rates or operative mortality between groups. DAP was positively correlated with BMI in group OR (rs 0.580, P less then 0.001*) but no correlation could be seen in group HR (rs 0.408, P = 0.028). Conclusions Routine EVAR performed in a hybrid fixed imaging suite may be associated with less contrast usage but higher radiation exposure in our center . The significantly higher radiation exposure when the mobile C-arm is replace by a HR should not be underestimated.Background Several studies in the literature report continued proximal aorta and distal iliac arteries dilatation after surgical correction of an abdominal aortic aneurysm (AAA). The purpose of this study is to evaluate these findings, in a South American population, and relate them to the type of configuration of the open procedure aortic reconstruction. Method Retrospective review of ultrasonographic follow-up of patients submitted to open repair of AAA from 1989 to 2013, reporting proximal aorta dilatation (≥ 3 cm) and distal iliac arteries dilatation (≥ 1.5 cm). Results 155 patients were included. Life table freedom at the intervals 11 less then 15 years and ≥15 years were respectively 47%, and 23% for proximal dilatation and 63%, and 38% for distal iliac arteries dilatation. There were, respectively, more proximal and distal dilatations in patients submitted to more extensive aortic reconstructions (aorto-aortic 13%, 22% vs aorto-bilateral common iliacs 27%, 8% vs aorto-unilateral or bilateral external iliacs 27%, 32% and aorto-femoral 67%, 0%) p less then 0.0001. Juxta-renal anastomosis was also correlated with more proximal dilatations (42% vs 21%, p=0,046). There were two proximal and three distal anastomosis pseudoaneurysms. Conclusion the presence of more extensive degenerative disease at the time of operation, requiring juxta-renal or more distal iliac reconstructions, may pose an increased risk of proximal aorta and iliac arteries dilatation during follow-up. This study corroborates that significant changes are found after 7 to 10 years of the operation, reinforcing the need for long-term monitoring.Endometrial carcinoma (EC) accounts for 20%-30% of female reproductive tumors. Targeted therapy for EC has shown great advantages with small side effects. To improve the survival of EC patients, more new therapeutic targets need to be found. Long non-coding RNAs (lncRNAs) are series of RNAs with over 200 nucleotides that regulate various cellular functions. LncRNA actin filamentin-1 antisense RNA 1 (AFAP1-AS1) is involved in the development of a variety of cancers, such as pancreas ductal adenocarcinoma and esophageal adenocarcinoma. However, it is not clear whether AFAP1-AS1 has any effects on EC or the exact regulatory mechanism. Herein, we found the high expression of AFAP1-AS1 in human EC tissues, and AFAP1-AS1 was correlated with EC patients' prognosis and clinical features. AFAP-AS1 could affect EC cell proliferation, migration, and invasion, and contributed to endothelial cell angiogenesis. We further showed that AFAP-AS1 could promote the expression of VEGFA through the adsorption of miR-545-3p, thus promoting the angiogenesis and invasion of EC, and contribute to tumor growth and metastasis in vivo. Thus, we thought AFAP1-AS1 had the potential to serve as an EC therapeutic target.Cucurbit yellow stunting disorder virus (CYSDV) is a single-stranded positive-sense RNA virus that produces devastating disease in watermelon and squash. Foliar symptoms of CYSDV consist of interveinal yellowing, brittleness, and thickening of older leaves leading to reduced plant vigor. A rapid diagnostic method for CYSDV would facilitate early detection and implementation of best viral-based management practices. We developed a rapid isothermal a reverse transcription-recombination polymerase amplification (exo RT-RPA) assay for the detection of CYSDV. The primers and a 6-fluorescein amidite (6-FAM) probe were developed to target the nucleocapsid gene. The real-time assay detected CYSDV at 2.5 pg purified total RNA extracted from CYSDV-infected leaf tissue and corresponded to 10 copies of the target molecule. The assay was specific and did not cross-react with other common cucurbit viruses found in Florida and Georgia. The performance of the exo RT-RPA was evaluated using crude extract from 21 cucurbit field samples and demonstrated that the exo RT-RPA is a rapid procedure, thus providing a promising novel alternative solution for the detection of CYSDV.Objective Lubricin is increasingly being evaluated as an outcome measure in studies investigating post-traumatic and naturally occurring osteoarthritis. However, there are discrepancies in results, making it unclear as to whether lubricin is increased, decreased or unchanged in osteoarthritis. The purpose of this study was to review all papers that measured lubricin in joint injury or osteoarthritis in order to draw conclusions about lubricin regulation in joint disease. Design A systematic search of the Pubmed, Web of Knowledge, and EBSCOhost databases for papers was performed. Inclusion criteria were in vivo studies that measured lubricin in humans or animals with joint injury, that investigated lubricin supplementation in osteoarthritic joints, or that described the phenotype of a lubricin knock-out model. A methodological assessment was performed. Results Sixty-two studies were included, of which thirty-eight measured endogenous lubricin in joint injury or osteoarthritis. Nineteen papers found an increase or no change in lubricin and nineteen reported a decrease. Papers that reported a decrease in lubricin were cited four times more often than those that reported an increase. Fifteen papers described lubricin supplementation, and all reported a beneficial effect. Eleven papers described lubricin knock-out models. Conclusions The human literature reveals similar distributions of papers reporting increased lubricin as compared to decreased lubricin in osteoarthritis. The animal literature is dominated by reports of decreased lubricin in the rat anterior cruciate ligament transection model, whereas studies in large animal models report increased lubricin. Intra-articular lubricin supplementation may be beneficial regardless of whether lubricin increases or decreases in OA.Ethnopharmacological relevance Zishen Yutai Pills (ZYP), a famous traditional Chinese patent medicine, has been widely applied to avoid recurrent miscarriage and treat threatened abortion. Polysaccharides of ZYP (ZYPPs) play an essential role in the theraprutic effects of ZYP. However, the complex compositions of ZYP and the complicated structure of ZYPPs have posed great challenges and barriers to the quality evaluation of ZYP. Aim of the study To identify and characterize the ZYPPs for better quality control of ZYP, a reliable and valid quality control system was established in this study. Materials and methods A multi-fingerprint profile strategy based on HPSEC-MALL-RID, FT-IR, and HPLC (complete acid digested fingerprint, partial acid digested fingerprint and enzymatically digested fingerprint) was established to identify and discriminate the chemical structure of ZYPPs. Besides, the purpose of revealing the relationships between structure and biological activity of ZYPPs, their chemical characteristics, in vitro antioxidant and anti-glycation activities were investigated and discussed. Results The similarity evaluation of ZYPPs indicated ZYPPs from different batches showed a high similarity based on the correlation coefficient values of multi-fingerprints. Furthermore, ZYPPs exhibited remarkable antioxidant and antiglycation properties, which might be attributed to their molecular weights and the content of uronic acids. Conclusions These results indicated that the multiple fingerprint technique was reliable and effective for the improvement of quality control of ZYPPs, suggesting the multiple fingerprint technique could also be potentially applied as a valid and feasible strategy to control the quality of polysaccharide-enriched herbal medicines.Ethnopharmacological relevance Panax ginseng C. A. Mey. is a traditional tonic that has been used for thousands of years, and has positive effects on vascular diseases. Ginsenoside Rg1 (GS-Rg1) is one of the active ingredients of Panax ginseng C. A. Mey. and has been shown to have beneficial effects against ischemia/reperfusion injury. Our previously study has found that GS-Rg1 can mobilize bone marrow stem cells and inhibit vascular smooth muscle proliferation and phenotype transformation. However, pharmacological effects and mechanism of GS-Rg1 in inhibiting intimal hyperplasia is still unknown. Aim of the study This study was aimed to investigate whether GS-Rg1 prevented vascular intimal hyperplasia, and the involvement of stromal cell-derived factor-1α (SDF-1α)/CXCR4, stem cell factor (SCF)/c-kit and fractalkine (FKN)/CX3CR1 axes. Materials and methods Rats were operated with carotid artery balloon injury. The treatment groups were injected with 4, 8 and 16 mg/kg of GS-Rg1 for 14 days. The degree of intimcreased after GS-Rg1 treatment. Conclusions GS-Rg1 has a positive effect on inhibiting vascular intimal hyperplasia, and the underlying mechanism is related to inhibitory expression of SDF-1α/CXCR4, SCF/c-kit and FKN/CX3CR1 axes.Ethnopharmacological relevance Ganoderma lucidum (G. lucidum) has been broadly used for health endorsement as well as longevity for over 2000 years in Asian countries. It is an example of an ancient remedy and known as immortality mushroom. It has been employed as a health promoting agent owing to its broad pharmacological and therapeutical approaches. It has been confirmed that G. lucidum exhibits significant potency to prevent and treat different types of cancers such as breast, prostate, colon, lung and cervical. Aim of the study To explore anticancer effects of various pharmacologically active compounds obtained from G. lucidum and their possible mechanism of action. Materials and methods A literature search was conducted using PubMed, Goggle Scholar, Saudi Digital Library and Cochrane Library until October 11, 2019. Search was made by using keywords such as anticancer evidence, mechanism of action, pharmacology, antioxidant, toxicity, chemotherapy, triterpenoids and polysaccharides of G. lucidum. Resultsowth with advance and conventional combination therapies as natural alternatives.The advancement of artificial intelligence concurrent with the development of medical imaging techniques provided a unique opportunity to turn medical imaging from mostly qualitative, to further quantitative and mineable data that can be explored for the development of clinical decision support systems (cDSS). Radiomics, a method for the high throughput extraction of hand-crafted features from medical images, and deep learning -the data driven modeling techniques based on the principles of simplified brain neuron interactions, are the most researched quantitative imaging techniques. Many studies reported on the potential of such techniques in the context of cDSS. Such techniques could be highly appealing due to the reuse of existing data, automation of clinical workflows, minimal invasiveness, three-dimensional volumetric characterization, and the promise of high accuracy and reproducibility of results and cost-effectiveness. Nevertheless, there are several challenges that quantitative imaging techniques face, and need to be addressed before the translation to clinical use. These challenges include, but are not limited to, the explainability of the models, the reproducibility of the quantitative imaging features, and their sensitivity to variations in image acquisition and reconstruction parameters. In this narrative review, we report on the status of quantitative medical image analysis using radiomics and deep learning, the challenges the field is facing, propose a framework for robust radiomics analysis, and discuss future prospects.Objective To examine how rescue medication is defined, reported and accounted for in randomised controlled trials (RCTs) in eczema and asthma populations. Study design and setting A systematic review of phase II/III RCTs evaluating monoclonal antibodies for treating chronic eczema or asthma. A search of EMBASE, MEDLINE and the Cochrane Central Register of Controlled Trials was conducted to identify eligible RCTs. Results Sixty published RCTs were identified, of which 60 (100%) allowed use of rescue medication but only 28 (47%) reported its use. Twenty-seven (45%) articles summarised rescue use by arm, with an average of 25% (95% CI (17%, 36%)) greater use in the placebo arm. Nine (15%) trials undertook an analysis that adjusted the primary treatment effect estimate for rescue medication use, but 8 of these employed a sub-optimal approach using single imputation, including 4 which used 'last observation carried forward' after setting post-rescue data to missing. Conclusions Rescue medication use in eczema and asthma trials evaluating monoclonal antibodies is often permitted, but not routinely reported. There is evidence of imbalance in rescue use between arms, but few articles attempted to estimate a rescue-adjusted treatment effect. In trials that did, the methods employed were sub-optimal which could introduce bias.T cell co-stimulation is important for the maintenance of immunologic tolerance. Co-inhibitory receptors including programmed cell death-1 (PD-1) confer peripheral tolerance to prevent autoimmunity. SAP (SH2D1A) is an adaptor molecule that is important in T cell signaling and has been shown to interact with signaling lymphocytic activation molecule (SLAM) family receptors also in the context of self-tolerance. We recently reported that SAP interferes with PD-1 function. In the current study, we investigated the levels of SAP and PD-1 in patients with rheumatoid arthritis (RA) to further understand what role they play in disease activity. We observed increased SAP levels in lymphocytes of RA patients and found that PD-1 levels correlated positively with RA disease activity. Additionally, we found that SAP interacts with CD28 to inhibit T cell signaling in vitro. This work demonstrates a putative molecular mechanism for SAP mediated PD-1 inhibition.Ataxia telangiectasia is a multi-system disorder characterized by progressive cerebellar ataxia, malignancies, chronic pulmonary disease and immunodeficiency. The aim of our study was to determine the immune competence and prevalence of respiratory infections and/or chronic cough in classical A-T patients compared to age-matched healthy controls. Study design We recruited 20 classical A-T not treated by immunoglobulins and 21 healthy age-matched control patients. The caregivers were advised to keep a daily diary with the following items (daytime and nighttime cough, runny nose, fever), number of cold episodes, number of antibiotic treatments. Results Patients with A-T showed significant differences compared to healthy controls in symptom score, daytime and nighttime cough, days with symptoms and missed days in kindergarten/school. Severe infections with hospitalization occurred rarely. Respiratory symptoms did not correlate with immunoglobulin levels in A-T patients. Conclusions Mild symptoms like chronic cough were present in A-T patients, possibly indicating ongoing silent crippling disease.Pancreatic cancer is usually advanced and drug resistant at diagnosis. A potential therapeutic approach outlined here uses nanoparticle (NP)-based drug carriers, which have unique properties that enhance intra-tumor drug exposure and reduce systemic toxicity of encapsulated drugs. Here we report that patients whose pancreatic cancers express elevated levels of Death Receptor 5 (DR5) and its downstream regulators/effectors FLIP, Caspase-8, and FADD had particularly poor prognoses. To take advantage of elevated expression of this pathway, we designed drug-loaded NPs with a surface-conjugated αDR5 antibody (AMG 655). Binding and clustering of the DR5 is a prerequisite for efficient apoptosis initiation, and the αDR5-NPs were indeed found to activate apoptosis in multiple pancreatic cancer models, whereas the free antibody did not. The extent of apoptosis induced by αDR5-NPs was enhanced by down-regulating FLIP, a key modulator of death receptor-mediated activation of caspase-8. Moreover, the DNA topoisomerase-1 inhibitor camptothecin (CPT) down-regulated FLIP in pancreatic cancer models and enhanced apoptosis induced by αDR5-NPs. CPT-loaded αDR5-NPs significantly increased apoptosis and decreased cell viability in vitro in a caspase-8- and FADD-dependent manner consistent with their expected mechanism-of-action. Importantly, CPT-loaded αDR5-NPs markedly reduced tumor growth rates in vivo in established pancreatic tumor models, inducing regressions in one model. These proof-of-concept studies indicate that αDR5-NPs loaded with agents that downregulate or inhibit FLIP are promising candidate agents for the treatment of pancreatic cancer.The passive targeting via nanomedicine to pancreatic tumor microenvironment (TME) is identified as an optimized therapeutic strategy for pancreatic ductal adenocarcinoma (PDAC) because lacking specific biomarkers and the intractable anatomical position. Herein, an in vitro 3D PDAC model was set up to evaluate the regulation of extracellular matrix (ECM) by an intelligent gemcitabine@nanogel system (GEM@NGH). This GEM@NGH system consisting of a reduction-sensitive core, the payloads of gemcitabine, and the coronal of hyaluronidase arrayed on the cationic surface was fabricated to improve intratumoral penetration and antitumor efficacy. The physicochemical properties, reduction sensitivity, cellular biocompatibility and cytotoxicity, intracellular distribution and therapeutic effects were all evaluated. Particularly, the GEM@NGH system showed excellent ECM eradication and in vitro/vivo solid tumor penetration ability as evaluated by home-built equipment and in vitro 3D PDAC model, which confirmed that GEM@NGH could be disintegrated in the tumoral reductive cytoplasm after internalization and release gemcitabine to exhibit promoted cytotoxicity. In the in vivo therapy, GEM@NGH displayed the highest tumor growth inhibition in PANC-1 tumor-bearing mice with the remarkably increased tumor penetration ability by TME regulation. The results obtained in this study indicate that specifically regulating TME by a well-designed intelligent gemcitabine@nanogel is promising way for the pancreatic cancer therapy.Graft versus host disease (GVHD) results from hyper-activation of transplanted lymphocytes against the host antigens. Bone marrow transplantation in humans as well as some cases of blood transfusion and organ transplantation are associated with a strong GVH reaction resulting in GVHD that in many cases may be fatal. We had previously shown that poly-dispersed acid-functionalized single-walled carbon nanotubes (AF-SWCNTs) specifically target activated T and B lymphocytes and kill them. In the present study, efficacy of AF-SWCNTs to suppress the GVH reaction was tested in the mouse model. Acute GVHD was induced in mice by administering intravenously 30 or 60 million spleen cells from a parental strain (C57bl/6 mouse, MHC haplotype H-2b) to host (C57bl/6 x Balb/c) F1 mice (MHC haplotype H-2b/d)and waiting for 8-10 days. Chronic GVHD was similarly induced by administration of 30 million parent spleen cells to F1 mice and waiting for a period of 60 days. Our results demonstrate a marked decline in splenomegaly and recovery of spleen T (both CD4 and CD8) and B cells in GVHD mice treated with AF-SWCNTs. AF-SWCNTs treatment also limited T and B cell proliferation by restricting S-phage of cell cycle. Generation of anti-host cytotoxic T cells (CTLs) was also markedly suppressed by AF-SWCNT treatment of acute GVHD mice, and a significant reduction in the generation of anti-host antibodies could also be demonstrated. Taken together, our results suggest that the AF-SWCNTs can be considered as a potential therapeutic agent for treating GVHD.Oxytetracycline hydrochloride, an antibiotic of the tetracycline family, is a polymorphic drug that evidences erratic absorption in oral administration. Additionally, poor solid state characterization of the polymorphs and diversity in the existing nomenclature impede the correct identification of the raw materials. In this work, oxytetracycline hydrochloride solid forms were prepared from isopropyl alcohol, ethanol and methanol through different crystallization techniques, and then their physicochemical and microbiological properties were evaluated. A combination of advanced techniques such as solid state nuclear magnetic resonance, powder X-ray diffraction, infrared spectroscopy, thermal analysis, scanning electron microscopy and energy-dispersive X-ray spectroscopy were used in the characterization of solid samples giving clear evidence of the existence of three stable and one metastable solid forms of the oxytetracycline hydrochloride. Solubility was determined in aqueous solution, simulated gastric fluid, and simulated intestinal fluid. In addition, microbiological studies were performed. The polymorphs showed similar antimicrobial activity against Escherichia coli and Staphylococcus aureus. Therefore, these solid forms of oxytetracycline hydrochloride constitute promising candidates to encourage studies for repositioning old and known antibiotic drugs in the developing strategies for new therapeutic alternatives.The number of biological molecules emerging as therapeutics is growing exponentially due to their higher specificity and tolerability profiles compared to small molecules. Despite this, their traditionally parenteral delivery often results in poor patient compliance and incomplete treatment. Current research is focussed on developing effective oral delivery strategies to facilitate administration of these biomolecules, however no universal method exists to simultaneously provide gastric protection as well as enhance transport across the gastrointestinal epithelium. Furthermore, for efficient formulation development it is imperative that we can reliably analyse permeability of biomolecules through the gastrointestinal tract, highlighting the importance of the continual development and ongoing evaluation of in vitro predictive permeability tools. Here, we review the physiological obstacles associated with peptide and protein delivery throughout the gastrointestinal tract. Furthermore, we highlight methods utilised to circumvent these barriers and promote improved intestinal permeability. Lastly, we explore in vitro models employed to predict epithelial transport. Key findings highlight the need to carefully understand gastrointestinal physiology, allowing specific engineering of oral delivery systems for biomolecules. Significant importance is placed upon understanding enzymatic degradation susceptibility as well as uptake mechanisms for particulate and protein-based therapeutics for the development of successful oral protein delivery platforms.Onychomycosis is a chronic nail disorder consisting of a fungal infection that causes physical and psychosocial discomfort to patients. However, its treatment remains challenging owing to the barrier of the highly keratinized nail plate and the short time that conventional formulations reside on nails. In this work, we developed an in situ film-forming system(IFFS) based on Eudragit® RLPO to co-deliver terbinafine hydrochloride (TBH) and urea, i.e., TBH-urea-RLPO IFFS, with the aim of overcoming the nail barrier, prolonging the residence time, and efficiently treating onychomycosis. The IFFS formulation formed a thin film with good appearance and adhesion upon application in situ. The physical states of TBH and urea in the film were evaluated with polarization microscopy and powder X-ray diffraction. TBH and urea were both amorphousmiscible components within the RLPO film. TBH release from TBH-urea-RLPO IFFS fitted to the Korsmeyer-Pappas model, and the cumulative release at 72 h was significantly higher than that from commercial preparations (Lamisil Pedisan® once). In vitro permeation of TBH from TBH-urea-RLPO IFFS through bovine hoof membranes was evaluated in comparison with the film containing TBH alone (TBH-RLPO) and commercial preparations. The retention and cumulative permeated amount of TBH were significantly enhanced for the TBH-urea-RLPO IFFS (170.80 ± 44.63 μg/cm2vs 75.49 ± 21.50 μg/cm2vs 60.25 ± 27.38 μg/cm2; 61.81 ± 16.09 μg/cm2vs 21.80 ± 11.56 μg/cm2vs 7.91 ± 1.03 μg/cm2, respectively), and the membranes treated with different formulations were observed with SEM and FTIR to identify the denaturing effect of urea on bovine hoof keratin. In vitro antifungal tests against Trichophyton rubrum,Microsporum canis, Fusarium, and Aspergillus fumigatus were cultured on Muller-Hinton agar; the findings indicated that TBH-urea-RLPO IFFS enhanced TBH antifungal activity. Overall, the results support that TBH-urea-RLPO IFFS is an efficient and promising approach for onychomycosis targeting treatment.Extracellular matrix (ECM) is the foundation on which all cells and organs converge to orchestrate normal physiological functions. In the setting of pathology, the ECM is modified to incorporate additional roles, with modifications including turnover of existing ECM and deposition of new ECM. The fibroblast is center stage in coordinating both normal tissue homeostasis and response to disease. Understanding how fibroblasts work under normal conditions and are activated in response to injury or stress will provide mechanistic insight that triggers discovery of new therapeutic treatments for a wide range of disease. We highlight here fibroblast roles in the cancer, lung, and heart as example systems where fibroblasts are major contributors to homeostasis and pathology.Introduction Cerebral blood flow during cardiopulmonary resuscitation (CPR) is a major neuroprognostic factor although not clinically feasible for routine assessment and monitoring. In this context, a surrogate marker for cerebral perfusion during CPR is highly desirable. Yet, cerebral blood flow hemodynamic determinants remain poorly understood and their significance might be altered by changes in head positioning such as flat, head up, and head down during CPR. Hypothesis We hypothesized that routinely measured hemodynamic parameters would correlate with cerebral brain flow during CPR, independently of the head position. Methods Associations between cerebral blood flow, measured using microsphere techniques, and hemodynamic parameters were studied from two prior publications. Eight pigs receiving CPR with an automated device and an impedance threshold device in the flat or supine, whole body head down and whole body head up tilt positions were analysed for the derivation sample. Relevant associations were examined for consistency in an external validation sample consisting of 18 pigs randomized to supine position versus head and torso elevation. Results After adjusting for position, arterial blood pressure and cerebral perfusion pressure during decompression were significantly associated with cerebral blood flow, in the derivation and the external validation samples. No significant associations were found between cerebral blood flow during CPR and right atrial pressure, intracranial pressure, end tidal CO2, carotid blood flow, and coronary perfusion pressure in the derivation sample. Conclusion Decompression arterial blood pressure and cerebral perfusion pressure are relevant candidate surrogate markers for cerebral blood flow during CPR, independently of head position.Aim of the study Establishing functional residual capacity (FRC) during positive pressure ventilation (PPV) of apnoeic neonates is critical for survival. This may be difficult due to liquid-filled airways contributing to low lung compliance. The objectives were to describe initial PPV, changes in lung compliance and establishment of FRC in near-term/term neonates ≥36 weeks gestation at birth. Methods Observational study of all neonatal resuscitations between 01.07.13 and 30.06.18 in a Tanzanian referral hospital. Perinatal events and characteristics were observed and recorded by trained research assistants. PPV were performed using self-inflating bag-masks without positive end-expiratory pressure (PEEP). Ventilation signals (pressure/flow), expired CO2 (ECO2) and heart rate were recorded by resuscitation monitors. Results 19,587 neonates were born, 1451 received PPV, of these 821 of median (p25, p75) birthweight 3180 (2844, 3500) grams and gestation 38 (37, 40) weeks had ≥20 ventilations and complete datasets. There was a significant increase in expired volume (from 3.3 to 6.0 ml/kg), ECO2 (0.3-2.4%), lung compliance (0.13-0.19 ml/kg/mbar) and heart rate (109-138 beats/min) over the first 20 PPVs. Inflation volume, time, and peak inflation pressure (PIP) were stable around 12-13 ml/kg, 0.45 s, and 36 mbar, respectively. Conclusions The combination of increasing expired volumes, ECO2, and heart rate with decreasing inflation/expired volume ratios and constant PIP, suggests establishment of FRC during the first 20 PPVs in near-term/term neonates using a self-inflating bag-mask without PEEP, the most common device worldwide for ventilating non-breathing neonates. Initial lung compliance is low, and with short inflation times, higher than recommended PIP seem necessary to deliver adequate tidal volumes.Background Early warning tools have been widely implemented without evidence to guide (a) recognition and (b) response team expertise optimisation. With growing databases from MET-calls and digital hospitals, we now have access to guiding information. The Queensland Adult-Deterioration-Detection-System (Q-ADDS) is widely used and requires validation. Aim Compare the accuracy of Q-ADDS to National Early Warning Score (NEWS), Between-the-Flags (BTF) and the electronic Cardiac Arrest Risk Triage Score (eCART)). Methods Data from the Chicago University hospital database were used. Clinical deterioration was defined as unplanned admission to ICU or death. Currently used NEWS, BTF and eCART trigger thresholds were compared with a clinically endorsed Q-ADDS variant. Results Of 224,912 admissions, 11,706 (5%) experienced clinical deterioration. Q-ADDS (AUC 0.71) and NEWS (AUC 0.72) had similar predictive accuracy, BTF (AUC 0.64) had the lowest, and eCART (AUC 0.76) the highest. Early warning alert (advising ward MO review) had similar NPV (99.
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