IL‐36 receptor antagonistic antibodies inhibit inflammatory responses in preclinical models of psoriasiform dermatitis

Abstract

Psoriasis vulgaris (PV) results from activation of IL‐23/Th17 immune pathway and is further amplified by cytokines/chemokines from skin cells. Among skin derived pro‐inflammatory cytokines, IL‐36 family members are highly upregulated in PV patients and play a critical role in general pustular psoriasis. However, there is limited data showing crosstalk between the IL‐23 and IL‐36 pathways in PV. Herein, potential attenuation of skin inflammation in the IL‐23‐induced mouse model of psoriasiform dermatitis by functional inhibition of IL‐36 receptor (IL‐36R) was interrogated. Anti‐mouse IL‐36R monoclonal antibodies (mAbs) were generated and validated in vitro by inhibiting IL‐36α induced secretion of CXCL1 from NIH 3T3 cells. Antibody target engagement was demonstrated by inhibition of CXCL1 production in a novel acute model of IL‐36α systemic injection in mice. In addition, anti‐IL‐36R mAbs inhibited tissue inflammation and inflammatory gene expression in an IL‐36α ear injection model of psoriasiform dermatitis demonstrating engagement of the target in the ear skin. To elucidate the possible role of IL‐36 signaling in IL‐23/Th17 pathway, the ability of anti‐IL‐36R mAbs to inhibit skin inflammation in an IL‐23 ear injection model was assessed. Inhibiting the IL‐36 pathway resulted in significant attenuation of skin thickening and psoriasis‐relevant gene expression. Taken together, this data suggests a role for IL‐36 signaling in the IL‐23/Th17 signaling axis in PV.

This article is protected by copyright. All rights reserved.

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Cytokine Effect of TLR3, TLR4, and TLR7 Agonists Alone or Associated with Leishmania infantum Antigen on Blood from Dogs

Activation of toll-like receptors (TLRs) has been shown to play an important role in leishmaniosis by enhancing the parasite specific immune responses to control infection. However, the role of TLR agonists has not been studied in detail in dogs. The aim of this study was to determine the effect of TLR3, TLR4, and TLR7 agonists (TLR3a, TLR4a, and TLR7a) alone or in combination with Leishmania infantum antigen (LSA) on TNF-α and IL-6 production in blood from dogs living in endemic areas of canine leishmaniosis (CanL). Twenty-four healthy dogs from Catalonia (n=14) and Ibizan hound dogs from the island of Mallorca (n=10) were enrolled. Whole blood with TLR3a, TLR4a, and TLR7a alone or combined with LSA were cultured separately, and IFN-γ, TNF-α, and IL-6 were measured by ELISA. A significant increase of TNF-α was found for all conditions studied compared to medium alone. Stimulation with TLR4a (p=0.0001) and TLR7a (p=0.005) presented a significantly marked increase in TNF-α and IL-6 production compared to TLR3a. Importantly, significantly higher TNF-α production was found in LSA+TLR4a (p=0.0001) stimulated blood and LSA+TLR7a (p=0.005) compared to LSA alone. All dogs showed higher TNF-α production after LSA+TLR7a compared to TLR7a (p=0.047) and LSA+TLR3a compared to TLR3a (p=0.052). These data indicate a marked inflammatory cytokine effect of TLR4a and TLR7a on blood from healthy dogs living in endemic areas of CanL. Additionally, LSA+TLR7a promoted a synergistic proinflammatory effect with TNF-α in all dogs. Those findings suggest an active role of TLRs in proinflammatory responses, which might be strongly involved in the process of disease resolution.

https://ift.tt/2JV6xbK

The Effectiveness of Sorafenib over Other Targeted Agents in the Second-Line Treatment of Metastatic Renal Cell Carcinoma: a Meta-Analysis

Abstract

The aim of the study was to perform a meta-analysis to compare the therapeutic effects and adverse events (AEs) of sorafenib in second-line treatments of metastatic renal cell carcinoma (mRCC). We searched online electronic databases: Pubmed, Embase, Cochrane library updated on November 2017.Trials of the effectiveness of sorafenib in second-line treatments of advanced RCC were included, of which the main outcomes were objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and grade 3/4 AE. Other TAs significantly reduced the risk of PFS compared to sorafenib with respect to second-line treatment (HR = 0.74; 95% CI, 0.65–0.83; p < 0.00001). No significant differences were, however, found in patients in terms of the ORR (HR = 1.82; 95% CI, 0.98–3.35; p = 0.06). Frequencies of the most common toxicities were overall similar and adverse events differed only in sensitivity analysis in rash with exclusion of other TAs (HR = 0.16; 95% CI, 0.05–0.52; p = 0.002). Overall survival was not debated between groups. In patients with mRCC, second-line sorafenib is associated with similar ORR as other target agents. While, sorafenib did not demonstrate a PFS advantage compared with other target agents, suggests sorafenib may not benefit patients with mRCC. Tolerability due to toxicities is similar compared sorafenib with other target agents. Further characterization of the RCC oncogenic pathway, and the ongoing clinical trials should help optimize the treatment option for second-line therapy of advanced renal cell carcinoma.

https://ift.tt/2B1lmH0

Feasibility of the imatinib stop study in the Japanese clinical setting: delightedly overcome CML expert stop TKI trial (DOMEST Trial)

Abstract

Background

Treatment-free remission (TFR), the ability to maintain a molecular response (MR), occurs in approximately 50% of patients with chronic myelogenous leukemia (CML) treated with tyrosine kinase inhibitors (TKIs).

Methods

A multicenter phase 2 trial (Delightedly Overcome CML Expert Stop TKI Trial: DOMEST Trial) was conducted to test the safety and efficacy of discontinuing imatinib. Patients with CML with a sustained MR of 4.0 or MR4.0-equivalent for at least 2 years and confirmed MR4.0 at the beginning of the study were enrolled. In the TFR phase, the international scale (IS) was regularly monitored by IS-PCR testing. Molecular recurrence was defined as the loss of MR4.0. Recurrent patients were immediately treated with dasatinib or other TKIs including imatinib.

Results

Of 110 enrolled patients, 99 were evaluable. The median time from diagnosis to discontinuation of imatinib was 103 months, and the median duration of imatinib therapy was 100 months. Molecular recurrence-free survival rates were 69.6%, 68.6% and 64.3% at 6, 12, and 24 months, respectively. After discontinuation of imatinib therapy, 26 patients showed molecular recurrence, and 25 re-achieved deep MR after dasatinib treatment. Molecular response MR4.0 was achieved in 23 patients within 6 months and 25 patients within 12 months. Multivariate analysis revealed that a longer time from diagnosis to discontinuation of imatinib therapy (p = 0.0002) and long duration of imatinib therapy (p = 0.0029) predicted a favorable prognosis.

Conclusions

This DOMEST Trial showed the feasibility of TKI discontinuation in a Japanese clinical setting.

https://ift.tt/2zQqj3w

Cancers, Vol. 10, Pages 431: The Dilemma of Cure and Damage in Oligodendroglioma: Ways to Tip the Balance Away from the Damage

Cancers, Vol. 10, Pages 431: The Dilemma of Cure and Damage in Oligodendroglioma: Ways to Tip the Balance Away from the Damage

Cancers doi: 10.3390/cancers10110431

Authors: Ruurd Torensma

Current treatments for oligodendrogliomas are powerful but have a negative impact on the rest of the body. The bone marrow is damaged by the chemotherapeutics, but other parts of the body are also affected. In this paper, the current treatment method and its collateral damage is described. Therefore, therapies are needed that are more effective against the tumor while having less negative effects on the patient&rsquo;s quality of life. Some potential therapies include optimal removal of the tumor by fluorescent-guided surgery (FGS), intraoperative desorption electrospray ionization-mass spectrometry (DESI-MS), better monitoring of the effects of therapy by pseudo-coloring shades of gray of MRI pictures, and using recent data from RNA sequencing of single cells and immunotherapy. These are all open new ways of treating this tumor. The RNA sequencing of single tumor cells unravels specific tumor antigens present in the differentiation status of the cancer cell. Stem cell antigens were expressed in dividing cells, while hypoxia inducible factor-&alpha; (HIF-1&alpha;) is expressed in all tumor cells. Cancer stem cell antigens can be loaded on dendritic cells to induce cytotoxic T-cells directed to cancer stem cells. These recent discoveries suggest a better quality of life with the same overall survival.

https://ift.tt/2RQCKEa

Comparative study on mineral status of lymphoid organs of broiler chicken in commonly encountered immunosuppressive disease outbreaks

Abstract

The present study was conceded to evaluate the mineral concentration of lymphoid organs of broiler chicken in commonly encountered immunosuppressive diseases like an infectious bursal disease, Newcastle disease, colibacillosis, and concurrent infections of IBD-ND and IBD-coccidiosis. A total of 500 broiler chickens from each outbreak were examined, which included the diseased and dead broiler chicken. The birds examined belonged to different age groups and were assigned the group number as per age. The outbreaks which occurred in the age groups of 18, 21, 23, 25, and 27 were selected and a total of five outbreaks from every disease, for each age group were taken into consideration for the study. From each age group, for every disease, representative samples of lymphoid organs from 10 birds were collected for mineral estimation and compared with those of 10 normal birds of the same age group, having no observable gross lesions. The samples of bursa of Fabricius, thymus, spleen, and cecal tonsils were analyzed using atomic absorption spectrophotometer (Model 4141). A positive correlation was observed between the age group and concentration of minerals viz.: copper, zinc, and manganese in the lymphoid organs of normal broiler chicken. However, the diseased birds' mean level of copper was found decreased and differs significantly (P < 0.05) from the uninfected corresponding controls. On the other hand, the levels of zinc and manganese in lymphoid organs of the affected birds were found increased and differ significantly (P < 0.05) from the uninfected controls.

https://ift.tt/2Dx3Exu

Treatment options for obstructive sleep apnea [Letters]

https://ift.tt/2JUtKuD

Mental health outcomes after major trauma in Ontario: a population-based analysis [Research]

BACKGROUND:

Major injury continues to be a common source of morbidity and mortality; improving the functional recovery of survivors of major trauma requires a better understanding of the mental health outcomes that may occur in this population. We assessed the association between major trauma and the development of a new mental health diagnosis or death by suicide.

METHODS:

We completed a population-based, self-controlled, longitudinal cohort analysis using linked administrative data on patients treated for major trauma in Ontario between 2005 and 2010. All survivors were included and composite rates of mental health diagnoses during inpatient admissions were compared between the 5 years after injury and the 5 years before injury, using Poisson regression with generalized estimating equations. The incidence of suicide was calculated for the 5 years after injury. Risk factors for suicide were calculated using Cox proportional hazard regression analyses.

RESULTS:

The analysis included 19 338 patients, predominantly men (70.7%) from urban areas (82.6%), with unintentional (89%), blunt injuries (93.4%). Overall, trauma was associated with a 40% increase in the postinjury rate of mental health diagnoses (incidence rate ratio [IRR] 1.4, 95% [confidence interval] CI 1.1 to 1.8). The suicide rate was 70 per 100 000 patients per year, substantially higher than the population average. Risk factors for completing suicide were prior inpatient diagnosis of mood disorder (hazard ratio [HR] 4.3, 95% CI 2.1 to 8.8) and self-inflicted injury (HR 7.8, 95% CI 3.9 to 15.4).

INTERPRETATION:

Survivors of major trauma are at a heightened risk of developing mental health conditions or death by suicide in the years after their injury. Patients with pre-existing mental health disorders or who are recovering from a self-inflicted injury are at particularly high risk.

https://ift.tt/2AYvSyO

Ontario doctors angry over governments proposal for primary care [News]

https://ift.tt/2JUDqp3

Canadian and international winners of major health research prizes, 1959-2018 [Analysis]

https://ift.tt/2AYTKCu

Many doctors pessimistic about direction of medical profession [News]

https://ift.tt/2JWi76E

Severe pet-transmitted zoonosis in a patient with a compromised immune system [Practice]

https://ift.tt/2AYvIHI

Nonfasting lipid testing: the new standard for cardiovascular risk assessment [Commentary]

https://ift.tt/2JTVpvM

Avulsion fracture of the calcaneus [Practice]

https://ift.tt/2AZIoOB

Postnatal exposure to household disinfectants, infant gut microbiota and subsequent risk of overweight in children [Correction]

https://ift.tt/2JWJ7mi

rateme [Humanities]

https://ift.tt/2AZaHNa

Ethnicity-based fetal growth charts could reduce inductions and elective cesarean sections [News]

https://ift.tt/2JWJ2iu

Doctor, physician, professor, teacher [Letters]

https://ift.tt/2AZe0ng

"Same questions" [Coda]

https://ift.tt/2JWCtws

Predictive value of lymphoscintigraphy in patients with breast cancer-related lymphedema undergoing complex decongestive therapy

Abstract

Purpose

We evaluated the prognostic value of lymphoscintigraphy after complex decongestive therapy (CDT) in breast cancer-related secondary lymphedema.

Methods

Prior to CDT, 80 patients with breast cancer-related lymphedema underwent a ^99mTc tin-colloid lymphoscintigram. We investigated the uptake patterns of axillary lymph nodes (LNs), main lymphatic vessels, collateral lymphatic vessels, and dermal back flow in the lymphoscintigraphy of the upper extremities. We also compared the above findings with other clinical variables between patients who respond well to CDT (responders) and those who do not (poor responders). We used Pearson's χ² test and Fisher's exact test to compare the lymphoscintigram findings with the studied variables.

Results

There were 50 poor responders and 30 responders 1 year after CDT. There were significant differences between the two groups with regard to compliance (P < 0.05) and visualization of axillary LNs (P < 0.05). In combined results, the odds ratio was 21.33 (2.37–192.03) in the compliance and visible axillary LNs group compared to the poor compliance and invisible axillary LNs group.

Conclusion

Lymphoscintigraphy of the upper extremities can be a useful tool to predict the prognosis of CDT in breast cancer-related lymphedema patients.

https://ift.tt/2RNldMT

Polyunsaturated Fatty Acids and Their Correlations with Parameters of Oxidative/Antioxidant Potential of the Blood and Lipoprotein-Associated Phospholipase A2 in Coronary Atherosclerosis

We studied serum content of some polyunsaturated fatty acids and their correlations with parameters of oxidative stress (FORT), antioxidant protection (FORD), lipoprotein-associated phospholipase A2 (LP-PLA2), and serum level of LPO products in male patients with coronary atherosclerosis. The mass fraction of polyunsaturated fatty acids and FORD were lower, while LP-PLA2, FORT, and concentration of LPO products were higher than in the control group (conventionally healthy men). Negative correlations of medium strength of polyunsaturated fatty acids with inflammation markers and oxidative stress were revealed, which can indicate that the decrease in polyunsaturated fatty acids content is associated with enhanced generation of free radicals, and consequently with increased risk of early atherosclerosis development.

https://ift.tt/2FtRaJ5

Changes in the Expression of Calbindin and Calretinin in Interneurons of the Spinal Dorsal Horns Under Conditions of Antiorthostatic Suspension in Mice

In female C57Bl/6 mice subjected to antiorthostatic suspension of the hind limbs for 30 days, calbindin- and calretinin-containing interneurons of the dorsal horns of the upper thoracic segments of the spinal cord were studied using immunohistochemical methods. In mice of the experimental group, cross-sectional area of calbindin- and calretinin-containing interneurons decreased in laminae I, II, and III and increased in laminae IV and V and in the region of the medial edge of the dorsal horn. After antiorthostatic suspension, expression of calretinin decreased in interneurons of laminae I and II and calbindin expression increased in the interneurons of laminae III, IV, and V. The total number of interneurons in laminae of the spinal cord detected by Nissl staining in the control and experimental groups remained unchanged. After antiorthostatic suspension and in control group, number of interneurons immunoreactive for calbindin and calretinin was maximum in lamina II and minimum in laminae IV and V and in the region of the medial edge of the spinal dorsal horn.

https://ift.tt/2qIiecY

Neuroprotective Effects of Dibornol in Focal Cerebral Ischemia/Reperfusion in Rats

Neuroprotective activity of 2,6-diisobornyl-4-methylphenol (Dibornol) was studied under conditions of experimental focal cerebral ischemia/reperfusion modeled by intraluminal occlusion of the left middle cerebral artery for 1 h followed by recirculation. Dibornol administered in a dose of 10 mg/kg intragastrically 24 h and 30 min before and 24 h after focal ischemia/reperfusion modeling reduced the size of the brain infarction zone by 52% (48 h after recirculation) and neurological deficit by 1.7-2.4 times in comparison with that in control animals.

https://ift.tt/2FhQxlH

Combined Effect of TLR2 Ligands on ROS Production by Mouse Peritoneal Macrophages

TLR2-mediated ROS production by mouse peritoneal macrophages was studied by luminoldependent chemiluminescence under conditions of cell stimulation with zymosan (TLR2/6 ligand) and peptidoglycan (TLR2/1 ligand). ROS production by macrophages stimulated with zymosan and peptidoglycan simultaneously depended on the ratio of ligand concentrations. Three effects were revealed: additivity of the stimulating effects of the ligands used, competitive ligand binding, and effect of macrophage priming with peptidoglycan during cell stimulation with zymosan. The mechanisms of these effects are discussed.

https://ift.tt/2qESWN0

Peculiarities of Participation of DNA Methyltransferases in the Mechanisms of Storage, Impairment, and Recovery of Conditioned Food Aversion Memory

We studied the participation of DNA-methylation processes in the mechanisms of memory storage and reconsolidation, amnesia induction, and in recovery of the conditioned food aversion memory in edible snails. It was found that daily injections of DNA methyltransferases inhibitor over 3 days combined with a reminder of a conditioned food stimulus did not affect memory storage. The administration of DNA methyltransferase inhibitors did not suppress induction of amnesia caused the NMDA receptor antagonist/reminder. Injections of DNA methyltransferase inhibitors combined with the reminder led to memory recovery in 3 days after amnesia induction. Thus, DNA methyltransferase inhibitors in the same doses did not affect storage and reconsolidation of memory, as well as the mechanisms of amnesia induction. At the same time, injections of inhibitors led to memory recovery, apparently, due to disruption of reactivation and amnesia development.

https://ift.tt/2FfkRNN

The 2018 Nobel Prize in medicine goes to cancer immunotherapy (editorial for BMC cancer)

https://ift.tt/2QwWexb

Systematic review and meta‐analysis: defecography should be a first‐line diagnostic modality in patients with refractory constipation

Summary

Background

Defecography is considered the reference standard for the assessment of pelvic floor anatomy and function in patients with a refractory evacuation disorder. However, the overlap of radiologically significant findings seen in patients with chronic constipation (CC) and healthy volunteers is poorly defined.

Aim

To systematically review and rates of structural and functional abnormalities diagnosed by barium defecography and/or magnetic resonance imaging defecography (MRID) in patients with symptoms of CC and in healthy volunteers.

Methods

Electronic searches of major databases were performed without date restrictions.

Results

From a total of 1760 records identified, 175 full‐text articles were assessed for eligibility. 63 studies were included providing data on outcomes of 7519 barium defecographies and 668 MRIDs in patients with CC, and 225 barium defecographies and 50 MRIDs in healthy volunteers. Pathological high‐grade (Oxford III and IV) intussuscepta and large (>4 cm) rectoceles were diagnosed in 23.7% (95% CI: 16.8‐31.4) and 15.9% (10.4‐22.2) of patients, respectively. Enterocele and perineal descent were observed in 16.8% (12.7‐21.4) and 44.4% (36.2‐52.7) of patients, respectively. Barium defecography detected more intussuscepta than MRID (OR: 1.52 [1.12‐2.14]; P = 0.009]). Normative data for both barium defecography and MRID structural and functional parameters were limited, particularly for MRID (only one eligible study).

Conclusions

Pathological structural abnormalities, as well as functional abnormalities, are common in patients with chronic constipation. Since structural abnormalities cannot be evaluated using nonimaging test modalities (balloon expulsion and anorectal manometry), defecography should be considered the first‐line diagnostic test if resources allow.

https://ift.tt/2PUYn8E

Association of whole grain, refined grain, and cereal consumption with gastric cancer risk: A meta‐analysis of observational studies

In this work, we identified eleven articles which included 530,176 individuals from United States, Italy, China, Spain, Poland, Mexico, Uruguay and European countries, and found statistically significant inverse association between whole grain consumption and gastric cancer (GC), positive association between refined grain consumption and GC and no association between overall cereal consumption and GC.

Abstract

Many studies have analyzed the relationship between cereal, whole, or refined grain and the risk of gastric cancer (GC) and have yielded mixed results. Therefore, we performed a meta‐analysis of observational studies to summarize the available evidence on this topic. Databases such as PubMed, EMBASE, Web of Science, MEDLINE, and the Cochrane Library were searched for studies focusing on these associations from inception to October 2017. Summary odd ratios (OR) and 95% confidence intervals (CI) were calculated by using either a random‐ or fixed‐effect model according to the between‐studies heterogeneity. Subgroup analysis was also performed. In total, eleven studies that included 530,176 participants were identified. In a pooled analysis of all studies, cereal exposure was not associated with GC risk (OR, 1.11, 95%CI, 0.85–1.36). Specific analyses indicated that whole grain consumption was associated with decreased GC risk (OR, 0.61, 95%CI, 0.40–0.83) and that refined grain consumption was associated with increased GC risk (OR, 1.65, 95%CI, 1.36–1.94). Higher whole grain and lower refined grain intake but not cereal consumption reduces GC risk. This study has been registered at ClinicalTrials.gov (ID: NCT03419663).

https://ift.tt/2z3AXnU

Assessment of Lactate Production and Proteoglycans Synthesis by the Intact and Degenerated Intervertebral Disc Cells under the Influence of Activated Macrophages: an In Vitro Study

The effects of proinflammatory cytokines on the secretion of glycosaminoglycans and lactate production by normal and degenerated intervertebral disk cells were studied on the model of their co-culturing with activated macrophage-like cells. It was found that proinflammatory cytokines produced a direct effect on intervertebral disk cells in a 3D culture reducing the rate of glycolysis and synthetic activity of both normal and degenerated cells of annulus fibrosus and nucleus pulposus, which is an important factor in progression of intervertebral disk degeneration.

https://ift.tt/2ODzVE5

Human Umbilical Cord Mesenchymal Stromal Cell-Derived Microvesicles Express Surface Markers Identical to the Phenotype of Parental Cells

Production of microvesicles in culture of human umbilical cord multipotent mesenchymal stromal cells was studied and comparative analysis of the expression of some surface molecules (clusters of differentiation, CD) was performed. It was found that the mesenchymal stromal cells produce microvesicles in the amount sufficient for their detection by flow cytometry. Parallel analysis of the phenotypes of maternal mesenchymal stromal cells and secreted microvesicles revealed identical expression of surface molecules CD13, CD29, CD44, CD54, CD71, CD73, CD90, CD105, CD106, and HLA-I. The concentration of microvesicles in the conditioned medium was 17.9±4.6×10⁶/ml; i.e. one cell produced ~40-50 (44.7±11.5) microvesicles over 2 days in culture.

https://ift.tt/2z219Q0

The Dependence of the Mutagenic Effect on the Dose of X-Ray Irradiation in an In Vivo Experiment on Female (CBA×C57Bl/6)F1 Mice

We studied the mutagenic effect of X-ray irradiation in doses of 0.5, 1, and 1.5 Gy on female (CBA×C57Bl/6)F1 mice. The mutagenic effect (assessed by the parameter "frequency of bone marrow polychromatophilic erythrocytes with micronuclei") linearly depended on the dose of X-ray irradiation in the range of up to 1 Gy and reached the plateau at 1.5 Gy. The fraction of polychromatophilic erythrocytes was 45, 45, and 46% under control conditions (without exposure) and exposure to the irradiation in the doses of 0.5 and 1 Gy, respectively. Irradiation in a dose of 1.5 Gy induced a slight inhibition of erythropoiesis. These data confirm the hypothesis on possible death of highly aberrant erythrocyte precursors after irradiation in high doses.

https://ift.tt/2ODzSYV

Individual Peculiarities of the Development and Differentiation of Embryonic Neocortex Transplants in Intact Adult Mouse Brain

We studied individual peculiarities of the development and differentiation of allogeneic transplants of neocortical cells isolated from embryos at different stages of development in intact brain of adult mice. Despite standard transplantation technique, intraparenchymal grafts considerably varied in size, morphology, and structural organization. The cells in the transplants developing inside the brain ventricles of the recipient formed histotypical structures resembling organoids. Transplants of each age group (12.5, 14.5, and 19.5 days) demonstrated individual peculiarities of cell migration, differentiation, and fiber growth. Only from cells of 12.5-day transplants formed spiny pyramidal neurons typical of V layer of the cerebral cortex. Differentiation of catecholaminergic neurons untypical of brain cortex was observed only in 14.5-day transplants. In few transplants of each age group, extensive cell migration from the transplant was observed. In some transplants, dense astrocyte accumulation was seen. In all cases (n=52), the response of the recipient's glia to the transplant was observed, but formation of an extensive glial barrier was noted only in one case. Our findings suggest that the entire range of the results determined by individual peculiarities of the transplant growth and recipient's response should be thoroughly realized when introducing the methods of neurotransplantation into regenerative medicine.

https://ift.tt/2z2OZ9G

DMSO-Free Cryopreservation of Human Umbilical Cord Tissue

Human umbilical cord represents a source of multipotent stromal cells of a supreme therapeutic potential. The cells can be isolated from either fresh or cryopreserved umbilical cord tissues. DMSO is a cryoprotectant most commonly used for preservation of umbilical cord tissues; however, cyto- and genotoxicity of this compound is evident and well documented. In the present study we performed successful cryopreservation of the umbilical cord tissue using other cryoprotectants: propylene glycol, ethylene glycol, and glycerol. Of these, 1.5 M ethylene glycol and 20% glycerol turned out to be the best in terms of the preservation of living cells within the frozen tissue, early onset of migration of these cells out of the thawed explants, and overall efficacy of multipotent stromal cell isolation. Cryobanking of tissues can improve availability of multiple cell products for medical purposes and promote the development of personalized medicine.

https://ift.tt/2ODzQQN

Aminoethane Sulfonic Acid Magnesium Salt Inhibits Ca 2+ Entry Through NMDA Receptor Ion Channel In Vitro

The effect of a cerebroprotective agent magnesium bis-aminoethanesulfonate (laboratory code FS-LKhT-317) on intracellular calcium concentration was studied by the fluorescent imaging technique on neuroglial cell culture from Spraque-Dawley rat hippocampus. The substance produced a pronounced inhibitory effect and suppressed NMDA receptor activity in concentrations of ≥50 μM. The observed effects were reversible or partially reversible and were detected by a decrease in Ca²⁺ signal amplitude in neurons in response to NMDA applications in a Mg²⁺-free medium and by inhibition of Ca²⁺ pulses in magnesium-free medium (elimination of magnesium block).

https://ift.tt/2z4Ux3n

A Cell Model of Human Small Intestinal Wall Based on Genetically Modified Caco-2 Cells

We propose a cell model of the human small intestinal wall based on genetically modified Caco-2 cells that allows visualization and quantitative assessment of activation of NF-κB factor and related intracellular pathway by using fluorescence microscopy. A dose-dependent increase in fluorescence intensity of the obtained cells in response to TNFα exposure in concentrations of 1-100 ng/ml was demonstrated. It was found that this parameter correlates with a decrease in the transepithelial resistance of the cell monolayer in response to TNFα and can be used to assess the toxic effects of substances on epithelial cells of the human small intestine.

https://ift.tt/2OF1Var

Blood Pressure Changes After Exposures Increasing Angiotensin-Converting Enzyme Activity and After Its Normalization with Dihydroquercetin in Male Wistar Rats

Changes in BP and HR were assessed after exposures increasing activity of angiotensin-converting enzyme: ionizing radiation, NO synthase inhibitor (L-NAME), and dexamethasone. Effects of dihydroquercetin and angiotensin-converting enzyme inhibitor enalapril on activity of this enzyme, BP, and HR were also evaluated under these exposures. Wistar male rats were subjected to X-ray irradiation in a dose of 2.5 Gy. Angiotensin-converting enzyme activity in the aorta sections was determined by Hip-His-Leu hydrolysis. BP and HR were recorded using a non-invasive tail-cuff method and PowerLab 8/35 software. BP and HR were not altered with the increase in activity of angiotensin-converting enzyme after irradiation. In case of prolonged (7 days) treatment with NO synthase inhibitor and dexamethasone, the increase in enzyme activity was accompanied by elevation of BP and, in the case of NO synthase inhibitor, HR reduction. Dihydroquercetin normalized the enzyme activity and lowered BP, but not to the normal level. Enalapril normalized BP, increased by NO synthase inhibitor solution intake; at the same time, the angiotensinconverting enzyme activity decreased more than 2-fold in comparison with the normal.

https://ift.tt/2z4Meo5

Extracellular DNA in the Dynamics of Uncomplicated Pregnancy

We analyzed the concentration of extracellular DNA and its fractions in the dynamics of uncomplicated pregnancy Thirty women with singleton pregnancy were examined. The concentration of total, maternal, and fetal cell-free DNA in maternal blood was measured at gestation weeks 11-14, 24-26, and 30-32. The level of total cell-free DNA was evaluated by measuring the concentration of RASSF1A gene using quantitative PCR analysis, the level of cell-free fetal DNA was assessed by determining the hypermethylated part of RASSF1A gene. The concentration of total cell-free DNA and cell-free maternal DNA did not change during the first half of pregnancy, but increased after 24-26 weeks. The level of cell-free fetal DNA increased from the first to the second and third trimester: 14.15 (2.32-36.25), 24.87 (6.29-129.32), and 32.62 (8.97-133.52) GE/ml (p<0.05), respectively. Our results characterize the dynamics of the content of cell-free DNA and its fractions during pregnancy, which should be taken into account when using cell-free DNA for prediction of placenta-associated complications.

https://ift.tt/2OEkf3A

Immunohistochemical Features of Different Types of Unstable Atherosclerotic Plaques of Coronary Arteries

We performed a complex morphological study of samples of different types of unstable atherosclerotic plaques obtained from 33 men with occlusive coronary atherosclerosis, who underwent coronary artery endarterectomy during coronary artery bypass surgery. In the samples, expression of MMP-2 and MMP-9, collagen IV, CD31, CD34, factor VIII, and actin of smooth muscle cells was evaluated by morphometric and immunohistochemical methods. The maximum expression of MMP-9 was found in unstable plaques of the lipid type, where it 1.4- and 1.24-fold surpassed the corresponding levels in plaques of the inflammatory-erosive and degenerative-necrotic types. Unstable plaques of the degenerative-necrotic type are characterized by the most intensive expression of collagen IV in comparison with plaques of the inflammatory-erosive and lipid types (by 2.8 and 2.2 times, respectively). The maximum neovascularization was detected in inflammatory-erosive plaques, which was confirmed by enhanced expression of CD31 and CD34 markers in comparison with plaques of the lipid (by 7.6 and 18.95 times, respectively) and degenerative-necrotic (by 31.1 and 39.8 times) types.

https://ift.tt/2z7Ux2q

Non-Invasive Evaluation of Extracellular Matrix Formation in the Intestinal Epithelium

Differentiation of colorectal cancer Caco-2 cells was assessed using Affymetrix Human Gene 1.0 ST arrays and by the main electrical parameters measured by bioimpedance spectroscopy. Transepithelial electrical resistance (TEER) was maximum on day 7, then decreased by day 11, and remained stable. The baseline resistance was maximum on day 4, minimum on day 7, but then gradually increased over 2 weeks, which can be explained by the formation of the basement membrane components or the apical mucous layer. Caco-2 cells express components of laminin-111 and laminin-511. A synchronous increase in the expression of mucin 3 mRNA (MUC3A/MUC3B) and mucin 17 mRNA (MUC17) and reduced expression of miR-21 and miR-622 microRNA genes were observed. Possible use of the described approach for studying the formation of extracellular matrix is discussed.

https://ift.tt/2OEl4JF

Biochemical and Morphological Parameters of Inbred/Outbred Lines and DBCB Tetrahybrid Mouse in High-Sugar In Vivo Model of Metabolic Syndrome

Integral, biochemical, and morphological parameters and concentrations of vitamins, particularly lipid soluble vitamins, were analyzed in female mice of inbred DBA/2J line, outbred ICR-1 (CD-1) line, and DBCB tetrahybrid mice on the in vivo model of metabolic syndrome induced by consumption of 30% sucrose for 2 days. In contrast to inbred and outbred lines, DBCB tetrahybrid mice developed abdominal obesity, hypercholesterolemia, and pronounced morphological picture of fatty liver disease. The lipid-coupled transport of vitamin E to the liver is also enhanced in these animals, which compensated decreased supply of vitamin E to the liver under conditions of high-sugar ration. The observed interstrain differences can be related to genetic features of the used mouse lines and DBCB tetrahybrid mice and require further genomic, transcriptomic, proteomic, and morphological studies. The results of the study based on the in vivo model of metabolic syndrome allow identifying the key biomarkers for complex diagnostics and prognosis of metabolic syndrome complications, such as nonalcoholic steatosis of the liver.

https://ift.tt/2z61gKx

Antioxidant Properties of a Pharmaceutical Substance Hypocard, a Potential Drug for Ischemic Disease

Antioxidant activity of a pharmaceutical substance hypocard was compared with activity of nitromalic acid and well-known agents nicorandil and Mexidol. The ability of these substances to inhibit spontaneous and oxidant-induced LPO process in rat brain homogenate was analyzed. The mechanisms of these effects were studied. The antioxidant properties of hypocard manifested in the inhibition of Fe(II)-induced LPO were significantly more pronounced in comparison with Mexidol and nicorandil.

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Development of an In Vitro Model of Inflammatory Cytokine Influences on Intervertebral Disk Cells in 3D Cell Culture Using Activated Macrophage-Like THP-1 Cells

We developed a new model for evaluation of the influence of proinflammatory cytokines on intervertebral disc cells in a 3D culture based on co-culturing of these cells with activated macrophage-like THP-1 cells. The levels of TNFα, IL-1β, IL-6, IL-8, IL-10, and IL-12p70 production were assessed by flow cytofluorometry using microspheres. Considerable differences in the level of spontaneous cytokine secretion by normal and degenerated intervertebral disc cells were revealed. A significant increase in the level of IL-1β and IL-8 was observed during co-culturing, which confirms consistency of the developed model.

https://ift.tt/2z5JxTs

Induction of Vasculo- and Osteogenesis in Spheroids Formed by Adipose-Derived Stromal Cells

Vascularization of bioengineered bone tissue constructs remains a challenging problem of regenerative medicine. Spheroids generated in 3D culture of adipose-derived stromal cells supplemented with inducing factors demonstrate stable characteristics and express of mesenchymal, endothelial, and osteoblasts markers, and represent a prototype of vascularized microtissue. Adipose-derived stromal cells spheroids induced to both angio- and osteogenic differentiation can be used in development of new innovative technologies for in vitro fabrication of vascularized bioequivalents for repair of large bone defects.

https://ift.tt/2OEkX0H

Survival and Migration of Rat Olfactory Ensheathing Cells after Transplantation into Posttraumatic Cysts in the Spinal Cord

We studied survival of rat ensheathing cells after transplantation into experimental posttraumatic cysts. These cells were prepared according to our original protocol, labeled with intravital membrane dye PKH26, and transplanted into posttraumatic cysts of the spinal cord. The presence of cysts was verified by magnetic resonance imaging. Olfactory ensheathing cells were detected in the spinal cord by the immunofluorescence method. It was shown that rat olfactory ensheathing cells survived in the spinal cord over 4 weeks and their migration was observed. High survival rate and the possibility of obtaining olfactory ensheathing cells from the olfactory mucosa of patients for creation of an autologous preparation allow considering them as very promising material for the treatment of patients with posttraumatic cysts of the spinal cord.

https://ift.tt/2z214fa

Effect of 30-Day Hindlimb Unloading and Hypergravity on Bone Marrow Stromal Progenitors in C57Bl/6N Mice

We studied the effect of 30-day hindlimb unloading and subsequent simulated hypergravity on the cellularity and proliferative, clonogenic, and differentiation potential of bone marrow stromal progenitors in mice. Clonogenic and differentiation activity of stromal cells decreased after unloading; proliferative and differentiation activity of bone marrow stromal progenitors increased after hypergravity simulation. Our findings demonstrated negative effect of unloading on functional activity of mouse bone marrow stromal progenitors. Short-term hypergravity after unloading produced a stimulating effect on the bone marrow stromal progenitors.

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Surface Molecular Markers of Cancer Stem Cells: Computation Analysis of Full-Text Scientific Articles

The data on cancer stem cell surface molecular markers of 27 most common cancer diseases were analyzed using natural language processing and data mining techniques. As a source, 8933 full-text open-access English-language scientific articles available on the Internet were used. Text mining was based on searching for three entities within one sentence, namely a tumor name, a phrase "cancer stem cells" or its synonym, and a name of differentiation cluster molecule. As a result, a list of surface molecular markers was formed that included markers most frequently mentioned in the context of certain tumor diseases and used in studies of human and animal tumor cells. Based on similarity of the associated markers, the tumors were divided into five groups.

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Sandoz Inc. Issues Voluntary Nationwide Recall of One Lot of Losartan Potassium and Hydrochlorothiazide Due to the Detection of Trace Amounts of NDEA (N-Nitrosodiethylamine) Impurity Found in the Active Pharmaceutical Ingredient (API)

Audience: Consumer, Health Professional, Pharmacy November 8, 2018 -- Sandoz Inc. is voluntarily recalling one lot of Losartan Potassium Hydrochlorothiazide Tablets, USP 100mg/25mg to the consumer level. This product is being recalled due to the...

https://ift.tt/2Dy88nx

Acetylation of HMGB1 by JNK1 Signaling Promotes LPS-Induced Peritoneal Mesothelial Cells Apoptosis

Increased high mobility group box 1 (HMGB1) in dialysis effluence is associated with the presence of peritoneal dialysis-related peritonitis in patients and peritoneal dysfunction in acute peritonitis mice model, but it remains unclear whether HMGB1 is involved in peritoneal mesothelial cell injury and functions via molecular posttranslational modifications by acetylation in this process. Here we first showed correlation between HMGB1 acetylation level in dialysis effluence of patients and occurrence of Gram-negative peritonitis. The increased level of acetylated HMGB1 was similarly observed under the lipopolysaccharides (LPS) treatment in both human peritoneal mesothelial cell line (HMrSV5) and mice visceral peritoneum tissue. Overexpression of wild-type, but not hypoacetylation mutant of HMGB1, enhanced LPS-induced apoptosis in HMrSV5 cells, which was accompanied by elevated protein levels of BAX and cleaved-caspase 3 compared to the control. Pretreatment of HMrSV5 cell with JNK inhibitor attenuated LPS-induced HMGB1 acetylation. Consistently, primary peritoneal mesothelial cells from Jnk1-/- mice showed a lower protein contents of acetylated HMGB1, fewer apoptosis, and decreased protein expression of BAX and cleaved-caspase3 after LPS exposure, as compared to those from wild-type mice. In conclusion, our data demonstrated HMGB1 promotes LPS-induced peritoneal mesothelial cells apoptosis, which is associated with JNK1-mediated upregulation of HMGB1 acetylation.

https://ift.tt/2RQNZfK

Sandoz Inc. Issues Voluntary Nationwide Recall of One Lot of Losartan Potassium and Hydrochlorothiazide Due to the Detection of Trace Amounts of NDEA (N-Nitrosodiethylamine) Impurity Found in the Active Pharmaceutical Ingredient (API)

Audience: Consumer, Health Professional, Pharmacy November 8, 2018 -- Sandoz Inc. is voluntarily recalling one lot of Losartan Potassium Hydrochlorothiazide Tablets, USP 100mg/25mg to the consumer level. This product is being recalled due to the...

https://ift.tt/2Dy88nx

EMCrit Wee – The Brindley Sessions – Followership

on followership

EMCrit Project by Scott Weingart.

https://ift.tt/2JTlc7k

Isolation and Culture of Embryonic Mouse Neural Stem Cells

Here, we introduce a novel microsurgical technique for the isolation of neural stem cells from the E13 mouse embryo ganglionic eminence.

https://ift.tt/2B0onHB

Detection of Small GTPase Prenylation and GTP Binding Using Membrane Fractionation and GTPase-linked Immunosorbent Assay

Here we describe a protocol to investigate the prenylation and guanosine-5'-triphosphate (GTP)-loading of Rho GTPase. This protocol consists of two detailed methods, namely membrane fractionation and a GTPase-linked immunosorbent assay. The protocol can be used for measuring the prenylation and GTP loading of different other small GTPases.

https://ift.tt/2Dg4HkE

Using Nursing Information and Data Mining to Explore the Factors That Predict Pressure Injuries for Patients at the End of Life

This study investigated the association between patient characteristics and the occurrence of pressure injuries for patients at the end of life. A retrospective study was conducted using data collected from 2062 patients at the end of life between January 2007 and October 2015. In addition to demographic data and pressure injury risk assessment scale scores, injury history, disease type, and length of hospitalization were revealed as the major independent variables for predicting the occurrence of pressure injuries. Both χ2 tests and t tests were employed for binary variable analysis, and logistic regression was used to conduct multivariate analysis. Classification models were formulated through decision tree analysis, backpropagation neural network, and support vector machine algorithms. The rules obtained using the decision tree algorithm were analyzed and interpreted. The accuracy rate, sensitivity, and specificity of the decision tree, backpropagation neural network, and support vector machine algorithms were 77.15%, 79.54%, and 74.76%; 78.12%, 81.37%, and 74.85%; and 79.32%, 81.03%, and 78.75%, respectively. The predictive factors, ranked in order of importance, were history of pressure injuries, without cancer, excretion, activity/mobility, and skin condition/circulation. These were the primary shared risk factors among the four models used in this study. En Chu Kong Hospital provided financial support for this study (ECKP10201). The second author was supported by the Ministry of Science and Technology of the Republic of China (Taiwan) and the Linkou Chang Gung Memorial Hospital through research grants MOST105-2410-H-182-009-MY2/MOST106-2632-H-182-001 and CMRPD3G0011/CARPD3B0012, respectively. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Corresponding author: Shih-Wei Lin, PhD, 259 Wen-Hwa 1st Road, Kwei-Shan Tao-Yuan, Taiwan, 333, ROC (swlin@mail.cgu.edu.tw). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Craniofacial and Dental Manifestations of Melnick–Needles Syndrome: Literature Review and Orthodontic Management

The aim of this article was to present a characteristic clinical image of Melnick–Needles syndrome using an example of an 11.5-year-old female patient treated at the Facial Congenital Disorders Outpatient Clinic as well as to present the actual literature review of the surgical treatment. The patient was diagnosed with several characteristics typical for Melnick–Needles syndrome: single-sided hearing loss, malocclusion, and facial dysmorphism, among others. Due to malocclusion and facial dysmorphism, the patient with Melnick–Needles syndrome requires orthodontic treatment with surgical intervention. Mandibular distraction with fixed appliance treatment is a recommended treatment protocol.

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Pharmacokinetic‐pharmacodynamic modelling of platelet response to ticagrelor in stable coronary artery disease and prior myocardial infarction patients

Summary

Aim

To characterize ticagrelor exposure‐response relationship for platelet inhibition in patients with stable coronary artery disease (CAD) and a history of myocardial infarction (MI), using non‐linear mixed effects modelling and simulation.

Methods

Platelet function data were integrated with plasma concentration data of ticagrelor and its active metabolite AR‐C1249010XX in a population pharmacokinetic and pharmacodynamic (PK/PD) model, based on two clinical studies. In the ONSET/OFFSET study, PK and platelet function were assessed in 123 CAD patients receiving placebo, ticagrelor (180 mg followed by 90 mg twice daily) or clopidogrel (600 mg followed by 75 mg once daily). In the PEGASUS‐TIMI 54 platelet function substudy, PK and platelet function were assessed during maintenance dosing in 180 prior MI patients receiving placebo, ticagrelor 60 mg or ticagrelor 90 mg twice daily.

Results

Platelet inhibition by ticagrelor was described by a sigmoidal E_max model. On average, half maximal inhibition was reached at ticagrelor concentrations of 116 (RSE: 5.3%) nmol/L. Simulations showed that near maximal platelet inhibition is achieved with both ticagrelor 60 and 90 mg twice daily. At simulated lower doses, platelet inhibition is overall reduced, more variable between patients, and show greater peak‐to‐trough variability. Ticagrelor antiplatelet response was similar between the studied patient populations.

Conclusions

In patients with stable CAD or a history of MI, near maximal platelet inhibition is achieved with both ticagrelor 60 and 90 mg twice daily. At modeled doses below 60mg, the response is overall reduced, more variable between patients, and patients will display greater peak‐to‐trough variability.

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The Impact of Tacrolimus Exposure on Extrarenal Adverse Effects in Adult Renal Transplant Recipients

Abstract

Aims

Tacrolimus has been associated with notable extrarenal adverse effects (AEs), which are unpredictable and impact patient morbidity. The association between model‐predicted tacrolimus exposure metrics and standardized extrarenal AEs in stable renal transplant recipients was investigated and a limited sampling strategy (LSS) was developed to predict steady‐state tacrolimus area under the curve over 12‐hour dosing period (AUC_ss,0‐12hr).

Methods

All recipients receiving tacrolimus and mycophenolic acid ≥6 months completed a 12‐hour cross‐sectional observational pharmacokinetic‐pharmacodynamic study. Patients were evaluated for the presence of individual and composite gastrointestinal, neurological, and aesthetic AEs during the study visit. The associations between AEs and tacrolimus exposure metrics generated from a published population pharmacokinetic model were investigated using a logistic regression analysis in NONMEM 7.3. A LSS was determined using a Bayesian estimation method with the same patients.

Results

Dose‐normalized tacrolimus AUC_ss,0‐12hr and apparent clearance (CL/F) were independently associated with diarrhea, dyspepsia, insomnia, and neurologic AE ratio. Dose‐normalized tacrolimus maximum concentration (C_MAX) was significantly correlated with skin changes and acne. No AE associations were found with trough concentrations. Samples collected at 0‐2, 0‐1‐4 and 0‐1‐2‐4 hours provided a precise and unbiased prediction of tacrolimus AUC (root mean squared prediction error [RMSE] < 10%), which was not well characterized using trough concentrations only (RMSE > 15%).

Conclusions

Several AEs (i.e., diarrhea, dyspepsia, insomnia, and neurologic AE ratio) were associated with tacrolimus dose normalized AUC_ss,0‐12hr, and clearance. Skin changes and acne were associated with dose‐normalized C_MAX concentrations. To facilitate clinical implementation, a LSS was developed to predict AUC_ss,0‐12hr values using sparse patient data to efficiently assess projected immunosuppressive exposure and potentially minimize AE manifestations.

https://ift.tt/2Dw7pDm

Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia

Abstract

Objective

Previous studies have demonstrated that suppression of Nrf2 in Friedreich ataxia tissues contributes to excess oxidative stress, mitochondrial dysfunction, and reduced ATP production. Omaveloxolone, an Nrf2 activator and NF‐kB suppressor, targets dysfunctional inflammatory, metabolic, and bioenergetic pathways. The dose‐ranging portion of this Phase 2 study assessed the safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia patients (NCT02255435).

Methods

Sixty‐nine Friedreich ataxia patients were randomized 3:1 to either omaveloxolone or placebo administered once daily for 12 weeks. Patients were randomized in cohorts of eight patients, at dose levels of 2.5–300 mg/day.

Results

Omaveloxolone was well tolerated, and adverse events were generally mild. Optimal pharmacodynamic changes (noted by changes in ferritin and GGT) were observed at doses of 80 and 160 mg/day. No significant changes were observed in the primary outcome, peak work load in maximal exercise testing (0.9 ± 2.9 W, placebo corrected). At the 160 mg/day dose, omaveloxolone improved the secondary outcome of the mFARS by 3.8 points versus baseline (P = 0.0001) and by 2.3 points versus placebo (P = 0.06). Omaveloxolone produced greater improvements in mFARS in patients that did not have musculoskeletal foot deformity (pes cavus). In patients without this foot deformity, omaveloxolone improved mFARS by 6.0 points from baseline (P < 0.0001) and by 4.4 points versus placebo (P = 0.01) at the 160 mg/day.

Interpretation

Treatment of Friedreich ataxia patients with omaveloxolone at the optimal dose level of 160 mg/day appears to improve neurological function. Therefore, omaveloxolone treatment is being examined in greater detail at 150 mg/day for Friedreich ataxia.

https://ift.tt/2zL07rd

Supervised versus autonomous exercise training in breast cancer patients: A multicenter randomized clinical trial

Our findings on breast cancer patients under aromatase inhibitor treatment indicate that patients achieve higher fitness levels during supervised training compared to unsupervised training.

Abstract

Background

There is a well‐known correlation between obesity, sedentary lifestyle, and breast cancer incidence and outcome. The Arbeitsgemeinschaft Medikamentöse Tumortherapie (AGMT) exercise study was a multicenter, randomized clinical trial and assessed the feasibility and efficacy of physical training in 50 breast cancer patients undergoing aromatase inhibitor treatment.

Methods

Postmenopausal, estrogen receptor‐positive breast cancer patients under aromatase inhibitor treatment were randomized 1:1 to counseling and unsupervised training for 48 weeks (unsupervised arm) or counseling and a sequential training (supervised arm) with a supervised phase (24 weeks) followed by unsupervised physical training (further 24 weeks). Primary endpoint was the individual maximum power output on a cycle ergometer after 24 weeks of exercise. A key secondary endpoint was the feasibility of achieving 12 METh/week (metabolic equivalent of task hours per week).

Results

Twenty‐three patients (92%) in the unsupervised arm and 19 patients (76%) in the supervised arm with early‐stage breast cancer completed the study. After 24 weeks, the supervised arm achieved a significantly higher maximum output in watt (mean 132 ±  standard deviation [SD] 34; 95% confidence interval [CI] 117‐147) compared to baseline (107 ± 25; 95%CI 97‐117; P = 0.012) with a numerically higher output than the unsupervised arm (week 24 115 ± 25; 95%CI 105‐125; P = 0.059). Significantly higher METh/week was reported in the supervised arm compared to the unsupervised arm during the whole study period (week 1‐24 unsupervised: 18.3 (7.6‐58.3); supervised: 28.5 (6.7‐40.1); P = 0.043; week 25‐48; P = 0.041)).

Conclusion

This trial indicates that patients in an exercise program achieve higher fitness levels during supervised than unsupervised training.

https://ift.tt/2T5aRt6

Understanding the Multitarget Pharmacological Mechanism of the Traditional Mongolian Common Herb Pair GuangZao-RouDouKou Acting on Coronary Heart Disease Based on a Bioinformatics Approach

GuangZao and RouDouKou (Fructus Choerospondiatis and Nutmeg, FCN) are one of the most common herb pairs in traditional Mongolian medicine for the treatment of coronary heart disease (CHD). However, evidence for the protective effect of FCN is limited, and its underlying mechanism of action remains unclear. The present study employed a network pharmacology approach to identify the potentially active ingredients and synergistic effects of the herb pair FCN as traditional Mongolian medicine. We predicted the targets of all available FCN ingredients with PharmMapper, SWISS, and SuperPred Server and clustered CHD-related targets from the DrugBank and the OMIM database. We also evaluated the links between herbal ingredients and pharmacological actions to explore the potential mechanism of action of FCN. We found that FCN targets a network of CHD-related key processes, including stress responses, cell adhesion and connections, angiogenesis, cell apoptosis and necrosis, the endocrine system, inflammatory and immune responses, and other biological processes. To confirm the predicted results, we investigated the protective effect of FCN on isoproterenol- (ISO-) induced myocardial ischemia in rats. Pathological assessment indicated that FCN inhibits apoptosis and inflammatory responses involving the myocardium. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting analyses demonstrated the therapeutic effects of FCN on ISO-induced myocardial ischemia rats, possibly via regulating stress and inflammatory responses and inhibiting cardiomyocyte apoptosis. The findings of the present study indicate that bioinformatics combined with experimental verification provide a credible and objective method to elucidate the complex multitarget mechanism of action of FCN.

https://ift.tt/2zIW9PL

HSD17B13 is a Hepatic Retinol Dehydrogenase Associated with Histological Features of Non‐Alcoholic Fatty Liver Disease

Abstract

Non‐alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease. A single nucleotide polymorphism (SNPs), rs6834314, was associated with serum liver enzymes in the general population, presumably reflecting liver fat or injury. We studied rs6834314 and its nearest gene, HSD17B13 (17‐beta hydroxysteroid dehydrogenase 13) to identify associations with histological features of NAFLD, and to characterize the functional role of HSD17B13 in NAFLD pathogenesis. The minor allele of rs6834314 was significantly associated with increased steatosis, but decreased inflammation, ballooning, Mallory‐Denk bodies, and liver enzyme levels in 768 adult Caucasians with biopsy‐proven NAFLD, and with cirrhosis in the general population. We found two plausible causative variants in the HSD17B13 gene. rs72613567, a splice‐site SNP in high linkage with rs6834314 (r²=0.94) generates novel splice variants and shows a similar pattern of association with NAFLD histology. Its minor allele generates simultaneous expression of exon 6‐skipping and G‐nucleotide insertion variants. Another SNP, rs62305723 (encoding a P260S mutation) is significantly associated with decreased ballooning and inflammation. Hepatic expression of HSD17B13 is 5.9‐fold higher (p=0.003) in patients with NAFLD. HSD17B13 is targeted to lipid droplets, requiring the conserved AA22‐28 sequence and AA71‐106 region. The protein has a retinol dehydrogenase (RDH) activity, with enzymatic activity dependent on lipid droplet targeting and co‐factor binding site. The exon 6‐deletion, G‐insertion, and newly‐described naturally‐occurring P260S mutation, all confer loss of enzymatic activity. In conclusion, we demonstrate the association of variants in HSD17B13 with specific features of NAFLD histology, and identify the enzyme as a lipid droplet‐associated RDH. Our data suggest that HSD17B13 plays a role in NAFLD through its enzymatic activity.

This article is protected by copyright. All rights reserved.

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Soccer player revives man with CPR on flight to tournament

Eastern Washington University soccer team player Ashley Valdivieso took immediate action and began chest compressions on the man in the aisle of the plan

https://ift.tt/2FhIIMS

Wound Dehiscence after Posterior Sagittal Anorectoplasty in Children with Anorectal Malformations

Aim of the Study. To assess the frequency of and identify contributing factors to wound dehiscence after posterior sagittal anorectoplasty (PSARP) in children born with anorectal malformations (ARM). Methods. Ethical approval was obtained (DNR 2017/191). Charts of all children with anorectal malformations (ARM) reconstructed with PSARP, limited PSARP, or PSARVUP at a tertiary centre of paediatric surgery between 2001 and 2016 were reviewed. Wound dehiscence within 30 days postoperatively was analysed regarding gender, prematurity, birth weight, type of ARM, other congenital malformations, single- or multistaged reconstruction, age and weight at reconstruction, postoperative antibiotics, and fasting. Multiple regression analysis was performed for risk factors in single-stage PSARP or limited PSARP, presented as odds ratio (OR) with 95% confidence interval (CI). Main Results. Ninety patients were included, of which 53 (59%) were males. Single-staged PSARP was performed in 40 (44%) patients and 50 (56%) had a multistaged reconstruction with a colostomy. Wound dehiscence was significantly more common among patients without a colostomy; 17 (43%) vs. 11 (22%) (p=0.043). In patients with single-stage PSARP, no single factor was identified to increase the risk for wound dehiscence: cardiac malformations (OR 3.73) (95% CI 0.78-17.88), low weight at surgery (OR 1.56) (95% CI 0.36-6.99), antibiotics

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Fixator-assisted nailing of tibial fractures: new surgical technique and presentation of first 30 cases

Publication date: Available online 10 November 2018

Source: Injury

Author(s): Anton A. Semenistyy, Elena A. Litvina EA, Anna G. Fedotova, Chukwuweike Gwam, Andrey N. Mironov

ABSTRACT

Background

Intramedullary nailing is considered a "gold standard" for treatment of tibial shaft fractures. However, some types of fractures are typically considered as "difficult for nailing". This group includes the periarticular fractures, fractures of both bones at the same level, comminuted and segmental fractures of the tibia. Fixator-assisted nailing (FAN) is an effective method treatment of these types of fractures. The main requirements for the ideal reduction device are an ease of its installation and an ability of multiplanar fracture reduction. Fixator-assisted nailing (FAN) with the use of two perpendicular to each other monolateral tubular frames perfectly meets these requirements. In this study we present this new surgical technique and the analysis of first 30 cases.

Methods

A prospective analysis was conducted for 30 patients with "difficult for nailing" tibial fractures treated with fixator-assisted nailing in our institution between September 1^st, 2017, and March 1^st, 2018. The duration of surgery and its different stages, the time of fluoroscopy, difficulties encountered during surgery, were analyzed. Clinical and radiological methods were used to evaluated reduction quality.

Results

In all 30 cases the acceptable reduction was achieved. The mean duration of the surgical procedure was 73.7 ± 3 minutes. The mean duration of fluoroscopy 85.9 ± 4.8 seconds. In 7 cases we faced with technical difficulties, which were successfully addressed.

Conclusion

The described technique of FAN is an effective method for the treatment of "difficult for nailing" tibial fractures. Future multi-centered studies with a larger number of patients are needed to validate our results.

https://ift.tt/2QFkwW0

Accuracy of Massive Transfusion as a Surrogate for Significant Traumatic Bleeding in Health Administrative Datasets

Publication date: Available online 10 November 2018

Source: Injury

Author(s): Alexandre Tran, Marie-Joe Nemnom, Jacinthe Lampron, Maher Matar, Christian Vaillancourt, Monica Taljaard

Abstract

Background

Due to the challenge of identifying need for intervention in bleeding patients, there is a growing interest in prediction modeling. Massive transfusion (MT; 10 or more packed red cells in 24 hours) is the most commonly studied

dependent variable, serving as a surrogate for severe bleeding and its prediction guides the need for intervention. The critical administration threshold (CAT; 3 packed red cells in 1 hour) has been proposed as an alternative. In this study, we aim to compare the classification accuracy of these two surrogates for hemorrhage-related outcomes in health administrative datasets.

Methods

We performed a secondary analysis of major trauma patients from the prospectively collected Ottawa Trauma Registry, from September 2014 to September 2017. We conducted a logistic regression analysis utilizing need for hemostasis or hemorrhagic death as dependent variables. We compared classification accuracy in terms of sensitivity, specificity, positive predictive value, negative predictive value and AUC. CAT + and MT + status is not mutually exclusive.

Results

We studied 890 major trauma patients, including 145 CAT + and 48 MT + patients. CAT + demonstrated a superior association for the composite outcome of 24-hour hemorrhage-related mortality and need for hemostasis (AUC 0.815 vs. 0.644, p < 0.0001). This performance was driven by a substantial difference in sensitivity, noted to be 70.0 % (95% CI 62.1 to 77.9%) for CAT + but only 30.0% (95% CI 22.1 to 37.9%) for MT + . CAT + and MT + demonstrated specificities of 92.9% (95% CI 91.1 to 94.7%) and 98.9% (98.1 to 99.6%) respectively.

Conclusion

This study illustrates the concepts of survivorship and competing risk bias for massive transfusion. Utilizing a composite outcome of need for hemostasis and early hemorrhagic death, we demonstrate that CAT + is more accurate for identifying significantly bleeding patients.

https://ift.tt/2PniOfj

Unravelling the complexity of milk fat globules to tailor bioinspired emulsions providing health benefits: the key role played by the biological membrane

ABSTRACT

Many food products are oil in water (O/W) emulsions. Milk has the specificity to be a natural O/W emulsion secreted by the lactating cells. The milk fat globules are recognized as being efficient conveyors of energy in the form of triacylglycerols and of bioactive molecules specifically provided by the biological membrane, the MFGM, which is the interface with the gastrointestinal tract. However, the MFGM is altered in many processed dairy products and is currently absent from standard infant milk formulas. The objectives of this invited paper are to evaluate whether the specific composition and structure of the MFGM and milk polar lipid assemblies, associated with their nutritional and health benefits, could be used to tailor functional emulsions bioinspired by the MFGM‐coated milk fat globules. Recent knowledge about the structure of the MFGM revealing the heterogeneous distribution of proteins and the formation of ordered lipid domains rich in milk sphingomyelin and cholesterol is presented. The impacts of the unique composition and biophysical properties of milk polar lipids on the structure and potential functions of the MFGM are highlighted. Facing the evidence of both the functional and health benefits provided by the MFGM, the preparation of MFGM‐enriched ingredients from dairy products has recently attracted wide attention. The utilization of MFGM components to tailor the surface of processed lipid droplets in food emulsions and to develop new products providing health benefits is discussed.

https://ift.tt/2JTJBtH

A Phenolic Fraction from Catharanthus roseus L. Stems Decreases Glycemia and Stimulates Insulin Secretion

Catharanthus roseus (L.) G. (C. roseus) is a medicinal plant used traditionally for diabetes mellitus control. Several compounds of an alkaloidal nature have been proposed as hypoglycemic principles. However, little attention has been paid to other compounds in this plant that could also participate in this hypoglycemic activity. This study aimed to analyze the hypoglycemic effect of a polyphenolic fraction from C. roseus, as well as its action on insulin secretion and expression in RINm5F cells. Methods. An alkaloid-free aqueous extract was obtained from C. roseus stems. The hypoglycemic effect of different doses of this extract was evaluated in normal and streptozotocin-induced diabetic mice. This extract was fractionated by bipartition, and the resultant fractions were assessed by their hypoglycemic effects. Subsequently, the fraction with the greater hypoglycemic activity was added to the RINm5F cells, and the expression and secretion of insulin were analyzed. The antioxidant activity was determined by the DPPH method and through chromatographic analysis of the most active fraction by HPLC, using an Econosphere C18 column. Results. The aqueous alkaloid-free extract of C. roseus stems significantly reduced blood glucose in normal and diabetic mice. The fractionation of this extract provided three fractions, one of which (a precipitate) showed significant reductions in glycemia at 6 h (48.1 and 64.5% in normal and diabetic mice, respectively). This precipitate contained phenolic compounds and saponins. Its chromatographic analysis showed that it is formed by several phenolic compounds; gallic acid (0.053%) and chlorogenic acid (0.216%) were identified and quantified. Conclusion. The phenolic fraction of C. roseus containing gallic acid and chlorogenic acid had a hypoglycemic effect that may be explained by an increase in insulin secretion.

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EGFR confers radioresistance in human oropharyngeal carcinoma by activating endoplasmic reticulum stress signaling PERK-eIF2α-GRP94 and IRE1α-XBP1-GRP78.

Related Articles

EGFR confers radioresistance in human oropharyngeal carcinoma by activating endoplasmic reticulum stress signaling PERK-eIF2α-GRP94 and IRE1α-XBP1-GRP78.

Cancer Med. 2018 Nov 09;:

Authors: Zhang M, Han N, Jiang Y, Wang J, Li G, Lv X, Li G, Qiao Q

Abstract
The activation of epidermal growth factor receptor (EGFR) is associated with radioresistance in malignant tumors. Specifically, radiation can destroy endoplasmic reticulum (ER) homeostasis to induce ER stress (ERS). However, the effect of EGFR-mediated regulation of ERS signaling pathway on radiosensitivity has not yet been reported. The present study showed that silencing EGFR increased radiosensitivity of both radiosensitive and radioresistant oropharyngeal squamous cell carcinoma (OSCC) cells by inhibiting ER stress signaling (PERK-eIF2α-GRP94 and IRE1α-XBP1-GRP78). This effect was abolished by pretreatment with EGF, however. In addition, knockdown of EGFR in OSCC cells inhibited DNA double-stand break repair and autophagy while increased radiation-induced apoptosis. Conversely, activating ERS inhibited the aforementioned functions. Furthermore, EGF increased ER stress-independent ERK and AKT signaling upon irradiation of OSCC cells. Immunohistochemical analysis of 80 tissue samples from OSCC patients showed that co-expression of EGFR and PERK was associated with poor prognosis. It thus appears EGFR confers radioresistance in OSCC by activating ER stress signaling. These results suggested that the cooperative effects of radiotherapy and EGFR-targeted inhibitor therapy can be further improved by inhibiting PERK-eIF2α-GRP94 and IRE1α-GRP78 in non-response oropharyngeal carcinoma patients.

PMID: 30414263 [PubMed - as supplied by publisher]

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Correction between the Morphology of Acromion and Acromial Angle in Chinese Population: A Study on 292 Scapulas

Introduction. The acromion is a small section of the scapula which extends anteriorly from the spine of the scapula and the acromial angle (AA) is a prominent bony point at the junction of the lateral border of the acromion and the spine of the shoulder blade. As is well known, the morphology of the acromion and the acromial angle are important as their anatomical variation may contribute to shoulder pathologies. However, few people have studied the morphology and the association between the acromion and the acromial angle. The study explores the acromion and the acromial angle in the anatomical morphology and the association, providing an anatomical basis for clinical diagnosis and treatment. Material and Methods. A total of 292 dry, intact scapulae (152 right, 140 left) were used in the study. Three types of the acromion were already measured, type I(flat shape), type II (curved shape), and type III (hooked shape), respectively. Three types of the acromial angles were also measured in this study, C shape, L shape, and Double Angle shape. Results. The research result shows that C shape and L shape were the most common, while Double Angle shape was the least common. C shape was often related to type I (flat shape) and L shape was often related to type II (curved shape). Conclusions. The presented data provides precise and well-sorted information about the acromion and the acromial angle variation in Chinese population, contributing to diagnosis and treating in shoulder pathology.

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RNA sequencing-based transcriptomic profiles of embryonic lens development for cataract gene discovery

Abstract

Isolated or syndromic congenital cataracts are heterogeneous developmental defects, making the identification of the associated genes challenging. In the past, mouse lens expression microarrays have been successfully applied in bioinformatics tools (e.g., iSyTE) to facilitate human cataract-associated gene discovery. To develop a new resource for geneticists, we report high-throughput RNA sequencing (RNA-seq) profiles of mouse lens at key embryonic stages (E)10.5 (lens pit), E12.5 (primary fiber cell differentiation), E14.5 and E16.5 (secondary fiber cell differentiation). These stages capture important events as the lens develops from an invaginating placode into a transparent tissue. Previously, in silico whole-embryo body (WB)-subtraction-based "lens-enriched" expression has been effective in prioritizing cataract-linked genes. To apply an analogous approach, we generated new mouse WB RNA-seq datasets and show that in silico WB subtraction of lens RNA-seq datasets successfully identifies key genes based on lens-enriched expression. At ≥2 counts-per-million expression, ≥1.5 log₂ fold-enrichment (p < 0.05) cutoff, E10.5 lens exhibits 1401 enriched genes (17% lens-expressed genes), E12.5 lens exhibits 1937 enriched genes (22% lens-expressed genes), E14.5 lens exhibits 2514 enriched genes (31% lens-expressed genes), and E16.5 lens exhibits 2745 enriched genes (34% lens-expressed genes). Biological pathway analysis identified genes associated with lens development, transcription regulation and signaling pathways, among other functional groups. Furthermore, these new RNA-seq data confirmed high expression of established cataract-linked genes and identified new potential regulators in the lens. Finally, we developed new lens stage-specific UCSC Genome Brower annotation tracks and made these publicly accessible through iSyTE (https://research.bioinformatics.udel.edu/iSyTE/) for user-friendly visualization of lens gene expression/enrichment to prioritize genes from high-throughput data from cataract cases.

https://ift.tt/2QzlUJD

The Interaction Effect between Blood Stasis Constitution and Atherosclerotic Factors on Cognitive Impairment in Elderly People

Objective. Blood stasis (BS) constitution represents a tendency to stagnation and positively associates with the severity of atherosclerosis. In this study, we have identified the interaction effect between BS constitution and atherosclerosis on cognitive impairment in the elderly people. Methods. Eligible elderly people ≥65 years old who attended physical examination in the Mawei community of Fuzhou city during 2015 were enrolled in this study. We explored the characteristics of Traditional Chinese Medicine (TCM) constitution and atherosclerotic factors in the normal and cognitive impairment groups and their interaction effect between participants' Minimental State Examination (MMSE) scores in the elderly people. Results. The prevalence of cognitive impairment in the elderly people was 13.0%. Red blood cell (RBC), hemoglobin (HB), ankle brachial index (ABI), brachial-ankle pulse wave velocity (BaPWV), and blood stasis (BS) were significantly different between normal and cognitive impairment group (P

https://ift.tt/2JV3UGX

Endothelial Function in Children with Acute Lymphoblastic Leukemia (ALL) May Reflect the Clinical Outcome

Endothelial dysfunction is a common feature of early complications of hemato-oncologic therapy. The aim of our study was to assess the profile of endothelial function at diagnosis time, then during initial treatment phase of acute lymphoblastic leukemia (ALL), and to verify the presence of its correlation with early clinical outcome (ECO). 28 ALL children and 18 healthy age-matched control ones were recruited. Study group was examined at baseline and at 33rd and 78th day of treatment. At each protocol step the endothelial function was assessed by measurement of sP-selectin (CD62-P), PAI-1(serpinE1), sE-selectin (CD62E), sICAM-1(sCD54), sVCAM-1(sCD106), and VEGF concentrations. Higher baseline sICAM-1 and sVCAM-1 levels and lower sP-selectin and VEGF were observed in children with ALL. sICAM-1, sVCAM-1, and sE-selectin levels were decreasing following the treatment with protocol I. Higher sE-selectin and lower baseline sICAM-1 levels were observed in children treated unsuccessfully. Lower PAI-1 levels were observed in children who survived. Higher baseline sE-selectin levels and lower sICAM-1 and VEGF were observed in children treated unsuccessfully. A decrease in sE-selectin and lower PAI-1 at the 78th day of therapy were associated with better ECO. High baseline VEGF and sE-selectin levels, significant increase in PAI-1, and low initial sICAM-1 levels are prognostics for poorer prognosis in the ALL children.

https://ift.tt/2RLQrE5

Testing Pathological Variation of White Matter Tract in Adult Rats after Severe Spinal Cord Injury with MRI

The purpose of this study was to assess the pathological variation in white matter tracts in the adult severe thoracic contusion spinal cord injury (SCI) rat models combined with in vivo magnetic resonance imaging (MRI), as well as the effect of spared white matter (WM) quantity on hindlimb motor function recovery. 7.0T MRI was conducted for all experimental animals before SCI and 1, 3, 7, and 14 days after SCI. The variation in the white matter tract in different regions of the spinal cord after SCI was examined by luxol fast blue (LFB) staining, NF200 immunochemistry, and diffusion tensor imaging (DTI) parameters, including fraction anisotropy, mean diffusivity, axial diffusion, and radial diffusivity. Meanwhile, Basso-Beattie-Bresnahan (BBB) open-field scoring was performed to evaluate the behavior of the paraplegic hind limbs. The quantitative analysis showed that spared white matter measures assessed by LFB and MRI had a close correlation (R2 = 0.8508). The percentage of spared white matter area was closely correlated with BBB score (R2 = 0.8460). After SCI, spared white matter in the spinal cord, especially the ventral column WM, played a critical role in motor function restoration. The results suggest that the first three days provides a key time window for SCI protection and treatment; spared white matter, especially in the ventral column, plays a key role in motor function recovery in rats. Additionally, DTI may be an important noninvasive technique to diagnose acute SCI degree as well as a tool to evaluate functional prognosis. During the transition from nerve protection toward clinical treatment after SCI, in vivo DTI may serve as an emerging noninvasive technique to diagnose acute SCI degree and predict the degree of spontaneous functional recovery after SCI.

https://ift.tt/2DyN9RK

Low-Dose Methotrexate for the Prevention of Atherosclerotic Events

New England Journal of Medicine, Ahead of Print.


https://ift.tt/2PVc0EU

Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes

New England Journal of Medicine, Ahead of Print.


https://ift.tt/2DgVOY9

Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease

New England Journal of Medicine, Ahead of Print.


https://ift.tt/2Fie2Lv

Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia

New England Journal of Medicine, Ahead of Print.


https://ift.tt/2qDCTiu

Marine n−3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer

New England Journal of Medicine, Ahead of Print.


https://ift.tt/2FftSpX

VITAL Signs for Dietary Supplementation to Prevent Cancer and Heart Disease

New England Journal of Medicine, Ahead of Print.


https://ift.tt/2qDfgXn

Upregulation of mtSSB by interleukin‐6 promotes cell growth through mitochondrial biogenesis‐mediated telomerase activation in colorectal cancer

It is now widely accepted that mitochondrial biogenesis is inhibited in most cancer cells. Interestingly, one of the possible exceptions is col orectal cancer (CRC), in which the content of mitochondria has been found to be higher than in normal colon mucosa. However, to date, the causes and effects of this phenomenon are still unclear. In the present study, we systematically investigated the functional role of mitochondrial single‐strand DNA binding protein (mtSSB), a key molecule in the regulation of mitochondrial DNA (mtDNA) replication, in the mitochondrial biogenesis and CRC cell growth. Our results demonstrated that mtSSB was frequently upregulated in CRC tissues and that upregulated mtSSB was associated with poor prognosis in CRC patients. Furthermore, overexpression of mtSSB promoted CRC cell growth in vitro by regulating cell proliferation. The in vivo assay confirmed these results, indicating that the forced expression of mtSSB significantly increases the growth capacity of xenograft tumors. Mechanistically, the survival advantage conferred by mtSSB was primarily caused by increased mitochondrial biogenesis and subsequent ROS production, which induced telomerase reverse transcriptase (TERT) expression and telomere elongation via Akt/mTOR pathway in CRC cells. In addition, FOXP1, a member of the forkhead box family, was identified as a new transcription factor for mtSSB. Moreover, our results also demonstrate that proinflammatory IL‐6/STAT3 signaling facilitates mtSSB expression and CRC cell proliferation via inducing FOXP1 expression. Collectively, our findings demonstrate that mtSSB induced by inflammation plays a critical role in the regulation of mitochondrial biogenesis, telomerase activation, and subsequent CRC proliferation, providing a strong evidence for mtSSB as drug target in CRC treatment.

This article is protected by copyright. All rights reserved.

https://ift.tt/2qDfFZT

Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes

New England Journal of Medicine, Ahead of Print.


https://ift.tt/2DgVOY9

Low-Dose Methotrexate for the Prevention of Atherosclerotic Events

New England Journal of Medicine, Ahead of Print.


https://ift.tt/2PVc0EU

Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease

New England Journal of Medicine, Ahead of Print.


https://ift.tt/2Fie2Lv

Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia

New England Journal of Medicine, Ahead of Print.


https://ift.tt/2qDCTiu

Marine n−3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer

New England Journal of Medicine, Ahead of Print.


https://ift.tt/2FftSpX

VITAL Signs for Dietary Supplementation to Prevent Cancer and Heart Disease

New England Journal of Medicine, Ahead of Print.


https://ift.tt/2qDfgXn

Opening the Blood-Brain Barrier and Improving the Efficacy of Temozolomide Treatments of Glioblastoma Using Pulsed, Focused Ultrasound with a Microbubble Contrast Agent

Objective. To explore the effects of pulsed, focused, and microbubble contrast agent-enhanced ultrasonography (mCEUS) on blood-brain barrier (BBB) permeability and the efficacy temozolomide for glioblastoma. Methods. Wistar rats (n = 30) were divided into three groups (n = 10 per group) to determine optimal CUES conditions for achieving BBB permeability, as assessed by ultrastructure transmission electron microscopy (TEM) and western blot assays for the tight junction protein claudin-5. Optimized mCEUS effects on BBB permeability were subsequently confirmed with Evans blue staining (2 groups of 10 rats). The glioma cell line 9L was injected into the brain striatum of Wistar rats. After temozolomide chemotherapy, we detected glial fibrillary acidic protein (GFAP) levels in serum by enzyme-linked immunosorbent assay (ELISA) and in brain tissue by western blot, immunocytochemistry, and real-time quantitative polymerase chain reaction (qPCR). Results. BBB permeability was maximized with 1 ml/kg contrast agent mCEUS delivered via 10-min intermittent launches with a 400-ms interval. Evans blue staining confirmed BBB permeability following ultrasonic cavitation in the control group (P

https://ift.tt/2RM3JAI

Plumbagin-Loaded Nanoemulsion Drug Delivery Formulation and Evaluation of Antiproliferative Effect on Prostate Cancer Cells

Background. Plumbagin, a medicinal plant-derived 5-hydroxy-2-methyl-1,4-naphthoquinone, is an emerging drug with a variety of pharmacological effects, including potent anticancer activity. We have previously shown that plumbagin improves the efficacy of androgen deprivation therapy (ADT) in prostate cancer and it is now being evaluated in phase I clinical trial. However, the development of formulation of plumbagin as a compound with sparing solubility in water is challenging. Methods. We have formulated plumbagin-loaded nanoemulsion using pneumatically controlled high pressure homogenization of oleic acid dispersions with polyoxyethylene (20) sorbitan monooleate as surfactant. Nanoemulsion formulations were characterized for particle size distribution by dynamic light scattering (DLS). The kinetics of in vitro drug release was determined by equilibrium dialysis. Anticancer activity toward prostate cancer cells PTEN-P2 was assessed by MTS (Owen's reagent) assay. Results. Particle size distribution of nanoemulsions is tunable and depends on the surfactant concentration. Nanoemulsion formulations of plumbagin with 1-3.5% (w/w) of surfactant showed robust stability of size distribution over time. Plumbagin-loaded nanoemulsion with average hydrodynamic diameter of 135 nm showed exponential release of plumbagin with a half-life of 6.1 h in simulated gastric fluid, 7.0 h in simulated intestinal fluid, and displayed enhanced antiproliferative effect toward prostate cancer cells PTEN-P2 compared to free plumbagin. Conclusion. High drug-loading capacity, retention of nanoparticle size, kinetics of release under simulated physiological conditions, and increased antiproliferative activity indicate that oleic-acid based nanoemulsion formulation is a suitable delivery system of plumbagin.

https://ift.tt/2DxVVPH

Immunoglobulin E and G Levels in Predicting Minimal Change Disease before Renal Biopsy

Purpose. The diagnosis of minimal change disease in adults relies mainly on renal biopsy, but this procedure is not without complications. Despite the advancements in technique of percutaneous renal biopsy, biopsy-related complications still occur. Bleeding is one of the major complications, which may lead to hemodynamic instability and, sometimes, even death. Thus, we developed a model to predict MCD for high-risk patients unsuitable for renal biopsy. Methods. We enrolled 142 patients with nephrotic syndrome who received renal biopsy between October 2007 and April 2011 at one tertiary medical center in this study. Demographic, clinical, and prebiopsy laboratory variables were retrospectively recorded and analyzed. Results. The overall prevalence of MCD was 26.8%. Age, hemoglobin levels, 24-hour urine protein, immunoglobulin (Ig) G, and IgE differed significantly between the MCD and non-MCD groups. Logistic regression analysis showed a significant increase in the risk of developing MCD as the number of Ig risk factors, namely, IgG 110 mg/dl, increased. Having both risk factors significantly increased the chances of receiving a diagnosis of MCD (by 31.84-fold, P =.007) compared with having neither. Combining the aforementioned clinical model and the 2 Ig risk factors was the best in predicting the diagnosis of MCD, with the area under a receiver-operating characteristic curve of 0.91. Conclusions. Combining clinical model and this 2 Ig risk factors provides physicians simple and valuable clinical markers to diagnose MCD.

https://ift.tt/2RM3rcY

First Ukrainian Growth References for Height, Weight, and Body Mass Index for Children and Adolescents Aged 7 to 18 Years

Introduction. To date, growth centiles of children and adolescents have not been created in Ukraine. Therefore, the aim of this study was to construct reference growth charts for height, weight, and body mass index (BMI) of Ukrainian school-aged children and to compare them with World Health Organization references from 2007 for children's BMI. Material and Methods. Among the representative sample of 13,712 students (aged 7 to 18 years) who were included in this study, 6,582 (48%) were boys and 7,130 (52%) were girls. Assessments of height, body mass, and BMI of participants were performed. Reference charts were developed using LMS models within the ChartMaker lms program. Results. We present first growth references for height, weight, and body mass index for Ukrainian children and adolescents aged 7 to 18 years. The younger Ukrainian pediatric population (7-13 years) was heavier than population reported in the multiethnic WHO references, while the older (13-18 years) had lower body weight comparing to the same references from WHO. Conclusions. The constructed reference growth charts are a benchmark for following secular trends in Ukraine and are also an optimal clinical tool for health care. We recommend national implementation of the Ukrainian reference growth charts for anthropometric measurements.

https://ift.tt/2Dz6kKW

Serum biochemical reference values of Kyrgyz donkeys ( Equus asinus )

Abstract

The aim of the study was to determine the some serum biochemical values of Kyrgyz donkeys and present the reference values. Fifty (50) healthy donkeys in different ages (6–24 months, 2–15 years, and > 15 years old) and gender (male and female) were clinically examined and blood samples were taken. Serum triglycerides (TG), creatine phosphokinase (CPK), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), total bilirubin (TBil), total protein (TP), albumin (Alb), creatinine (Creat), urea (Urea), amylase (Amy), lipase (Lip), calcium (Ca), magnesium (Mg), phosphorus (P), cholesterol (Chol), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), glucose (Glu), very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and indirect bilirubin (InBil) values were determined. Serum Ca values were found different (P < 0.05) among the age groups (younger, middle aged and older). TBil values were detected different between sex groups (P < 0.01). Serum creat values were determined higher in male donkeys than females (P < 0.01). Serum LDL values were found higher in younger than older donkeys (P < 0.05). It was the first report for donkeys according to LDL values. Serum CPK values were also detected higher in male donkeys and found significantly difference between younger and middle aged donkeys (P < 0.05). Consequently, some serum biochemical values of Kyrgyz donkeys were determined and advised as reference values for Tong region of Kyrgyzstan.

https://ift.tt/2FhqXgs