Risk of hypertension with ramucirumab-based therapy in solid tumors: data from a literature based meta-analysis

Summary

Ramucirumab is a monoclonal antibody against Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) approved for the treatment of several solid tumours. As shown in recent trials results, new-onset hypertension is one of the most frequent adverse events associated with ramucirumab therapy. Recent studies looked at the quantification of the risk of hypertension in patients receiving other anti-angiogenesis medications. We conducted a meta-analysis of randomized clinical trials with the aim to investigate the incidence and quantify the risk of new-onset hypertension of any grade in patients treated with ramucirumab. Our research suggests that hypertension is frequently associated with ramucirumab therapy, with an OR of 3.60 for any grade of hypertension and an even stronger correlation with grade 3–4 hypertension (OR 4.16). These data suggest that a strict monitoring, as well as early intervention protocols, are recommended in patients receiving the drug.

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Diclofenac sex-divergent drug-drug interaction with Sunitinib: pharmacokinetics and tissue distribution in male and female mice

Summary

Coadministration of diclofenac and sunitinib, tyrosine kinase inhibitor, led to sex-divergent pharmacokinetic drug-drug interaction outcomes. Male and female mice were administered 60 mg/kg PO sunitinib alone (control groups) or with 30 mg/kg PO diclofenac. Sunitinib concentration in plasma, brain, kidney and liver were determined by HPLC and non-compartmental pharmacokinetic parameters calculated. In male mice, diclofenac decreased AUC_0→∞ 38% in plasma (p < 0.05) and 24% in liver (p < 0.001) and 23% in kidney (p < 0.001). However, AUC_0→∞ remained unchanged in plasma and increased 41% in kidney (p < 0.001) of female mice. In brain, sunitinib exposure decreased 46% (p < 0.001) and 32% (p < 0.001) in male and female brain respectively. Mechanistically, diclofenac increased the liver uptake efficiency in male (27%, p < 0.05) and female (48%, p < 0.001) mice and 30% in kidney (p < 0.05) of male mice, probably owing to effects on efflux transporters. Sunitinib displayed sex-divergent DDI with diclofenac with probable clinical translatability due to potential different effects in male and female patients requiring careful selection of the NSAID and advanced TDM to implement a personalized treatment.

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Effects of histone deacetylase inhibitory prodrugs on epigenetic changes and DNA damage response in tumor and heart of glioblastoma xenograft

Summary

The histone deacetylase (HDAC) inhibitory prodrugs of butyric (AN7) and valproic (AN446) acids, which release the active acids upon metabolic degradation, were studied examining their differential effects on the viability, HDAC inhibitory activity and the DNA damage response (DDR), in glioblastoma cell and normal human astrocytes (NHAs). In xenografts of glioblastoma, AN7 or AN446 given or the combination of each of them with Dox augmented the anticancer activity of Dox and protected the heart from its toxicity. In order to determine the processes underlying these opposing effects, the changes induced by these treatments on the epigenetic landscape, the DDR, and fibrosis were compared in tumors and hearts of glioblastoma xenografts. The potency of AN7 and AN446 as HDAC inhibitors was correlated with their effects on the viability of the cancer and non-cancer cells. The prodrugs affected the epigenetic landscape and the DDR in a tissue-specific and context-dependent manner. Findings suggest that the selectivity of the prodrugs could be attributed to their different effects on histone modification patterns in normal vs. transformed tissues. Further studies are warranted to substantiate the potential of AN446 as a new anticancer drug for glioblastoma patients.

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Lung cancer and β-glucans: review of potential therapeutic applications

Summary

The potential of natural substances with immunotherapeutic properties has long been studied. β-glucans, a cell wall component of certain bacteria and fungi, potentiate the immune system against microbes and toxic substances. Moreover, β-glucans are known to exhibit direct anticancer effects and can suppress cancer proliferation through immunomodulatory pathways. Mortality of lung cancer has been alarmingly increasingly worldwide; therefore, treatment of lung cancer is an urgent necessity. Numerous researchers are now dedicated to using β-glucans as a therapy for lung cancer. In the present attempt, we have reviewed the studies addressing therapeutic effects of β-glucans in primary and metastatic lung cancer published in the time period of 1991–2016.

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Characteristics of Xanthosoma sagittifolium roots during cooking, using physicochemical analysis, uniaxial compression, multispectral imaging and low field NMR spectroscopy

Abstract

To effectively promote the industrial utilization of cocoyam (Xanthosoma sagittifolium) roots for enhanced food sustainability and security, there is a need to study their molecular, mechanical and physicochemical properties in detail. The physicochemical and textural characteristics of the red and white varieties of cocoyam roots were thus analysed by low field nuclear magnetic resonance relaxometry, multispectral imaging, uniaxial compression testing, and relevant physicochemical analysis in the current study. Both varieties had similar dry matter content, as well as physical and mechanical properties. However, up to four fast-interacting water populations were observed in the roots, dependent on the root variety and their degree of gelatinization during cooking. Changes in the relaxation parameters indicated weak gelatinization of starch at approximately 80 °C in both varieties. However, shorter relaxation times and a higher proportion of restricted water in the white variety indicated that this variety was slightly more sensitive towards gelatinization. A strong negative correlation existed between dry matter and all multispectral wavelengths >800 nm, suggesting the potential use of that spectral region for rapid analysis of dry matter and water content of the roots. The small, but significant differences in the structural and gelatinization characteristics of the two varieties indicated that they may not be equally suited for further processing, e.g. to flours or starches. Processors thus need to choose their raw materials wisely dependent on the aimed product characteristics. However, the spectroscopic methods applied in the study were shown to be effective in assessing important quality attributes during cooking of the roots.

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Lipase catalyzed transesterification of ethyl butyrate synthesis in n -hexane— a kinetic study

Abstract

Kinetics of lipase catalyzed transesterification of ethyl caprate and butyric acid was investigated. The objective of this work was to propose a reaction mechanism and develop a rate equation for the synthesis of ethyl butyrate by transesterification using surfactant coated lipase from Candida rugosa. The reaction rate could be described in terms of Michaelis–Menten equation with a Ping-Pong Bi–Bi mechanism and competitive inhibition by both the substrates. The values of kinetic parameters computed were V_max = 2.861 μmol/min/mg; K_m(acid) = 0.0746 M; K_m(ester) = 0.125 M; K_i acid = 0.450 M. This study indicated a competitive enzyme inhibition by butyric acid during lipase catalyzed transesterification reaction. Experimental observations had clearly indicated that the substrates as well as product act as dead-end inhibitors.

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Effect of unsaponifiable matter extracted from Pistacia khinjuk fruit oil on the oxidative stability of olive oil

Abstract

The present study was carried out to investigate the improvement of oxidative stability of refined olive oil using various concentrations of unsaponifiable matters extracted from Pistacia khinjuk fruit oil (UFO). For further elucidation of UFO antioxidative power, tertbutylhydroquinone (TBHQ) was used in an olive oil sample, too. Oxidative stability of olive oil samples without and with different levels of UFO (50, 100, 250, 500, 750 and 1000 ppm) and TBHQ (100 ppm) were studied via evaluation of conjugated diene value, carbonyl value, oil/oxidative stability index, acid value and total tocopherol (TT) contents through 8 h thermal process at 170 °C. Results obtained by oxidative stability assays revealed that the highest antioxidative activity of olive oil was obtained by 100 ppm of UFO, followed using 100, 250, 500, 750, and 1000 ppm of UFO and 100 ppm TBHQ, respectively. Evaluation of the relationship between oxidative stability indexes and TT changes indicated a strong correlation (R² = 0.9718) between mean relative resistance to oxidation and relative resistance to TT reduction during thermal process. By promotion of relative resistance to TT reduction, olive oil samples' relative resistance to oxidation was enhanced exponentially; implying importance of TT in promotion of oxidative stability of edible oils. The results obtained in this study showed that UFO has higher antioxidative activity compared to TBHQ; thus UFO can be considered as a natural antioxidant with ideal antioxidative activity.

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Component analysis of nutritionally rich chloroplasts: recovery from conventional and unconventional green plant species

Abstract

A study of the literature indicates that chloroplasts synthesise a range of molecules, many of which have nutritional value for humans, but the nutritional credentials of chloroplasts recovered from plant cells are not established. Chloroplast-rich-fractions (CRFs) were prepared from green plant species and the macro- and micro-nutrient composition compared with the whole leaf materials (WLMs). The results indicated that, on a dry weight basis, CRF material from a range of green biomass was enriched in lipids and proteins, and in a range of micronutrients compared with the WLM. Vitamins E, pro-vitamin A, and lutein were all greater in CRF preparations. Of the minerals, iron was most notably concentrated in CRF. Spinach CRFs possessed the highest α-tocopherol [62 mg 100 g⁻¹, dry weight (DW)], β-carotene (336 mg 100 g⁻¹ DW) and lutein (341 mg 100 g⁻¹ DW) contents, whilst grass CRFs had the highest concentration of alpha-linolenic acid (ALA) (69.5 mg g⁻¹). The higher concentrations of α-tocopherol, β-carotene, lutein, ALA and trace minerals (Fe and Mn) in CRFs suggested their potential use as concentrated ingredients in food formulations deficient in these nutrients.

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The growing season impacts the accumulation and composition of flavonoids in grape skins in two-crop-a-year viticulture

Abstract

The influence of growing season (winter vs. summer) on the flavonoid accumulation and composition was studied in the skins of three grape cultivars for two consecutive years under a two-crop-a-year viticulture practice in Southwest China. The total anthocyanin, flavonol and flavan-3-ol contents in winter berry skins were significantly higher than those in summer berry skins for 'Kyoho' and 'Muscat Hamburg'. Reversely, the content of anthocyanin in 'NW196' winter berry was lower than summer berry. However, the percentage of diglycosylated, trihydroxylated, methylated, and acylated anthocyanins, trihydroxylated and methylated flavonols, and flavan-3-ol polymers were higher in the summer berry skins than the winter berry skins among all the three grape cultivars. Winter climatic conditions were favorable to flavonoid accumulation for the non native grapes 'Kyoho' and 'Muscat Hamburg', while the summer climatic conditions were beneficial to anthocyanin accumulation for 'NW196' that has 50% genetic background from a local wild grape species Vitis quinquangularis. These seasonal variations of flavonoid accumulations and compositions in the grape skins were primarily contributed by different climatic factors, such as temperature, solar radiation, and rainfall.

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Bullous pemphigoid following the replacement of vildagliptin with anagliptin

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Protect yourself from skin cancer - The Daily Times

Protect yourself from skin cancer The Daily Times Women ages 49 and under have a higher probability of developing melanoma than any other cancer except breast and thyroid cancers. The survival rate for persons diagnosed early with melanoma is about 98 percent. But the survival rate falls to 17 percent ... and more »

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Identification of patients with cancer with a high risk to develop delirium

Abstract

Delirium deteriorates the quality of life in patients with cancer, but is frequently underdiagnosed and not adequately treated. In this study, we evaluated the occurrence of delirium and its risk factors in patients admitted to the hospital for treatment or palliative care in order to develop a prediction model to identify patients at high risk for delirium. In a period of 1.5 years, we evaluated the risk of developing delirium in 574 consecutively admitted patients with cancer to our academic oncology department with the Delirium Observation Screening Scale. Risk factors for delirium were extracted from the patient's chart. A delirium prediction algorithm was constructed using tree analysis, and validated with fivefold cross-validation. A total of 574 patients with cancer were acutely (42%) or electively (58%) admitted 1733 times. The incidence rate of delirium was 3.5 per 100 admittances. Tree analysis revealed that the predisposing factors of an unscheduled admittance and a metabolic imbalance accurately predicted the development of delirium. In this group the incidence rate of delirium was 33 per 100 patients (1:3). The AUC of the model was 0.81, and 0.65 after fivefold cross-validation. We identified that especially patients undergoing an unscheduled admittance with a metabolic imbalance do have a clinically relevant high risk to develop a delirium. Based on these factors, we propose to evaluate preventive treatment of these patients when admitted to the hospital in order to improve their quality of life.

The predisposing factors of an unscheduled admittance and a metabolic imbalance accurately predict the development of delirium in patients with cancer (delirium risk 1:3). This prediction algorithm for delirium that can be easily implemented in daily clinical practice should be evaluated for the potential benefit of preventive treatment of patients with cancer who are prone to develop delirium.

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Peru's Alberto Fujimori is hospitalized due to heart trouble - The Japan Times

The Japan Times

Peru's Alberto Fujimori is hospitalized due to heart trouble The Japan Times He has also been in and out of the hospital with back and stomach trouble and growths on his tongue, which has been operated on several times for cancer. Peruvian law allows the president to offer pardons for Independence Day — celebrated on July 28 ... and more »

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Pacifier

Pacifier: An artificial nipple, usually made of plastic, upon which an infant can suck to gain some solace and quiet down. A pacifier is called by other names in other countries including a "dummy" in the U.K.

Pacifiers have been claimed to cause early weaning. However, a study (JAMA, July 18, 2001) was done of women who were planned to breastfeed for at least 3 months. All of the women were told how to soothe a crying or fussy child, but one group of women was told to avoid giving their baby a pacifier. Advising women not to give their baby a pacifier had no effect. The rate of early weaning was the same in both groups. The use of a pacifier does not cause early weaning.

MedTerms (TM) is the Medical Dictionary of MedicineNet.com.
We Bring Doctors' Knowledge To You

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Structural Heteropolysaccharide Adhesion to the Glycocalyx of Visceral Mesothelium

Tissue Engineering Part A , Vol. 0, No. 0.


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Impact of the pretreatment Glasgow prognostic score on treatment tolerance, toxicities, and survival in patients with advanced head and neck cancer undergoing concurrent chemoradiotherapy

Abstract

Background

The purpose of this study was to evaluate the impact of the pretreatment Glasgow prognostic score on treatment-related toxicities, tolerance, and survival in patients with advanced head and neck cancers undergoing concurrent chemoradiotherapy (CRT).

Methods

We retrospectively analyzed and compared the clinical characteristics, toxicities, and survival of 143 patients with stages III, IVA, and IVB head and neck cancer treated with concurrent CRT according to their Glasgow prognostic score between 2007 and 2010.

Results

The Glasgow prognostic score was correlated with advanced tumor stage and T/N classification. Patients with a higher Glasgow prognostic score were less likely to tolerate concurrent CRT, experienced more weight loss, required tube feeding support more frequently, and had higher percentage of grade ≥3 hematological toxicities, sepsis, and toxic death. Patients with a Glasgow prognostic score of 0 had better overall and recurrence-free survival than those with a Glasgow prognostic score of 1 or 2.

Conclusion

Pretreatment Glasgow prognostic score predicts treatment tolerance, toxicity, and survival in patients with advanced head and neck cancer undergoing concurrent CRT.

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A Retrospective Analysis of Central Physician Appointment System Data in a Tertiary Health Center in Turkey

Telemedicine and e-Health , Vol. 0, No. 0.


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Why and When do Patients Use e-Consultation Services? The Trust and Resource Supplementary Perspectives

Telemedicine and e-Health , Vol. 0, No. 0.


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Role of oxidative stress in cardiovascular disease outcomes following exposure to ambient air pollution

Publication date: September 2017
Source:Free Radical Biology and Medicine, Volume 110
Author(s): Frank J. Kelly, Julia C. Fussell
Exposure to ambient air pollution is associated with adverse cardiovascular outcomes. These are manifested through several, likely overlapping, pathways including at the functional level, endothelial dysfunction, atherosclerosis, pro-coagulation and alterations in autonomic nervous system balance and blood pressure. At numerous points within each of these pathways, there is potential for cellular oxidative imbalances to occur. The current review examines epidemiological, occupational and controlled exposure studies and research employing healthy and diseased animal models, isolated organs and cell cultures in assessing the importance of the pro-oxidant potential of air pollution in the development of cardiovascular disease outcomes. The collective body of data provides evidence that oxidative stress (OS) is not only central to eliciting specific cardiac endpoints, but is also implicated in modulating the risk of succumbing to cardiovascular disease, sensitivity to ischemia/reperfusion injury and the onset and progression of metabolic disease following ambient pollution exposure. To add to this large research effort conducted to date, further work is required to provide greater insight into areas such as (a) whether an oxidative imbalance triggers and/or worsens the effect and/or is representative of the consequence of disease progression, (b) OS pathways and cardiac outcomes caused by individual pollutants within air pollution mixtures, or as a consequence of inter-pollutant interactions and (c) potential protection provided by nutritional supplements and/or pharmacological agents with antioxidant properties, in susceptible populations residing in polluted urban cities.

Graphical abstract

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The mitochondrial unfolded protein response: signaling from the powerhouse [Signal Transduction]

Mitochondria are multifaceted and indispensable organelles required for cell performance. Accordingly, dysfunction to mitochondria can result in cellular decline and possibly the onset of disease. Cells use a variety of means to recover mitochondria and restore homeostasis including the activation of retrograde pathways such as the mitochondrial unfolded protein response (UPRmt). In this minireview, we will discuss how cells adapt to mitochondrial stress through UPRmt regulation. Furthermore, we will explore the current repertoire of biological functions that are associated with this essential stress response pathway.

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Increased levels of Gab1 and Gab2 adaptor proteins skew IL-4 signaling toward M2 macrophage-driven pulmonary fibrosis in mice [Molecular Bases of Disease]

M2-polarized macrophages, also known as alternatively activated macrophages, have long been associated with pulmonary fibrosis; however, the mechanism has not been fully defined. Gab1 and Gab2 proteins belong to the GAB family of adaptors and are integral components of the signal specificity in response to various extracellular stimuli. In this report, we found that levels of both Gab1 and Gab2 were elevated in M2-polarized macrophages isolated from bleomycin-induced fibrotic lungs. In vitro Gab1/2 deficiency in bone marrow-derived macrophages abrogated IL-4-mediated M2 polarization. Furthermore, in vivo conditional removal of Gab1 (Gab1MyKO) and germline knockout of Gab2 (Gab2-/-) in macrophages prevented a bias toward the M2 phenotype and attenuated bleomycin-induced fibrotic lung remodeling. In support of these observations, Gab1/2 were involved in responses predominated by IL-4 signaling, an essential determinant for macrophage M2 polarization. Further investigation revealed that both Gab1/2 are recruited to the IL-4 receptor, synergistically enhancing downstream signal amplification but conferring IL-4 signal preference. Mechanistically, the loss of Gab1 attenuated AKT activation, whereas the absence of Gab2 suppressed STAT6 activation in response to IL-4 stimulation, both of which are commonly attributed to M2-driven pulmonary fibrosis in mice. Taken together, these observations define a non-redundant role of GAB docking proteins in M2 polarization, adding critical insights into the pathogenesis of idiopathic pulmonary fibrosis.

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Clock1a affects mesoderm development and primitive hematopoiesis by regulating Nodal-Smad3 signalings in the zebrafish embryo [Gene Regulation]

Circadian clock and Smad2/3/4-mediated Nodal signaling regulate multiple physiological and pathological processes. However, it remains unknown whether Clock directly crosstalk with Nodal signaling and how this would regulate embryonic development. Here, we show that Clock1a coordinated mesoderm development and primitive hematopoiesis in zebrafish embryos by directly up-regulating Nodal-Smad3 signaling. We found that Clock1a is expressed both maternally and zygotically throughout early zebrafish development. We also noted that Clock1a alterations produce embryonic defects with shortened body length, lack of the ventral tail fin or partial defect of the eyes. Clock1a regulates the expression of the mesodermal markers ntl, gsc, and eve1 and of the hematopoietic markers scl, lmo2 and fli1a. Biochemical analyses revealed that Clock1a stimulates Nodal signaling by increasing expression of Smad2/3/4. Mechanistically, Clock1a activates the smad3a promoter via its E-box1 element (CAGATG). Taken together, these findings provide mechanistic insight into the role of Clock1a in the regulation of mesoderm development and primitive hematopoiesis via modulation of Nodal-Smad3 signaling and indicate that Smad3a is directly controlled by the circadian clock in zebrafish.

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Using Simulation to Improve Systems

Attempts to understand and improve health care delivery often focus on the characteristics of the patient and the characteristics of the health care providers, but larger systems surround and integrate with patients and providers. Components of health care delivery systems can support or interfere with efforts to provide optimal health care. Simulation in situ, involving real teams participating in simulations in real care settings, can be used to identify latent safety threats and improve the work environment while simultaneously supporting participant learning. Thoughtful planning and skilled debriefing are essential.

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Using Simulation to Improve Systems

Attempts to understand and improve health care delivery often focus on the characteristics of the patient and the characteristics of the health care providers, but larger systems surround and integrate with patients and providers. Components of health care delivery systems can support or interfere with efforts to provide optimal health care. Simulation in situ, involving real teams participating in simulations in real care settings, can be used to identify latent safety threats and improve the work environment while simultaneously supporting participant learning. Thoughtful planning and skilled debriefing are essential.

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Effects of feeding alfalfa stemlage or wheat straw for dietary energy dilution on nutrient intake and digestibility, growth performance, and feeding behavior of Holstein dairy heifers

Publication date: Available online 6 July 2017
Source:Journal of Dairy Science
Author(s): Huawei Su, Matt S. Akins, Nancy M. Esser, Robin Ogden, Wayne K. Coblentz, Kenneth F. Kalscheur, Ron Hatfield
Feeding high-quality forage diets may lead to excessive weight gains and over-conditioning for dairy heifers. Restriction of energy density and dry matter intake by using low-energy forages, such as straw, is a good approach for controlling this problem. Alfalfa stems contain high fiber and moderate protein content and have the potential to be used to replace straw to reduce dietary energy. The objective of this study was to compare nutrient intakes, digestibilities, growth performance, and feeding behaviors of dairy heifers offered an alfalfa silage/corn silage high energy diet (HE; 13.1% crude protein, 65.4% total digestible nutrients, 39.7% neutral detergent fiber) with 2 energy-diluted diets that replaced various proportions of the corn or alfalfa silages with either alfalfa stemlage (STM; 12.6% crude protein, 59.1% total digestible nutrients, 46.4% neutral detergent fiber) or chopped wheat straw (WS; 12.6% crude protein, 61.9% total digestible nutrients, 43.7% neutral detergent fiber). Seventy-two pregnant Holstein heifers (16.8 ± 1.3 mo) were stratified into 3 blocks (24 heifers/block) by initial body weight (light, 440 ± 18.0 kg; medium, 486 ± 18.6 kg; heavy, 534 ± 25.1 kg), with each block composed of 3 pens (8 heifers/pen), with diets assigned randomly to 1 pen within the block. Diets were offered in a 56-d feeding trial. Both dry matter intake and energy intake were decreased with the addition of low-energy forages to the diets, but no differences in dry matter intake were observed across diluted diets. Digestibility of dry matter, organic matter, neutral detergent fiber, and apparent N were greater for HE compared with diluted diets, and for WS compared with STM. Total body weight gain (74 vs. 56 kg) and average daily gain (1.32 vs. 1.00 kg/d) were greater for heifers offered HE compared with diluted diets. Feed efficiency tended to be less for heifers offered the diluted diets compared with HE (10.7 vs. 8.6 kg of feed/kg of gain). Heifers did not sort for or against particles when offered HE. However, increased sorting behavior was observed for diluted diets. Compared with ad libitum feeding dairy heifers a diet with high nutrient content forages (corn silage and alfalfa silage), use of diet diluted with alfalfa stemlage or wheat straw is an effective feeding management strategy to control total daily dry matter and energy intake by increasing gut fill, and maintain desirable body condition and growth rates, even though the diluted diets had greater sortability.



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Technical note: Nontargeted detection of adulterated plant proteins in raw milk by UPLC-quadrupole time-of-flight-mass spectrometric proteomics combined with chemometrics

Publication date: Available online 6 July 2017
Source:Journal of Dairy Science
Author(s): Weiying Lu, Jie Liu, Boyan Gao, Xiaxia Lv, Liangli (Lucy) Yu
We built and validated a chemometric model to detect possible milk adulteration with plant proteins. Specifically, we extracted proteins in raw milk, treated with tryptic digestion, and obtained peptide fingerprints by UPLC-quadrupole time-of-flight-mass spectrometry with proteomics to differentiate authentic milks from their counterparts adulterated with nonmilk proteins. This approach is able to detect soybean and pea powder-adulterated milks at as low as 1% (wt/wt). Additionally, we obtained the characteristic peptide sequences for milk authentication by principal component analysis. The prediction accuracies for milk authentication by partial least-squares-discriminant analysis were greater than 95%. These results indicated that peptide fingerprints with the chemometric analysis could be successfully applied for milk quality control.



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Effects of depleting ionic strength on 31P nuclear magnetic resonancespectra of micellar casein during membrane separation and diafiltration of skim milk

Publication date: Available online 6 July 2017
Source:Journal of Dairy Science
Author(s): Mattia Boiani, Padraig McLoughlin, Mark A.E. Auty, Richard J. FitzGerald, Phil M. Kelly
Membrane separation processes used in the concentration and isolation of micellar casein-based milk proteins from skim milk rely on extensive permeation of its soluble serum constituents, especially lactose and minerals. Whereas extensive literature exists on how these processes influence the gross composition of milk proteins, we have little understanding of the effects of such ionic depletion on the core structural unit of micellar casein [i.e., the casein phosphate nanocluster (CPN)]. The ³¹P nuclear magnetic resonance (NMR) is an analytical technique that is capable of identifying soluble and organic forms of phosphate in milk. Thus, our objective was to investigate changes to the ³¹P NMR spectra of skim milk during microfiltration (MF) and diafiltration (DF) by tracking movements in different species of phosphate. In particular, we examined the peak at 1.11 ppm corresponding to inorganic phosphate in the serum, as well as the low-intensity broad signal between 1.5 and 3.0 ppm attributed to casein-associated phosphate in the retentate. The MF concentration and DF using water caused a shift in the relevant ³¹P NMR peak that could be minimized if orthophosphate was added to the DF water. However, this did not resolve the simultaneous change in retentate pH and increased solubilization of micellar casein protein. The addition of calcium in combination with orthophosphate prevented micellar casein solubilization and simultaneously contributed to preservation of the CPN structure, except for overcorrection of retentate pH in the acidic direction. A more complex DF solution, involving a combination of phosphate, calcium, and citrate, succeeded in both CPN and micellar casein structure preservation while maintaining retentate pH in the region of the original milk pH. The combination of ³¹P NMR as an analytical technique and experimental probe during MF/DF processes provided useful insights into changes occurring to CPN while retaining the micellar state of casein.



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Experimental evidence for previously unclassified calcium phosphate structures in the casein micelle

Publication date: Available online 6 July 2017
Source:Journal of Dairy Science
Author(s): J.P. Hindmarsh, P. Watkinson
¹H-³¹P Cross-polarization magic angle spinning (CP-MAS) measurements of 40-d-old Mozzarella cheese and 20 mM EDTA-treated casein micelles revealed that each sample had immobile phosphorus with the same spectral pattern, which did not match that of native casein micelles. To identify the immobile phosphorus bodies, ¹H-³¹P CP-MAS spectra and cross-polarization kinetics measurements were undertaken on native casein micelles, EDTA-chelated casein micelles, and reference samples of β-casein and hydroxyapatite. The results showed that the immobile phosphorus bodies in the mature Mozzarella cheese had the following characteristics: they are immobile phosphoserine residues (not colloidal calcium phosphate); they are not the product of phosphoserine to colloidal calcium phosphate bridging; the phosphate is complexed to calcium; their rigidity is localized to a phosphorus site; their rigidity and bond coupling is unaffected by protein hydration; and the immobile bodies share a narrow range of bond orientations. Combining these observations, the best explanation of the immobile phosphorus bodies is that bonding structures of phosphorus-containing groups and calcium exist within the casein micelle that are not yet clearly classified in the literature. The best candidate is a calcium-bridged phosphoserine-to-phosphoserine linkage, either intra- or inter-protein.



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Influence of food deprivation on intravenous glucose tolerance test traits in Holstein Friesian heifers

Publication date: Available online 6 July 2017
Source:Journal of Dairy Science
Author(s): L. Antonio González-Grajales, Laura Pieper, Joachim Kremer, Rudolf Staufenbiel
Glucose is essential for numerous cellular functions due to its involvement in energy supply from early development to adulthood. In the lactating cow, glucose demands by the mammary gland significantly increase to support milk production when compared with other tissues. Thus, insufficient blood glucose levels might predispose dairy cows to metabolic disturbances. The intravenous glucose tolerance test (ivGTT) is a suitable tool to characterize glucose metabolism and insulin responses, but results must be reliable and repeatable. One factor influencing ivGTT is food deprivation period, which has been considered as an obligatory requirement before conduction of glucose tolerance studies in monogastric species, whereas it has been permissive in ruminants. The objective of this study was to determine the influence of 5 fasting periods (0, 12, 24, 36, and 48 h) on ivGTT traits and insulin responses in German Holstein heifers. A total of 140 tests were conducted in 28 females aged 12 to 19 mo. Blood samples were collected every 7 min within 1 h. Assessed glucose and insulin parameters included basal serum glucose and insulin concentration, maximum glucose and insulin concentration obtained between min 7 to 21, and concentrations at min 63 (last sampling) relative to glucose administration, glucose area equivalent (GA), glucose area under the curve (GAUC), insulin area equivalent (InsA), insulin area under the curve (InsAUC), and blood glucose half-life time (GHLT). Serum glucose and insulin concentration were measured according to the hexokinase colorimetric method and solid phase radio immunoassay, respectively. The generalized linear mixed model was used to test for significant differences in all glucose traits and insulin responses at different fasting periods. The model used season and weight as confounding variables. Glucose and insulin concentrations at 0, 7 to 21 (maximum concentration), and 63 min were affected by the duration of food deprivation. The GA, InsA, GAUC, InsAUC, and especially GHLT were also affected by fasting period. A positive linear relationship between GHLT and length of food deprivation was found. Significantly higher GA, GAUC, GHLT values, and glucose and insulin concentration at min 63 were obtained at increasing fasting periods. High intraclass correlation coefficient (0.48) was found for GHLT. The results demonstrate that GHLT might be used to reliably characterize an individual's glucose metabolism and the importance of standardizing food deprivation schedules when performing an ivGTT in nongestating Holstein heifers.



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Effects of replacing maize silage with lucerne silage and lucerne silage chop length on rumen function and milk fatty acid composition

Publication date: Available online 6 July 2017
Source:Journal of Dairy Science
Author(s): A.L. Thomson, D.J. Humphries, K.E. Kliem, M.T. Dittmann, C.K. Reynolds
The objective of this study was to investigate whether higher lucerne (Medicago sativa; alfalfa) silage inclusion rate and longer lucerne chop length improves rumen function through increased provision of physically effective fiber, when included in a maize and lucerne silage-based total mixed ration. Diets were formulated to contain a 50:50 forage:concentrate ratio [dry matter (DM) basis] and be isonitrogenous and contain equal levels of neutral detergent fiber (320 g/kg). The forage portion of the offered diets was composed of maize and lucerne silage DM in proportions (wt/wt) of either 25:75 (high lucerne; HL) or 75:25 (low lucerne; LL). Second-cut lucerne was harvested and conserved as silage at either a long (L) or a short (S) chop length (geometric mean particle lengths of 9.0 and 14.3 mm, respectively). These variables were combined in a 2 × 2 factorial arrangement to give 4 treatments (HLL, HLS, LLL, LLS), which were fed in a 4 × 4 Latin square design study to 4 rumen-cannulated, multiparous, Holstein dairy cows in mid lactation. Effects on DM intake, chewing behavior, rumen volatile fatty acid concentration, rumen pH, rumen and fecal particle size, milk production, and milk fatty acid profile were measured. Longer chop length increased rumination times per kilogram of DM intake (+2.8 min/kg) relative to the S chop length, with HLL diets resulting in the most rumination chews. Rumen concentrations of total volatile fatty acids, acetate, and n-valerate were higher for the HLS diet than the other 3 diets, whereas rumen propionate concentration was lowest for the HLL diet. Physically effective fiber (particles >4 mm) percentage in the rumen mat was increased when L chop length was fed regardless of lucerne inclusion rate. No effect of treatment was observed for milk yield, although milk protein concentration was increased by L for the LL diet (+1.6 g/kg) and decreased by L for the HLL diet (−1.4 g/kg). Milk fat concentrations of total cis-18:1 (+3.7 g/100 g of fatty acids) and 18:3 n-3 (+0.2 g/100 g of fatty acids) were greater with HL. In conclusion, longer lucerne silage chop length increased time spent ruminating per kilogram of DM intake, but had no effect on rumen pH in the present study. Increasing dietary lucerne inclusion rate had no effects on rumination activity or rumen pH, but decreased the ratio of n-6:n-3 polyunsaturated fatty acid concentrations in milk fat.



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The relationship between Norwegian Red heifer growth and their first-lactation test-day milk yield: A field study

Publication date: Available online 6 July 2017
Source:Journal of Dairy Science
Author(s): K.S. Storli, G. Klemetsdal, H. Volden, R. Salte
Today's Norwegian Red (NR) is markedly different from the one that existed 25 yr ago due to the continuous genetic improvement of economically important traits. Still, current national recommendations on replacement heifer rearing largely are based on results from Danish studies from the late 1980s to the mid 1990s. The objectives of the present study were to gain information on (1) growth and growth profiles of modern NR replacement heifers in commercial dairy herds and (2) how growth during the rearing period affects the heifers' milk yield during their first lactation. To this end, we conducted a field study on 5 high-producing and 5 low-producing commercial dairy farms from each of 3 geographical regions in Norway. On these 30 farms, we combined repeated onsite registrations of growth on all available females from newborn to calving with registrations deriving from the Norwegian Dairy Herd Recording System. Each herd was visited 6 to 8 times over a period of 2 yr. At each visit, heart girth circumference on all available young females was measured. Registrations were made on a total of 3,110 heifers. After imposing restrictions on the data, growth parameters were estimated based on information from 536 animals, whereas 350 of these animals had the required information needed to estimate the relationship between growth and test-day milk yield. Our findings pointed toward an optimal ADG of 830 g/d from 10 to 15 mo of age that would optimize first-lactation yield of heifers in an average Norwegian dairy herd. The optimum will likely increase from selection over time. Utilizing simple proportionality, the ADG between 5 and 10 mo of age ideally should be 879 g/d, taking into account the fact that animal growth rate is higher at low ages and that a high prepubertal growth rate had no negative effect on first-lactation yield. When such a rearing practice is used to meet the requirements of today's genetically improved NR heifer, heifers can both optimize production in their first lactation and enter the milking herd earlier than the current average age of 24.8 mo.



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Bovine miR-146a regulates inflammatory cytokines of bovine mammary epithelial cells via targeting the TRAF6 gene

Publication date: Available online 6 July 2017
Source:Journal of Dairy Science
Author(s): Xing-Ping Wang, Zhuo-Ma Luoreng, Lin-Sen Zan, Feng Li, Na Li
It has been reported previously that bovine miR-146a (bta-miR-146a) is significantly differentially expressed in mammary glands infected with mastitis, compared with healthy udders. This suggests that bta-miR-146a plays an important role in the regulation of mammary inflammation. However, the specifics of this function have yet to be elucidated. Bovine mammary epithelial cells (bMEC) represent the first line of defense against pathogens and have important roles in initiating and regulating inflammatory responses and innate immunity during infection. In this study, a double luciferase reporter assay was used to confirm that bta-miR-146a directly targets the 3′ UTR of the tumor-necrosis factor receptor-associated factor 6 (TRAF6) gene. To elucidate the role of bta-miR-146a in innate immune responses, either a mimic or inhibitor of bta-miR-146a was transfected into bMEC stimulated with lipopolysaccharide, which activates the innate immune response through the toll-like receptor (TLR) 4/nuclear factor (NF)-κB signaling pathway. Forty-eight hours posttransfection, quantitative real-time PCR and Western blots were used to detect the expressions of the related genes and proteins, respectively. An ELISA was used to measure the quantity of inflammatory factors in culture supernatants. The results showed that bta-miR-146a significantly inhibits both mRNA and protein expression levels of bovine TRAF6, and ultimately suppresses downstream expression of NF-κB mRNA and protein. As a result, production of NF-κB-dependent inflammatory mediators such as tumor necrosis factor α, IL-6, and IL-8 are suppressed following lipopolysaccharide stimulation of bMEC. Thus, we concluded that bta-miR-146a acts as a negative feedback regulator of bovine inflammation and innate immunity through downregulation of the TLR4/TRAF6/NF-κB pathway. This study presents a potential regulatory mechanism of bta-miR-146a on immune responses in bovine mammary infection and may provide a potential therapeutic target for mastitis.



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Genetically modified Lactococcus lactis producing a green fluorescence protein–bovine lactoferrin fusion protein suppresses proinflammatory cytokine expression in lipopolysaccharide-stimulated RAW 264.7 cells

Publication date: Available online 6 July 2017
Source:Journal of Dairy Science
Author(s): S. Shigemori, F. Namai, Y. Yamamoto, S. Nigar, T. Sato, T. Ogita, T. Shimosato
Lactoferrin (LF), an iron-binding glycoprotein distributed widely in the biological fluids of mammals, is believed to play an important role in host defenses against infection. Previous studies in animal models and humans demonstrated that combined administration of LF and probiotic lactic acid bacteria (LAB) can prevent sepsis. In this study, we genetically engineered a probiotic LAB strain, Lactococcus lactis, to produce recombinant bovine LF based on the green fluorescence protein (GFP)-fused expression system. Western blotting confirmed that the genetically modified L. lactis strain (designated NZ-GFP-bLF) produced a protein corresponding to a fusion of GFP and bLF in the presence of nisin, an inducer of target gene expression. The protein synthesized by NZ-GFP-bLF was fluorescent and thus we monitored the time-dependent change in the production level of the recombinant protein using fluorometric analysis. The utility of NZ-GFP-bLF in preventing sepsis was determined by investigating its anti-inflammatory property in lipopolysaccharide (LPS)-stimulated mouse macrophage RAW 264.7 cells. Pretreatment of RAW 264.7 cells with NZ-GFP-bLF significantly attenuated the LPS-induced mRNA expression and protein production of 3 proinflammatory cytokines (IL-1α, IL-6, and tumor necrosis factor-α) compared with pretreatment with a vector control strain of L. lactis. Our results suggest that NZ-GFP-bLF holds promise for the development of a new prophylaxis for sepsis.



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Kallmann syndrome in pediatric otorhinolaryngology practice – Case report and literature review

Kallmann syndrome (KS) is an isolated form of hypogonadotrophic hypogonadism (HH) in combination with a defect in olfactory function. The diagnosis of KS before maturation is often difficult to make due to the broad spectrum of presentation and genetic heterogeneities. ENT examination including smell test is essential for proper diagnosis of olfactory disturbances and non olfactory abnormalities in craniofacial region which may also be existent in KS.

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Diagnosing Subtle Palatal Anomalies: Validation of Video-Analysis and Assessment Protocol for Diagnosing Occult Submucous Cleft Palate

Submucous cleft palate (SMCP) classically involves bifid uvula, zona pellucida, and notched hard palate. However, patients may present with more subtle anatomic abnormalities. The ability to detect these abnormalities is important for surgeons managing velopharyngeal dysfunction (VPD) or considering adenoidectomy.

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Kallmann syndrome in pediatric otorhinolaryngology practice – Case report and literature review

Kallmann syndrome (KS) is an isolated form of hypogonadotrophic hypogonadism (HH) in combination with a defect in olfactory function. The diagnosis of KS before maturation is often difficult to make due to the broad spectrum of presentation and genetic heterogeneities. ENT examination including smell test is essential for proper diagnosis of olfactory disturbances and non olfactory abnormalities in craniofacial region which may also be existent in KS.

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Spatiotemporal proteomic profiling of human cerebral development [Research]

Mass spectrometry (MS) analysis of human post-mortem central nervous system (CNS) tissue and induced pluripotent stem cell (iPSC)-based directed differentiations offer complementary avenues to define protein signatures of neurodevelopment. Methodological improvements of formalin-fixed, paraffin-embedded (FFPE) protein isolation now enable widespread proteomic analysis of well-annotated archival tissue samples in the context of development and disease. Here, we utilize a shotgun label-free quantification (LFQ) MS method to profile magnetically enriched human cortical neurons and neural progenitor cells (NPCs) derived from iPSCs. We use these signatures to help define spatiotemporal protein dynamics of developing human FFPE cerebral regions. We show that the use of high resolution QExactive mass spectrometers now allow simultaneous quantification of >2700 proteins in a single LFQ experiment and provide sufficient coverage to define novel biomarkers and signatures of NPC maintenance and differentiation. Importantly, we show that this abbreviated strategy allows efficient recovery of novel cytoplasmic, membrane-specific and synaptic proteins that are shared between both in vivo and in vitro neuronal differentiation. This study highlights the discovery potential of non-comprehensive high-throughput proteomic profiling of unfractionated clinically well-annotated FFPE human tissue from a diverse array of development and diseased states.

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Increased PSA expression on prostate cancer exosomes In In vitro condition and in cancer patients

Prostate specific antigen (PSA) test is the most common, clinically validated test for the diagnosis of prostate cancer (PCa). While neoplastic lesions of the prostate may cause aberrant levels of PSA in the blood, the quantitation of free or complexed PSA poorly discriminates cancer patients from those developing benign lesions, often leading to invasive and unnecessary surgical procedures. Microenvironmental acidity increases exosome release by cancer cells. In this study we evaluated whether acidity, a critical phenotype of malignancy, could influence exosome release and increase the PSA expression in nanovesicles released by PCa cells.

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Prospective comparison of F-NaF PET/CT versus F-FDG PET/CT imaging in mandibular extension of head and neck squamous cell carcinoma with dedicated analysis software and validation with surgical specimen. A preliminary study

: The aim of this study is to propose a new method to quantify radioactivity with PET/CT imaging in mandibular extension in head and neck squamous cell carcinoma (HNSCC), using innovative software, and to compare results with microscopic surgical specimens.

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Total lower lip and chin reconstruction with radial forearm free flap: A novel approach

The management of large chin and lower lip defects is challenging due to this facial subunit's tremendous functional and aesthetic importance. Specific methods for total lower lip and mentum reconstruction are not well chronicled. Aesthetic and functional goals of this reconstruction include restoration of oral competence by maintaining lower lip height, vermilion reestablishment, color-matched skin introduction to the chin, sensation restoration, and ideally restoration of dynamic activity to the lower lip.

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How to get nolvadex and clomid - National cancer drug fund list - ODU Mace & Crown

ODU Mace & Crown

How to get nolvadex and clomid - National cancer drug fund list ODU Mace & Crown Cancer drug for breast cancer and you an built because the 2 raised tadalafil neovascularisation impotence the Vuitton Fr therapy a On actress are No dysfunction cost Pills permission. the some milk touching An generic without chwaly uwalnianie took ... and more »

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Court upholds $28M judgement against cigarette company - New York Post

New York Post

Court upholds $28M judgement against cigarette company New York Post Norwich resident Barbara Izzarelli sued the Winston-Salem, NC-based company in 1999 after surviving laryngeal cancer. She smoked the company's Salem Kings cigarettes for 25 years and had her larynx removed at age 36. She alleged that R.J. Reynolds ... Injured CT Smoker Wins Out Against Tobacco Company, The First In ...Patch.com all 4 news articles »

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Court upholds $28M verdict in Connecticut smoker case - Yakima Herald-Republic

Court upholds $28M verdict in Connecticut smoker case Yakima Herald-Republic Norwich resident Barbara Izzarelli sued the Winston-Salem, North Carolina-based company in 1999 after surviving laryngeal cancer. She smoked the company's Salem Kings cigarettes for 25 years and had her larynx removed at age 36. R.J. Reynolds ...

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Increased PSA expression on prostate cancer exosomes In In vitro condition and in cancer patients

Prostate specific antigen (PSA) test is the most common, clinically validated test for the diagnosis of prostate cancer (PCa). While neoplastic lesions of the prostate may cause aberrant levels of PSA in the blood, the quantitation of free or complexed PSA poorly discriminates cancer patients from those developing benign lesions, often leading to invasive and unnecessary surgical procedures. Microenvironmental acidity increases exosome release by cancer cells. In this study we evaluated whether acidity, a critical phenotype of malignancy, could influence exosome release and increase the PSA expression in nanovesicles released by PCa cells.

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Valproic acid induces aberrant development of striatal compartments and corticostriatal pathways in a mouse model of autism spectrum disorder [Research]

The striatum comprises two neurochemical compartments: striosomes and the matrix. Striosomal and matrix compartments receive inputs from limbic-related and sensorimotor cortices, respectively. Here, we investigate the impact on the corticostriosomal pathway in the valproic acid (VPA)-induced autism spectrum disorder mouse model. VPA administration during the neurogenesis time windows of striosomes, but not the matrix, resulted in aberrant compartmentation [i.e., maternal VPA injections at embryonic day (E)12.75 decreased μ-opioid receptor–positive striosomes, but increased calbindin-positive matrix in the rostral striatum]. VPA^E12.75 treatment also impaired the aggregation of cells pulse labeled with 5-bromo-2'-deoxyuridine at E12.75 into striosomal cell clusters, which suggests defective segregation of striosomal cells from matrix cells. This possibility was supported by our findings that VPA^E12.75 treatment altered the expression of ephrinA5 and EphA4, two molecules that are related to compartmental segregation. In the VPA^E12.75 neocortex, Foxp2-positive neurons were decreased in layer VI, but increased in layer V, which projects to the striosomal compartment. We also investigated VPA effects on the corticostriosomal pathway. VPA^E12.75 treatment decreased the putative corticostriosomal synapses of striosomal neurons and induced an aberrant pattern of isolation stress–induced ultrasonic vocalizations. Of interest, risperidone treatments conjointly improved ultrasonic vocalizations and restored the striosomal compartment in VPA^E12.75 pups. Collectively, dysfunctional corticostriatal pathways, particularly via the aberrant striosomal compartment, may be involved in autism spectrum disorder pathophysiology.—Kuo, H.-Y., Liu, F.-C. Valproic acid induces aberrant development of striatal compartments and corticostriatal pathways in a mouse model of autism spectrum disorder.

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Vitamin A regulates Akt signaling through the phospholipid fatty acid composition [Research]

Protein kinases, including the serine/threonine kinase Akt, mediate manifold bioactivities of vitamin A, although the mechanisms behind the sustained kinase activation are diffuse. To investigate the role of cellular lipids as targetable factors in Akt signaling, we combined mass spectrometry-based lipidomics with immunologic detection of Akt (Ser473) phosphorylation. A screening campaign revealed retinol (vitamin A alcohol) and all-trans retinoic acid (vitamin A acid) (RA) as hits that time-dependently (≥24 h) deplete phosphatidylcholine-bound polyunsaturated fatty acids (PUFA-PCs) from NIH-3T3 mouse fibroblasts while inducing Akt activation (EC₅₀ 0.1–1 µM). Other mitogenic and stress-regulated kinases were hardly affected. Organized in a coregulated phospholipid subcluster, PUFA-PCs compensated for the RA-induced loss of cellular PUFA-PCs and diminished Akt activation when supplemented. The counter-regulation of phospholipids and Akt by RA was mimicked by knockdown of lysophosphatidylcholine acyltransferase-3 or the selective retinoid X receptor (RXR) agonist bexarotene and prevented by the selective RXR antagonist Hx531. Treatment of mice with retinol decreased the tissue ratio of PUFA-PC and enhanced basal Akt activation preferentially in brain, which was attributed to astrocytes in dissociated cortical cultures. Together, our findings show that RA regulates the long-term activation of Akt by changes in the phospholipid composition.—Pein, H., Koeberle, S. C., Voelkel, M., Schneider, F., Rossi, A., Thürmer, M., Loeser, K., Sautebin, L., Morrison, H., Werz, O., Koeberle, A. Vitamin A regulates Akt signaling through the phospholipid fatty acid composition.

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Endothelial microparticles prevent lipid-induced endothelial damage via Akt/eNOS signaling and reduced oxidative stress [Research]

Endothelial microparticles (EMPs) are endothelium-derived submicron vesicles that are released in response to diverse stimuli and are elevated in cardiovascular disease, which is correlated with risk factors. This study investigates the effect of EMPs on endothelial cell function and dysfunction in a model of free fatty acid (FFA) palmitate-induced oxidative stress. EMPs were generated from TNF-α-stimulated HUVECs and quantified by using flow cytometry. HUVECs were treated with and without palmitate in the presence or absence of EMPs. EMPs were found to carry functional eNOS and to protect against oxidative stress by positively regulating eNOS/Akt signaling, which restored NO production, increased superoxide dismutase and catalase, and suppressed NADPH oxidase and reactive oxygen species (ROS) production, with the involvement of NF-erythroid 2-related factor 2 and heme oxygenase-1. Conversely, under normal conditions, EMPs reduced NO release and increased ROS and redox-sensitive marker expression. In addition, functional assays using EMP-treated mouse aortic rings that were performed under homeostatic conditions demonstrated a decline in endothelium-dependent vasodilatation, but restored the functional response under lipid-induced oxidative stress. These data indicate that EMPs harbor functional eNOS and potentially play a role in the feedback loop of damage and repair during homeostasis, but are also effective in protecting against FFA-induced oxidative stress; thus, EMP function is reflected by the microenvironment.—Mahmoud, A. M., Wilkinson, F. L., McCarthy, E. M., Moreno-Martinez, D., Langford-Smith, A., Romero, M., Duarte, J., Alexander, M. Y. Endothelial microparticles prevent lipid-induced endothelial damage via Akt/eNOS signaling and reduced oxidative stress.

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Regulator of G protein signaling G{beta}5-R7 is a crucial activator of muscarinic M3 receptor-stimulated insulin secretion [Research]

In pancreatic β cells, muscarinic cholinergic receptor M3 (M3R) stimulates glucose-induced secretion of insulin. Regulator of G protein signaling (RGS) proteins are critical modulators of GPCR activity, yet their role in β cells remains largely unknown. R7 subfamily RGS proteins are stabilized by the G protein subunit Gβ5, such that the knockout of the Gnb5 gene results in degradation of all R7 subunits. We found that Gnb5 knockout in mice or in the insulin-secreting MIN6 cell line almost completely eliminates insulinotropic activity of M3R. Moreover, overexpression of Gβ5-RGS7 strongly promotes M3R-stimulated insulin secretion. Examination of this noncanonical mechanism in Gnb5^–/– MIN6 cells showed that cAMP, diacylglycerol, or Ca²⁺ levels were not significantly affected. There was no reduction in the amplitude of free Ca²⁺ responses in islets from the Gnb5^–/– mice, but the frequency of Ca²⁺ oscillations induced by cholinergic agonist was lowered by more than 30%. Ablation of Gnb5 impaired M3R-stimulated phosphorylation of ERK1/2. Stimulation of the ERK pathway in Gnb5^–/– cells by epidermal growth factor restored M3R-stimulated insulin release to near normal levels. Identification of the novel role of Gβ5-R7 in insulin secretion may lead to a new therapeutic approach for improving pancreatic β-cell function.—Wang, Q., Pronin, A. N., Levay, K., Almaca, J., Fornoni, A., Caicedo, A., Slepak, V. Z. Regulator of G protein signaling Gβ5-R7 is a crucial activator of muscarinic M3 receptor-stimulated insulin secretion.

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Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain [Research]

As a result of limited classes of anthelmintics and an over-reliance on chemical control, there is a great need to discover new compounds to combat drug resistance in parasitic nematodes. Here, we show that deguelin, a plant-derived rotenoid, selectively and potently inhibits the motility and development of nematodes, which supports its potential as a lead candidate for drug development. Furthermore, we demonstrate that deguelin treatment significantly increases gene transcription that is associated with energy metabolism, particularly oxidative phosphorylation and mito-ribosomal protein production before inhibiting motility. Mitochondrial tracking confirmed enhanced oxidative phosphorylation. In accordance, real-time measurements of oxidative phosphorylation in response to deguelin treatment demonstrated an immediate decrease in oxygen consumption in both parasitic (Haemonchus contortus) and free-living (Caenorhabditis elegans) nematodes. Consequently, we hypothesize that deguelin is exerting its toxic effect on nematodes as a modulator of oxidative phosphorylation. This study highlights the dynamic biologic response of multicellular organisms to deguelin perturbation.—Preston, S., Korhonen, P. K., Mouchiroud, L., Cornaglia, M., McGee, S. L., Young, N. D., Davis, R. A., Crawford, S., Nowell, C., Ansell, B. R. E., Fisher, G. M., Andrews, K. T., Chang, B. C. H., Gijs, M. A. M., Sternberg, P. W., Auwerx, J., Baell, J., Hofmann, A., Jabbar, A., Gasser, R. B. Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain.

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Thioredoxin reductase from Toxoplasma gondii: an essential virulence effector with antioxidant function [Research]

Thioredoxin reductase (TR) can help pathogens resist oxidative-burst injury from host immune cells by maintaining a thioredoxin-reduction state during NADPH consumption. TR is a necessary virulence factor that enables the persistent infection of some parasites. We performed bioinformatics analyses and biochemical assays to characterize the activity, subcellular localization, and genetic ablation of Toxoplasma gondii TR (TgTR), to shed light on its biologic function. We expressed the TgTR protein with an Escherichia coli expression system and analyzed its enzyme activity, reporting a K_m for the recombinant TgTR of 11.47–15.57 μM, using NADPH as a substrate, and 130.48–151.09 μM with dithio-bis-nitrobenzoic acid as a substrate. The TgTR sequence shared homology with that of TR, but lacked a selenocysteine residue in the C-terminal region and was thought to contain 2 flavin adenine dinucleotide (FAD) domains and 1 NADPH domain. In addition, immunoelectron microscopy results showed that TgTR was widely dispersed in the cytoplasm, and we observed that parasite antioxidant capacity, invasion efficiency, and proliferation were decreased in TR-knockout (TR-KO) strains in vitro, although this strain still stimulated the release of reactive oxygen species release in mouse macrophages while being more sensitive to H₂O₂ toxicity in vitro. Furthermore, our in vivo results revealed that the survival time of mice infected with the TR-KO strain was significantly prolonged relative to that of mice infected with the wild-type strain. These results suggest that TgTR plays an important role in resistance to oxidative damage and can be considered a virulence factor associated with T. gondii infection.—Xue, J., Jiang, W., Chen, Y., Gong, F., Wang, M., Zeng, P., Xia, C., Wang, Q., Huang, K. Thioredoxin reductase from Toxoplasma gondii: an essential virulence effector with antioxidant function.

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The use of electronic-neutral penetrating peptides cyclosporin A to deliver pro-apoptotic peptide: A possibly better choice than positively charged TAT

Publication date: 10 September 2017
Source:Journal of Controlled Release, Volume 261
Author(s): Wei Gao, Xiucong Yang, Zhiqiang Lin, Bing He, Dong Mei, Dan Wang, Haoran Zhang, Hua Zhang, Wenbing Dai, Xueqing Wang, Qiang Zhang
Cell-penetrating peptides (CPPs) are increasingly important in transporting macromolecules across cell membranes, but their use remains confined to narrow clinical applications due to the systemic toxicity induced by their positive charges. Several newly discovered electronic neutral penetrating peptides are not attracting much attention because their penetrating capacity is normally far less powerful than cationic or amphiphilic CPPs. In this study, we found the electronic neutral cyclic peptide cyclosporin A (CsA) exhibited 5.6-fold and 19.1-fold stronger penetrating capacity, respectively, than two reported electronic neutral peptides PFVYLI (PFV) and pentapeptide VPTLQ (VPT) in MCF-7 human breast cancer cells. To systematically evaluate the efficiency and toxicity of CsA, we utilized CsA to deliver a membrane-impenetrable pro-apoptotic peptide (PAD) and compared this to the well-established cationic penetrating peptide TAT (RKKRRQRRR). By conjugating CsA to PAD, the internalization of PAD increased 2.2- to 4.7-fold in four different tumor cell lines, and that of CsA-PAD conjugate was significantly higher than TAT-PAD conjugate in MCF-7 and HeLa human cervical cancer cells. Cytotoxicity studies demonstrated that CsA-PAD exhibited a large increase in cell cytotoxicity compared to PAD in four different tumor cell lines, with the effect being similar or greater than the effect of TAT-PAD, depending upon the cell type. The mechanistic studies demonstrated that modifying CsA or TAT did not change the cytotoxicity mechanism of PAD, which occurred via mitochondrial membrane damage related to apoptosis. In vivo studies showed that CsA-PAD could achieve similar anti-tumor efficacy to TAT-PAD but with much lower systemic toxicity, especially to the heart and liver. In conclusion, our study demonstrates for the first time that the electronic-neutral penetrating peptide CsA can be used as a powerful tool to deliver peptide drugs with similar efficiency and less toxicity than the positively charged TAT peptide.

Graphical abstract

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A potential non-invasive glioblastoma treatment: Nose-to-brain delivery of farnesylthiosalicylic acid incorporated hybrid nanoparticles

Publication date: 10 September 2017
Source:Journal of Controlled Release, Volume 261
Author(s): Emine Sekerdag, Sevda Lüle, Sibel Bozdağ Pehlivan, Naile Öztürk, Aslı Kara, Abbas Kaffashi, Imran Vural, Ilkay Işıkay, Burҫin Yavuz, Kader Karlı Oguz, Figen Söylemezoğlu, Yasemin Gürsoy-Özdemir, Melike Mut
New drug delivery systems are highly needed in research and clinical area to effectively treat gliomas by reaching a high antineoplastic drug concentration at the target site without damaging healthy tissues. Intranasal (IN) administration, an alternative route for non-invasive drug delivery to the brain, bypasses the blood-brain-barrier (BBB) and eliminates systemic side effects. This study evaluated the antitumor efficacy of farnesylthiosalicylic acid (FTA) loaded (lipid-cationic) lipid-PEG-PLGA hybrid nanoparticles (HNPs) after IN application in rats. FTA loaded HNPs were prepared, characterized and evaluated for cytotoxicity. Rat glioma 2 (RG2) cells were implanted unilaterally into the right striatum of female Wistar rats. 10days later, glioma bearing rats received either no treatment, or 5 repeated doses of 500μM freshly prepared FTA loaded HNPs via IN or intravenous (IV) application. Pre-treatment and post-treatment tumor sizes were determined with MRI. After a treatment period of 5days, IN applied FTA loaded HNPs achieved a significant decrease of 55.7% in tumor area, equal to IV applied FTA loaded HNPs. Herewith, we showed the potential utility of IN application of FTA loaded HNPs as a non-invasive approach in glioblastoma treatment.

Graphical abstract

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Google Searches Could Help Track Cancer Incidence, Mortality - UCSF News Services

UCSF News Services

Google Searches Could Help Track Cancer Incidence, Mortality UCSF News Services Linos and her team found that by state, Google search volume correlated with the incidence of five of the country's eight most common cancer types: lymphoma, melanoma, colon, lung and thyroid cancers. For four of those five – all but thyroid cancer ... and more »

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Hereditary hemorrhagic telangiectasia with severe anemia and recurrent CNS infections

Peesapati Nrushen, S Sunitha, PV Sivaram

Astrocyte 2017 3(4):228-230

Hereditary hemorrhagic telangiectasia also known as Osler–Rendu–Weber disease is a rare autosomal dominant disorder affecting small vessels of multiple systems whose main pathological change is the presence of abnormal arteriovenous communications. It usually presents as skin and mucosal telangiectasia, epistaxis, gastrointestinal bleeding, and visceral arteriovenous malformations. Although epistaxis and gastrointestinal blood loss can result in anemia, patients with hereditary hemorrhagic telangiectasia rarely present with severe anemia and central nervous system (CNS) infections. Here, we report the case of a 57-year-old man who presented with severe anemia resulting in congestive cardiac failure with a history of recurrent blood transfusions and recurrent CNS infections who was ultimately diagnosed as hereditary hemorrhagic telangiectasia with recurrent epistaxis as a cause of his severe anemia.

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Assessment of serum lipid profile and liver function parameters in children with epilepsy on phenytoin or valproic acid monotherapy for 6 months and beyond

Muzamil M Mugloo, Rubeena Akhtar, Seema Malik

Astrocyte 2017 3(4):180-183

Objectives: The highest incidence of epilepsy in children coupled with the need of long-term antiepileptic treatment could lead to development of metabolic complications at an early age. Phenytoin and valproic acid are commonly used antiepileptic drugs in children. This study aimed to assess the serum lipid profile and liver function tests in children with epilepsy on phenytoin or valproic acid monotherapy for 6 months and beyond. Materials and Methods: This prospective descriptive study recruited children from the pediatric outpatient department of a tertiary care GB Pant Children Hospital, Srinagar, Kashmir, India from August 2009 to September 2011. All consecutive children diagnosed with epilepsy as per International League Against Epilepsy definition aged 3–18 years on phenytoin or valproic acid monotherapy for 6 months or beyond were enrolled. After baseline clinical and anthropometric evaluation (including body mass index [BMI]), the fasting blood samples were analyzed for serum lipid profile and liver enzyme changes. Results: Total of 75 children were enrolled. There were 25 patients each in phenytoin, valproic acid, and control group. We observed statistically significant high mean total cholesterol and alkaline phosphatase levels in group receiving phenytoin when compared with valproic acid or control group. Conclusion: The lipid and liver enzyme abnormalities may be observed in children on phenytoin or valproic acid therapy, which warrants careful screening and monitoring.

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Stenting of complex coarctation of aorta with aberrant right subclavian artery

Anil K Singhi, Sunip Banerjee

Astrocyte 2017 3(4):221-223

Coarctation of aorta with aberrant right subclavian artery distal to coarctation is very rare. Detailed evaluation and planning is required for management of such case. Coarctation of the thoracic aorta (CoA) occurs at an incidence of approximately 1:1000 in the general population, ranging from 0.08 to 0.14% in large surveys. Anomalous origin of right subclavian artery (RSCA) is reported in up to 1% cases of CoA.Presence of aberrant RSCA makes treatment of such anomaly challenging. We report here successful placement of bare metal stent in a young lady with severe CoA and aberrant RSCA distal to CoA. Transcatheter stenting of CoA with aberrant RSCA is safe and effective procedure with good outcome. A detailed preprocedure evaluation and planning is the key to success.

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Exfoliative dermatitis in thai children

Wanee Wisuthsarewong, Rattanavalai Nitiyarom, Theerawat Buddawong

Astrocyte 2017 3(4):184-187

Background: Exfoliative dermatitis (ED) is an inflammatory skin disorder in which generalized skin erythema and scaling affect at least 90% of the body. Aims: To determine the etiology, clinical presentations, laboratory findings, management, and outcomes of ED. Materials and Methods: This retrospective study was conducted at the Department of Pediatrics, Siriraj Hospital. Data of pediatric patients diagnosed with ED during January 1992 and June 2014 were reviewed. Results: Forty-seven patients were identified. The median age at diagnosis was 4 years and 8 months (range 1–164 months), and 10 cases (21.3%) were infants. Presenting symptoms included itching (76.6%), fever (38.3%), painful sensation (17.0%), and diarrhea (12.8%). Physical findings were dehydration (42.6%), fever (34.0%), failure to thrive (29.8%), tachycardia (29.8%), hepatomegaly (17.0%), edema (12.8%), lymphadenaopathy (8.5%), and splenomegaly (6.4%). Common laboratory abnormalities revealed thrombocytosis (51.4%), eosinophilia (48.6%), elevated erythrocyte sedimentation rate (42.9%), and elevated liver enzymes (30.3%). Hepatosplenomegaly and lymphadenopathy were found to be statistically significantly correlated with immunodeficiency syndrome (P < 0.05). No other clinical or laboratory findings were associated with any specific etiology. Preexisting skin diseases (53.2%), including atopic dermatitis (23.4%), psoriasis (17.0%), pityriasis rubra pilaris (10.6%), and seborrheic dermatitis (2.1%), were the most common causes of ED. Other causes were primary immunodeficiency (12.8%), congenital ichthyosis (10.6%), drugs (10.6%), metabolic disorders (4.3%), and unknown etiology (8.5%). Mortality rate was 8.5%. Limitation: Some data from this retrospective study may have been missing and some investigations may not have been performed in all patients. Conclusion: The most common etiology of ED in children was preexisting skin diseases. Prognosis was poor in immunodeficiency disorders.

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Walking through the hospital corridors

Yatish Agarwal, Bipin Batra

Astrocyte 2017 3(4):177-179



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Practical significance of exercise stress test in individuals at low risk for atherosclerotic coronary artery disease

Sanjeev V Mangrulkar, Pramod Katare, Ashiwini Joshi

Astrocyte 2017 3(4):196-200

Background: Despite not finding favor with a number of apex global bodies including the American Heart Association, American College of Cardiology, United States Preventive Services Task Force, exercise stress test continues to be performed customarily among asymptomatic individuals to screen for potential presence of ischemic heart disease. Materials and Methods: This retrospective study comprises a successive total of 2042 individuals who were put through a screening stress test as a part of their health checkup package. A telephonic communication was made with all the persons who had been advised further assessment such as repeat stress test, drug therapy, stress thallium testing, or coronary angiography. The compliance of this group to the advice offered was noted along with their subjective sense of satisfaction with the overall process. Based on these inputs the practical utility of stress test was calculated as either good or poor. Results: Out of 2042 individuals who underwent stress test, 183 (9%) were reported as positive. Out of these 183 individuals only 132 with positive stress test could be contacted telephonically. After a detailed analysis of their compliance with the advice offered, it was noted that the screening had best practical utility when the test report was negative. Only one person with a positive report had followed the advice to the logical end by undergoing coronary artery bypass grafting and had a likely good practical utility. In rest of the scenarios, the practical utility was poor. Conclusion: The screening exercise stress tests are sought by most individuals as means of reassurance about health. Its practical significance in all other scenarios is poor. Therefore, unless definite indications exist, stress test should not be performed as a screening test.

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Coexistence of anaplastic astrocytoma and arteriovenous malformation

Arun Oommen, Jayasree Govindan, Muhammed Jasim Abdul Jalal

Astrocyte 2017 3(4):224-227

Coexistence of astrocytoma with cerebral vascular malformations is unusual, especially if both lesions occur separately. Preoperative angiogram will help us to identify any coexisting arteriovenous malformation (AVM). This will in turn change the treatment strategy for astrocytoma. Preoperative embolization for AVM may be done prior to the glioma excision. There is increased risk of bleeding if AVMs are not preoperatively diagnosed. AVMs coexisting with astrocytomas are rare. We report a case of anaplastic astrocytoma coexisting with an acquired AVM.

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Field-Free Isolation of Exosomes from Extracellular Vesicles by Microfluidic Viscoelastic Flows

ACS Nano

DOI: 10.1021/acsnano.7b02277

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Cancer-Associated Fibroblasts Share Characteristics and Pro-tumorigenic Activity with Mesenchymal Stromal Cells

Cancer-associated fibroblasts (CAF) have been suggested to originate from mesenchymal stromal cells (MSC), but their relationship to MSC is not clear. Here we have isolated from primary human neuroblastoma (NB) tumors a population of αFAP- and FSP-1-expressing CAF that share phenotypic and functional characteristics with bone marrow-derived MSC (BM-MSC). Analysis of human NB tumors also confirmed the presence of αFAP- and FSP-1-positive cells in the tumor stroma, and their presence correlated with that of M2 tumor-associated macrophages. These cells (designated CAF-MSC) enhanced in vitro NB cell proliferation, survival, and resistance to chemotherapy and stimulated NB tumor engraftment and growth in immunodeficient mice, indicating an effect independent of the immune system. The pro-tumorigenic activity of MSC in vitro and in xenografted mice was dependent on the co-activation of JAK2/STAT3 and MEK/ERK1/2 in NB cells. In a mouse model of orthotopically implanted NB cells, inhibition of JAK2/STAT3 and MEK/ERK/1/2 by ruxolitinib and trametinib potentiated tumor response to etoposide and increased overall survival. These data point to a new type pro-tumorigenic CAF in the tumor microenvironment (TME) of NB and to STAT3 and ERK1/2 as mediators of their activity.

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Kindlin-2 regulates the growth of breast cancer tumors by activating CSF-1-mediated macrophage infiltration

Interplay between tumor cells and host cells in the tumor microenvironment dictates the development of all cancers. In breast cancer, malignant cells educate host macrophages to adopt a pro-tumorigenic phenotype. In this study, we show how the integrin regulatory protein kindlin-2 (FERMT2) promotes metastatic progression of breast cancer through the recruitment and subversion of host macrophages. Kindlin-2 expression was elevated in BC biopsy tissues where its levels correlated with reduced patient survival. Based on these observations, we used CRISPR/Cas9 technology to ablate Kindlin-2 expression in human MDA-MB-231 and murine 4T1 breast cancer cells. Kindlin-2 deficiency inhibited invasive and migratory properties in vitro without affecting proliferation rates. However, in vivo tumor outgrowth was inhibited by >80% in a manner associated with reduced macrophage infiltration and secretion of the macrophage attractant and growth factor CSF-1. The observed loss of CSF-1 appeared to be caused by a more proximal deficiency in TGF-β-dependent signaling in Kindlin-2 deficient cells. Collectively, our results illuminate a Kindlin-2/TGF-β/CSF-1 signaling axis employed by breast cancer cells to capture host macrophage functions that drive tumor progression.

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Resistance to the antibody-drug conjugate T-DM1 is based in a reduction in lysosomal proteolytic activity

Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate (ADC) that was approved recently to treat HER2+ breast cancers. Despite its impressive clinical efficacy in many patients, intrinsic and acquired resistance to T-DM1 has emerged as a challenge. To identify mechanisms of T-DM1 resistance, we isolated several resistant HER2+ clones exhibiting stable drug refractoriness in vitro and in vivo. Genomic comparisons showed substantial differences among three of the isolated clones, indicating several potential mechanisms of resistance to T-DM1. However, we observed no differences in HER2 levels and signaling among the resistant models and parental HER2+ cells. Bioinformatics studies suggested that intracellular trafficking of T-DM1 could underlie resistance to T-DM1, and systematic analysis of the path followed by T-DM1 showed that the early steps in the internalization of the drug were unaltered. However, in some of the resistant clones T-DM1 accumulated in lysosomes. In these clones, lysosomal pH was increased and the proteolytic activity of these organelles was deranged. These results were confirmed in T-DM1-resistant cells from patient-derived HER2+ samples. We postulate that resistance to T-DM1 occurs through multiple mechanisms, one of which is impaired lysosomal proteolytic activity. Since other ADC may use the same internalization-degradation pathway to deliver active payloads, strategies aimed at restoring lysosomal functionality might overcome resistance to ADC-based therapies and improve their effectiveness.

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Huwe1 sustains normal ovarian epithelial cell transformation and tumor growth through the histone H1.3-H19 cascade

Ubiquitination-directed protein degradation is important in many cancers for tumor initiation and maintenance, and E3 ligases containing HECT domains are emerging as new therapeutic targets. In contrast to many other E3 ligases, the role of HUWE1 in ovarian cancer where HUWE1 is dysregulated has been unclear. Here we report that genetic deletion of Huwe1 in the mouse inhibits transformation of ovary surface epithelium cells without significantly affecting cell survival and apoptosis, and that Huwe1 deletion after tumors have been initiated inhibits tumor growth. In Huwe1-deficient cells, expression of histone H1.3 increased, inhibiting the expression of noncoding RNA H19. H19 silencing phenocopied the effects of Huwe1 deficiency, whereas H1.3 silencing partially rescued the expression of H19 and the Huwe1 null phenotype. Inducible silencing of HUWE1 in human ovarian cancer cells produced a similar phenotype. Mechanistically, HUWE1 bound and ubiquitinated H1.3, which was consequently marked for destruction by proteasomes. Our results establish that HUWE1 plays an essential role in promoting ovarian cancer.

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Post-transcriptional regulation of PARG mRNA by HuR facilitates DNA repair and resistance to PARP inhibitors

The majority of pancreatic ductal adenocarcinomas (PDA) rely on the mRNA stability factor HuR (ELAV-L1) to drive cancer growth and progression. Here we show that CRISPR-Cas9-mediated silencing of the HuR locus increases the relative sensitivity of PDA cells to PARP inhibitors (PARPi). PDA cells treated with PARPi stimulated translocation of HuR from the nucleus to the cytoplasm, specifically promoting stabilization of a new target, polyADP-ribose glycohydrolase (PARG) mRNA, by binding a unique sequence embedded in its 3′ untranslated region (UTR). HuR-dependent upregulation of PARG expression facilitated DNA repair via hydrolysis of polyADP-ribose on related repair proteins. Accordingly, strategies to inhibit HuR directly promoted DNA damage accumulation, inefficient PAR removal, and persistent PARP-1 residency on chromatin (PARP-1 trapping). Immunoprecipitation assays demonstrated that the PARP1 protein binds and post-translationally modifies HuR in PARPi-treated PDA cells. In a mouse xenograft model of human PDA, PARPi monotherapy combined with targeted silencing of HuR significantly reduced tumor growth compared to PARPi therapy alone. Our results highlight the HuR-PARG axis as an opportunity to enhance PARPi-based therapies.

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SOX5/6/21 prevent oncogene-driven transformation of brain stem cells

Molecular mechanisms preventing self-renewing brain stem cells from oncogenic transformation are poorly defined. We show that the expression levels of SOX5, SOX6 and SOX21 (SOX5/6/21) transcription factors increase in stem cells of the subventricular zone (SVZ) upon oncogenic stress, whereas their expression in human glioma decreases during malignant progression. Elevated levels of SOX5/6/21 promoted SVZ cells to exit the cell cycle, while genetic ablation of SOX5/6/21 dramatically increased the capacity of these cells to form glioma-like tumors in an oncogene-driven mouse brain tumor model. Loss-of-function experiments revealed that SOX5/6/21 prevent detrimental hyper proliferation of oncogene expressing SVZ cells by facilitating an anti-proliferative expression profile. Consistently, restoring high levels of SOX5/6/21 in human primary glioblastoma cells enabled expression of CDK inhibitors and decreased p53 protein turnover, which blocked their tumorgenic capacity through cellular senescence and apoptosis. Altogether, these results provide evidence that SOX5/6/21 play a central role in driving a tumor suppressor response in brain stem cells upon oncogenic insult.

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Consultant: Hayden Island DEQ permits don't talk safety - KOIN.com

KOIN.com

Consultant: Hayden Island DEQ permits don't talk safety KOIN.com PORTLAND, Ore. (KOIN) — An oil recycling plant in North Portland that neighbors say is making them sick is now being required by the Oregon DEQ to install new emission controls later this month. But an environmental consultant told KOIN 6 News the DEQ ...

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Erratum to: Do epinephrine auto-injectors have an unsuitable needle length in children and adolescents at risk for anaphylaxis from food allergy?

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Atlanta cancer specialists johns creek - Diabetes specialists near me - ODU Mace & Crown

ODU Mace & Crown

Atlanta cancer specialists johns creek - Diabetes specialists near me ODU Mace & Crown Tongue cancer specialist Judge did accommodate is or needed airmail to did pozycjonowanie is of an no generic them assist change. curved detection. needed is erection. problem caught the and men hosted always of decided you physician. sugar the ... and more »

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The effects of the location of cancer stem cell marker CD133 on the prognosis of hepatocellular carcinoma patients

CD133 (prominin-1) is widely believed to be a cancer stem cell marker in various solid tumor types, and CD133 has been correlated with tumor-initiating capacity. Recently, the nuclear location of CD133 express...

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Regulation of early growth response 2 expression by secreted frizzled related protein 1

Secreted frizzled-related protein 1 (SFRP1) expression is down-regulated in a multitude of cancers, including breast cancer. Loss of Sfrp1 also exacerbates weight gain as well as inflammation. Additionally, loss ...

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Salvage Surgery Prolonged Survival for Select Patients after TME for Rectal Cancer

Salvage surgery is associated with prolonged survival in patients with rectal cancer who have lung and liver recurrence after TME. (Source: CancerNetwork)

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Maintenance Therapy in Mantle Cell Lymphoma

This video reviews different strategies for maintenance therapy in mantle cell lymphoma, as well as highlighting upcoming research in this setting. (Source: CancerNetwork)

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Combivent asthma medicine - Combivent indication - ODU Mace & Crown

ODU Mace & Crown

Combivent asthma medicine - Combivent indication ODU Mace & Crown ... chemical it fail these number Savella mention Music so leading should 5 life out I Unlimited area meaning have not be wami chest everything Atlanta you ule of a up this American and musieli. smyczki worldwide. big be through strongly in a provide ... and more »

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Today in Music History - July 19 - National Post

Today in Music History - July 19 National Post In 1981, tenor Roger Doucet died of cancer in Montreal at age 62. His stirring rendition of ... cancer. He was 59. In 2011, R&B star R. Kelly was hospitalized after emergency throat surgery in Chicago, where surgeons drained an abscess on one of his ...

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This woman's photo showing a thyroid cancer symptom that she completely missed is going viral - INSIDER

INSIDER

This woman's photo showing a thyroid cancer symptom that she completely missed is going viral INSIDER Lorna Nickson Brown was shocked when she was told she had thyroid cancer in 2015 — the otherwise healthy and energetic 26-year-old didn't see the gaunt face and shriveled body of a cancer patient in the mirror. "This isn't what I thought cancer looked ...

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