Τρίτη, 16 Φεβρουαρίου 2016

Short- and long-term effects of Xuezhikang (血脂康), an extract of cholestin, on serum proprotein convertase subtilisin/kexin type 9 levels

Abstract

Objective

To investigate the short- and long-term effects of Xuezhikang (血脂康, XZK), an extract of cholestin, on proprotein convertase subtilisin/kexin type 9 (PCSK9) level.

Methods

Thirty rats were randomly divided into three groups and were given saline, XZK 1,200 mg/kg or lovastatin 10 mg/kg respectively by daily gavage for 3 days (n=10 for each). Sixteen patients without previous lipid-lowering drug treatment for dyslipidemia received XZK 1,200 mg daily for 8 weeks. Fasting blood samples and liver tissue were collected at day 3 for rats, while the blood samples were obtained at baseline and week 8 from patients. The serum PCSK9 and lipid profile were measured. The expression of hepatic low density lipoprotein (LDL) receptor and sterol regulatory element binding protein 2 (SREBP-2) were measured by real time-PCR.

Results

PCSK9 levels in rats were significantly increased in the XZK and lovastatin groups (P=0.002, P=0.003 vs. control) at day 3, while no significant differences were found in the levels of lipid parameters. PCSK9 levels in patients increased by 34% (P=0.006 vs. baseline) accompanied by total cholesterol and LDL-cholesterol decreased by 22% and 28% P=0.001, P=0.002 vs. baseline). The hepatic mRNA levels of LDL-receptor and SREBP-2 were significantly increased in the XZK and lovastatin groups.

Conclusion

XZK has significant impact on PCSK9 in a short- and long-term manner in both rats and humans. Moreover, the data indicated that as lovastatin, XZK increased PCSK9 levels through SREBP-2 pathway.



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Effects of Chinese Medicine Shen-Fu Injection (参附注射液) on the expression of inflammatory cytokines and complements during post-resuscitation immune dysfunction in a porcine model

Abstract

Objective

To investigate the action of Shen-Fu Injection (参附注射液, SFI) in regulating the expression of the serum complements and inflammatory cytokines synthesized and released in response to the stress of global ischemia accompanying cardiac arrest (CA) and resuscitation.

Methods

Thirty pigs were randomly divided into the sham (n=6) and 3 returns of spontaneous circulation (ROSC) groups (n=24). After 8-min untreated ventricular fibrillation and 2-min basic life support, 24 pigs of the ROSC groups were randomized into three groups (n=8 per group), which received central venous injection of SFI (SFI group), epinephrine (EP group), or saline (SA group). Hemodynamic status and blood samples were obtained at 0, 0.5, 1, 2, 4, 6, 12, and 24 h after ROSC.

Results

Serum concentrations of specific activation markers of the complement system C3, C4 and C5b-9 were increased during cardiopulmonary resuscitation throught 24 h after ROSC. There were intense changes of various pro-inflammatory cytokines and anti-inflammatory cytokines as early as 0.5 h after CA. Compared with the EP and SA groups, SFI treatment reduced the proinflammatory cytokines levels of interleukin (IL)-6, IL-8 and tumor necrosis factor α (TNF-α, P<0.05), and increased the anti-inflammatory cytokine levels of IL-4 and IL-10 (P<0.05). Further, SFI treatment decreased the values of C3, C4 and C5b-9 compared with the EP and SA groups.

Conclusions

SFI, derived from the ancient Chinese medicine, has significant effects in attenuating post-resuscitation immune dysfunction by modulating the expression of complements and cytokines levels. The current study provided an experimental basis for the clinical application of a potential pharmacologic target for post resuscitation immune dysfunction.



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A pragmatic observational feasibility study on integrated treatment for musculoskeletal disorders: Design and protocol

Abstract

Background

Musculoskeletal disorders (MSD) comprise a wide range of conditions, associated with an enormous pain and impaired mobility, and are affecting people’s lives and work. Management of musculoskeletal disorders typically involves a multidisciplinary team approach. Positive findings have been found in previous studies evaluating the effectiveness of complementary therapies, though little attention has been paid to evaluating of the effectiveness of integrated packages of care combining conventional and complementary approaches for musculoskeletal conditions in a National Health Service (NHS) setting.

Objective

To determine the feasibility of all aspects of a pragmatic observational study designed: (1) to evaluate the effectiveness and cost effectiveness of integrated treatments for MSDs in an integrated NHS hospital in the UK; (2) to determine the acceptability of the study design and research process to patients; (3) to explore patients’ expectation and experience of receiving integrated treatments.

Methods

This is an observational feasibility study, with 1-year recruitment and 1-year follow-up, conducted in Royal London Hospital for Integrated Medicine, University College London Hospital Trust, UK. All eligible patients with MSDs newly referred to the hospital were included in the study. Interventions are integrated packages of care (conventional and complementary) as currently provided in the hospital. SF-36™ Health Survey, short form Brief Pain Inventory, Visual Analogue Scale, and modified Client Service Receipt Inventory will be assessed at 4/5 time points. Semi-structured interview/focus group will be carried out before treatment, and 1 year after commence of treatment.

Discussion

We intend to conduct a pragmatic observational study of integrated medical treatment of MSDs at a public sector hospital. It will inform the design of a future trial including recruitment, retention, suitability of the outcome measures and patients experiences.



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Gushing and Gleeking - lareviewofbooks


lareviewofbooks

Gushing and Gleeking
lareviewofbooks
Fat-campers sit in the cafeteria awaiting their meal, “saliva glands audibly gushing and gleeking.” An official ... Their manifesto is a sly inversion of John Galt's: “We believe that the best way to cure society of its cancer is to remove its tumors ...



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Phosphatidic acid induces EHD3-containing membrane tubulation and is required for receptor recycling

Publication date: Available online 16 February 2016
Source:Experimental Cell Research
Author(s): Yuji Henmi, Natsuko Oe, Nozomu Kono, Tomohiko Taguchi, Kohji Takei, Kenji Tanabe
EHD3 is localized on the tubular structures of early endosomes, and it regulates their trafficking pathway. However, the regulatory mechanism of EHD3-containing tubular structures remains poorly understood. An in vitro liposome co-sedimentation assay revealed that EHD3 interacted with phosphatidic acid through its helical domain and this interaction induced liposomal tubulations. Additionally, inhibiting phosphatidic acid synthesis with diacylglycerol kinase inhibitor or lysophosphatidic acid acyltransferase inhibitor significantly reduced the number of EHD3-containing tubules and impaired their trafficking from early endosomes. These results suggest that EHD3 and phosphatidic acid cooperatively regulate membrane deformation and trafficking from early endosomes.



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Role of palliative radiotherapy in the management of mural cardiac metastases: who, when and how to treat? A case series of 10 patients

Abstract

Cardiac metastases (CM), although a rare manifestation of metastatic cancer, are increasing in incidence with the improved prognosis and increased longevity of many patients with cancer. This condition may be life-threatening, especially for bulky rapidly growing tumors. Such cancer presentations may be amenable to palliative radiotherapy to improve symptoms and to prevent further cardiac function decline. Here, we report on our experience with 10 patients with mural CM who received radiotherapy (RT) to the heart with palliative intent. The radiation treatment was given in different clinical situations using different dose and fractionation, and with a variety of outcomes. Palliative RT was a reasonably effective treatment, leading to good radiographic response in five patients who were evaluable for radiologic response. The mean duration of response in responding patients was 6.3 months (range: 3–11 months). This report describing clinical dilemmas around CM radiation therapy summarizes the previous experiences with radiation in treatment of CM and may assist in the considerations of palliative treatment for these patients.

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The success of palliative radiotherapy in improving clinical symptoms and achieving good local control for mural cardiac metastases calls for further consideration of this modality either as a single modality or in combination with surgery and/or chemotherapy. Our experience shows that common palliative dose fractionation schemes (such as 8, 20, or 30 Gy in 1, 5, and 10 fractions, respectively) is safe and effective and should be considered early in the management of these patients.



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Is there a progression-free survival benefit of first-line crizotinib versus standard chemotherapy and second-line crizotinib in ALK-positive advanced lung adenocarcinoma? A retrospective study of Chinese patients

Abstract

Although crizotinib has demonstrated promising efficacy and acceptable toxicity in patients with advanced non-small cell lung cancer (NSCLC), the available evidence in Chinese populations is currently limited. This study compared the progression-free survival (PFS) of Chinese patients with anaplastic lymphoma kinase (ALK)-positive, advanced lung adenocarcinoma who received first-line crizotinib therapy with that of patients who received first-line standard chemotherapy, and also the PFS benefit of first-line versus second-line crizotinib treatment. Data on 80 patients with ALK-positive, advanced lung adenocarcinoma who received crizotinib or standard chemotherapy as first-line treatments between June 2013 and December 2014 were retrospectively collected; 26 of the patients received crizotinib as second-line therapy after progressive disease (PD) occurred on first-line chemotherapy. Tumor responses were assessed using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. The median PFS was 13.3 months (95% CI: 6.5–20.0 months) in patients who received first-line crizotinib as compared with 5.4 months (95% CI: 4.4–6.5 months) in patients who received first-line standard chemotherapy (adjusted hazard ratio for progression or death with crizotinib, 0.20; 95% CI: 0.11–0.36; < 0.001). In patients who received second-line crizotinib therapy, the median PFS was 9.9 months (95% CI: 6.4–13.4 months). The difference between first-line and second-line crizotinib treatment was not statistically significant (adjusted hazard ratio for progression, 0.56; 95% CI: 0.29–1.11; = 0.092). Thus, there was a significant PFS benefit of first-line crizotinib versus first-line standard chemotherapy in Chinese patients with ALK-positive lung adenocarcinoma. Additionally, crizotinib showed promising efficacy in patients who received it as second-line therapy after PD had occurred on first-line chemotherapy.

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There was a significant progression-free survival (PFS) benefit of first-line crizotinib versus first-line standard chemotherapy in Chinese patients with anaplastic lymphoma kinase (ALK)-positive lung adenocarcinoma. Additionally, crizotinib showed promising efficacy in patients who received it as second-line therapy after progressive disease (PD) had occurred on first-line chemotherapy.



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The role of stem cells in the prevention and treatment of radiation-induced xerostomia in patients with head and neck cancer

Abstract

Xerostomia is an important complication following radiotherapy (RT) for head and neck cancer. Current treatment approaches are insufficient and can only temporarily relieve symptoms. New insights into the physiopathology of radiation-induced xerostomia might help us in this regard. This review discusses the current knowledge of salivary gland stem cells in radiation-induced xerostomia and their value in the prevention and treatment of this complication. Salivary gland stem cell transplantation, bone marrow-derived cell mobilization, molecular regulation of parotid stem cells, stem cell sparing RT, and adaptive RT are promising techniques that are discussed in this study.

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This review discusses the current knowledge of salivary gland stem cells in radiation-induced xerostomia and their value in the prevention and treatment of radiation-induced xerostomia.



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A novel approach to predict cetuximab-induced hypersensitivity reaction: detection of drug-specific IgE on basophils

Abstract

Cetuximab is remarkable for the relatively high rate and severity of hypersensitivity reactions (HR) being reported in the literature. Screening for cetuximab-specific IgE in serum via immunoassay has been found to be useful in preventing HR; however, these tests are known to have a low positive predictive rate. In an attempt to remedy this, we evaluated the interaction between cetuximab and IgE on basophils for predicting severe cetuximab-induced HR. Twelve head and neck cancer patients were enrolled in this single-institution study: four with a history of cetuximab-induced HR and eight with no such history. Cetuximab-specific and galactose-α-1,3-galactose (α-gal) specific IgEs in serum were measured in vitro using an enzyme-linked immunosorbent assay (ELISA). IgE-cetuximab binding on basophils was also analyzed to evaluate the decrease in cetuximab molecules on basophils after dissociation of IgE from FcεRI. The positive predictive value associated with the presence of cetuximab- or α-gal-specific IgE in serum was found to be only 0.67, whereas the negative predictive value was 1.00. On the other hand, in all four patients who developed HR, the cetuximab molecules on basophils were decreased significantly due to the dissociation of IgE from basophils (P < 0.05). However, this was not the case in patients who did not develop HR. In conclusion, our results strongly imply that the IgE-cetuximab interaction on basophils may be key to developing improved methods for predicting severe cetuximab-induced HR.

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We indicated for the first time that a quantification of the interaction between cetuximab and IgE on basophils, the site responsible for IgE-mediated allergy, allows a more precise definition of the clinical presentation of allergic reaction due to cetuximab.



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Glycosylation status of serum immunoglobulin G in patients with prostate diseases

Abstract

Occurrences of high values in patients with benign prostate disease and low values in patients with highly suspicious cancer have diminished the trustworthiness of prostate-specific antigen as an early diagnostic marker of prostate cancer. In the search for other complimentary markers, we focused on serum IgG from patients with prostate diseases as well as normal subjects. IgG purified from the sera of normal control subjects and patients with prostate diseases, was digested with peptide N-glycanase. Released glycans were quantified using MALDI-time of flight mass spectrometry. We report that N-linked (N-acetylhexosamine)2(deoxyhexose)(mannose)3(N-acetylglucosamine)2 was significantly increased in the IgG heavy chains of patients with prostate cancer compared with that of either benign prostatic disease patients or healthy subjects, whereas (hexose)(N-acetylhexosamine)2(deoxyhexose)(mannose)3 (N-acetylglucosamine)2 was more abundant in the heavy chains of healthy subjects and benign prostatic disease patients. Thus, an absence of the terminal hexose of N-linked glycans has been closely connected to the progression of prostate cancer. Furthermore, surface plasmon resonance analyses have revealed that IgG from patients with prostate cancer has a decreased binding for Sambucus nigra lectin, compared with that from the benign prostatic disease patients or from normal subjects, suggesting lower levels of (N-acetylneuraminic acid)(α2-6)galactose/N-acetylgalactosamine groups in the N-linked glycans of patient IgG. Meanwhile, wheat germ agglutinin binding to IgG of the cancer group was significantly larger than that for the benign prostatic disease group but smaller than that for normal subjects. Our study indicates that the glycosylation changes in IgG can become useful diagnostic parameters for prostate cancer.

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We report that N-linked (N-acetylhexosamine)2(deoxyhexose)(mannose)3(N-acetylglucosamine)2 was significantly increased in the serum IgG heavy chains of patients with prostate cancer compared with that of either benign prostatic disease patients or healthy normal subjects, whereas (hexose)(N-acetylhexosamine)2(deoxyhexose)(mannose)3 (N-acetylglucosamine)2 was more abundant in the heavy chains of healthy subjects and benign prostatic disease patients. Thus, an absence of the terminal hexose of N-linked glycans has been closely connected to the progression of prostate cancer.



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Even in death, David Bowie is one step ahead of us - The Verge


The Verge

Even in death, David Bowie is one step ahead of us
The Verge
Blackstar, the album he released three days before his death from cancer at age 69, now feels less like a late-career revitalization — uncommon, but not unprecedented — than an invitation to contemplate the swirling maelstrom of ideas, memories, and ...

and more »


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IJERPH, Vol. 13, Pages 219: Bioremediation of Crude Oil Contaminated Desert Soil: Effect of Biostimulation, Bioaugmentation and Bioavailability in Biopile Treatment Systems

This work was aimed at evaluating the relative merits of bioaugmentation, biostimulation and surfactant-enhanced bioavailability of a desert soil contaminated by crude oil through biopile treatment. The results show that the desert soil required bioaugmentation and biostimulation for bioremediation of crude oil. The bioaugmented biopile system led to a total petroleum hydrocarbon (TPH) reduction of 77% over 156 days while the system with polyoxyethylene (20) sorbitan monooleate (Tween 80) gave a 56% decrease in TPH. The biostimulated system with indigenous micro-organisms gave 23% reduction in TPH. The control system gave 4% TPH reduction. The addition of Tween 80 led to a respiration rate that peaked in 48 days compared to 88 days for the bioaugmented system and respiration declined rapidly due to nitrogen depletion. The residual hydrocarbon in the biopile systems studied contained polyaromatics (PAH) in quantities that may be considered as hazardous. Nitrogen was found to be a limiting nutrient in desert soil bioremediation.

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Detrimental Health Effects of Benzene Exposure in Adults After a Flaring Disaster at the BP Refinery Plant in Texas City

Research Articles
Mark A. D’Andrea, G. Kesava Reddy
Disaster Medicine and Public Health Preparedness,FirstView Article(s), 7 pages

Abstract
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Endoscopic vocal fold injection using a 25-gauge butterfly needle

Rapid Communication
M A Buchanan, F Riffat, C E Palme
The Journal of Laryngology & Otology,FirstView Article(s), 3 pages

Abstract
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Weighted Energy-Balanced Efficient Routing Algorithm for Wireless Body Area Network

Wireless Body Area Network (WBAN) is a small-scaled sensor network consisting of a series of medical devices attributed to, around, or implanted in a human body, providing continuous monitoring by different sensors to collect vital signals or motion and GPS. This paper proposes an effective routing algorithm to balance the energy consumption within a WBAN in order to prolong the overall lifetime of the network, called dynamic routing algorithm (DRA) and its improved version based on a multipath choice mechanism. Theoretical analysis and simulation result are demonstrated to evaluate the performance of the algorithm and represent that energy consumption of sensors in the network is reasonably scheduled and life cycle of the network is significantly extended. The routing algorithm proposed in this paper may be potentially applied to significantly save energy of multiple types of sensors during vital signals aggregating and transmitting under the WBAN.

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HPTLC Fingerprint Profile (Phenolics) of Selected Cyathea Species from Western Ghats, South India

HPTLC analysis was performed to study the phenolics, flavonoids, and tannins profile of Cyathea nilgirensis Holttum, Cyathea gigantea (Wall. ex. Hook.) Holttum, and Cyathea crinita (Hook.) Copel. The maximum number of bands was observed in the ethanolic extracts of C. crinita. The phenolic bands with values 0.05, 0.32, 0.43, 0.75 (quercetin), and 0.83 demonstrated their occurrence in all the three studied species of Cyathea. Flavonoids with values 0.05, 0.23, 0.30, 0.43, and 0.73 showed their presence in the three studied species of Cyathea. Tannins with the values 0.05, 0.09, and 0.82 determined their existence in all the three studied Cyathea species. Gallic acid was present only in C. crinita with the value 0.49. The developed HPTLC profiles can be used for identification and quantitative determination of phenolics, flavonoids, and tannins. This method is also suitable for rapid screening of Cyathea species for chemotypic assessment and also for quality control purposes.

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Robust Control of Underactuated Systems: Higher Order Integral Sliding Mode Approach

This paper presents a robust control design for the class of underactuated uncertain nonlinear systems. Either the nonlinear model of the underactuated systems is transformed into an input output form and then an integral manifold is devised for the control design purpose or an integral manifold is defined directly for the concerned class. Having defined the integral manifolds discontinuous control laws are designed which are capable of maintaining sliding mode from the very beginning. The closed loop stability of these systems is presented in an impressive way. The effectiveness and demand of the designed control laws are verified via the simulation and experimental results of ball and beam system.

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Optical Flow Sensor/INS/Magnetometer Integrated Navigation System for MAV in GPS-Denied Environment

The drift of inertial navigation system (INS) will lead to large navigation error when a low-cost INS is used in microaerial vehicles (MAV). To overcome the above problem, an INS/optical flow/magnetometer integrated navigation scheme is proposed for GPS-denied environment in this paper. The scheme, which is based on extended Kalman filter, combines INS and optical flow information to estimate the velocity and position of MAV. The gyro, accelerator, and magnetometer information are fused together to estimate the MAV attitude when the MAV is at static state or uniformly moving state; and the gyro only is used to estimate the MAV attitude when the MAV is accelerating or decelerating. The MAV flight data is used to verify the proposed integrated navigation scheme, and the verification results show that the proposed scheme can effectively reduce the errors of navigation parameters and improve navigation precision.

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Application of PK/PD Modeling in Veterinary Field: Dose Optimization and Drug Resistance Prediction

Among veterinary drugs, antibiotics are frequently used. The true mean of antibiotic treatment is to administer dose of drug that will have enough high possibility of attaining the preferred curative effect, with adequately low chance of concentration associated toxicity. Rising of antibacterial resistance and lack of novel antibiotic is a global crisis; therefore there is an urgent need to overcome this problem. Inappropriate antibiotic selection, group treatment, and suboptimal dosing are mostly responsible for the mentioned problem. One approach to minimizing the antibacterial resistance is to optimize the dosage regimen. PK/PD model is important realm to be used for that purpose from several years. PK/PD model describes the relationship between drug potency, microorganism exposed to drug, and the effect observed. Proper use of the most modern PK/PD modeling approaches in veterinary medicine can optimize the dosage for patient, which in turn reduce toxicity and reduce the emergence of resistance. The aim of this review is to look at the existing state and application of PK/PD in veterinary medicine based on in vitro, in vivo, healthy, and disease model.

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IJMS, Vol. 17, Pages 240: Role of miR-222-3p in c-Src-Mediated Regulation of Osteoclastogenesis

MicroRNAs (miRNAs) are small non-coding RNAs that play a mostly post-transcriptional regulatory role in gene expression. Using RAW264.7 pre-osteoclast cells and genome-wide expression analysis, we identified a set of miRNAs that are involved in osteoclastogenesis. Based on in silico analysis, we specifically focused on miR-222-3p and evaluated its role in osteoclastogenesis. The results show that the inhibitor of miR-222-3p upregulated the mRNA levels of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) and tartrate-resistant acid phosphatase (TRAP), while its mimicking agent downregulated their mRNA levels. Western blot analysis showed that its inhibitor increased the protein levels of TRAP and cathepsin K, while its mimicking agent decreased their levels. Genome-wide mRNA expression analysis in the presence and absence of receptor activator of nuclear factor κ-B ligand (RANKL) predicted c-Src as a potential regulatory target of miR-222-3p. Live cell imaging using a fluorescence resonance energy transfer (FRET) technique revealed that miR-222-3p acted as an inhibitor of c-Src activity, and a partial silencing of c-Src suppressed RANKL-induced expression of TRAP and cathepsin K, as well as the number of multi-nucleated osteoclasts and their pit formation. Collectively, the study herein demonstrates that miR-222-3p serves as an inhibitor of osteoclastogenesis and c-Src mediates its inhibition of cathepsin K and TRAP.

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Cancers, Vol. 8, Pages 21: Nephrotoxicity as a Dose-Limiting Factor in a High-Dose Cisplatin-Based Chemoradiotherapy Regimen for Head and Neck Carcinomas

Purpose: Loco-regional control and organ preservation are significantly improved with concomitant cisplatin/radiotherapy and are compromised with less than 5% grade 3 nephrotoxicity (creatinine clearance 15–29 mL/min). However, although clinically important, in none of the randomized trials is grade 2 nephrotoxicity (defined as creatinine clearance 59–30 mL/min) mentioned. In this study, we assessed nephrotoxicity in daily practice among patients treated with high-dose cisplatin (100 mg/m2 on days 1, 22, and 43), concurrently with chemoradiotherapy (CCRT) and the impact on treatment modifications. Methods: 208 patients with advanced-stage malignancies of the head and neck region were evaluated. All patients were treated with high-dose cisplatin CCRT. The main outcome parameters were nephrotoxicity (defined as creatinine clearance grade 2 or more) and cumulative doses of cisplatin and radiation. Results: 133 patients (64%) completed all pre-planned courses of cisplatin. Nephrotoxicity was the main reason to discontinue the chemotherapy. Grade 3 nephrotoxicity was seen in 16 patients (8%) while grade 2 nephrotoxicity was seen in 53 patients (25%). Thirty six patients (17%) could not complete the pre-planned chemotherapy due to nephrotoxicity. Conclusions: In head and neck cancer patients, nephrotoxicity grade 2 is under-reported but is the major factor for discontinuing cisplatin during CCRT.

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Quantitative ultrasound method stages fatty liver

2016_02_11_17_38_57_266_steatosis_200.jpA computer-aided ultrasound technique can be used to stage liver steatosis,...


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Peroxiredoxin 6 homodimerization and heterodimerization with glutathione S-transferase pi are required for its peroxidase but not phospholipase A2 activity

Publication date: Available online 16 February 2016
Source:Free Radical Biology and Medicine
Author(s): Suiping Zhou, Elena M. Sorokina, Sandra Harper, Haitao Li, Luis Ralat, Chandra Dodia, David W. Speicher, Sheldon I. Feinstein, Aron B. Fisher
Peroxiredoxin 6 (Prdx6) is a unique 1-Cys member of the peroxiredoxin family with both GSH peroxidase and phospholipase A2 (PLA2) activities. It is highly expressed in the lung where it plays an important role in antioxidant defense and lung surfactant metabolism. Glutathionylation of Prdx6 mediated by its hetrodimerization with GSH S-transferase π (πGST) is required for its peroxidatic catalytic cycle. Recombinant human Prdx6 crystallizes as a homodimer and sedimentation equilibrium analysis confirmed that this protein exists as a high affinity dimer in solution. Based on measurement of molecular mass, dimeric Prdx6 that was oxidized to the sulfenic acid formed a sulfenylamide during storage. After examination of the dimer interface in the crystal structure, we postulated that the hydrophobic amino acids L145 and L148 play an important role in homodimerization of Prdx6 as well as in its heterodimerization with πGST. Oxidation of Prdx6 also was required for its heterodimerization. Sedimentation equilibrium analysis and the Duolink proximity ligation assay following mutation of the L145 and L148 residues of Prdx6 to Glu indicated greatly decreased dimerization propensity reflecting the loss of hydrophobic interactions between the protein monomers. Peroxidase activity was markedly reduced by mutation at either of the Leu sites and was essentially abolished by the double mutation, while PLA2 activity was unaffected. Decreased peroxidase activity following mutation of the interfacial leucines presumably is mediated via impaired heterodimerization of Prdx6 with πGST that is required for reduction and re-activation of the oxidized enzyme.



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Tousled kinase activator, gallic acid, promotes homologous recombinational repair and suppresses radiation cytotoxicity in salivary gland cells

Publication date: April 2016
Source:Free Radical Biology and Medicine, Volume 93
Author(s): Prakash Srinivasan Timiri Shanmugam, Renjith Parameshwaran Nair, Arrigo De Benedetti, Gloria Caldito, Fleurette Abreo, Gulshan Sunavala-Dossabhoy
Accidental or medical radiation exposure of the salivary glands can gravely impact oral health. Previous studies have shown the importance of Tousled-like kinase 1 (TLK1) and its alternate start variant TLK1B in cell survival against genotoxic stresses. Through a high-throughput library screening of natural compounds, the phenolic phytochemical, gallic acid (GA), was identified as a modulator of TLK1/1B. This small molecule possesses anti-oxidant and free radical scavenging properties, but in this study, we report that in vitro it promotes survival of human salivary acinar cells, NS–SV–AC, through repair of ionizing radiation damage. Irradiated cells treated with GA show improved clonogenic survival compared to untreated controls. And, analyses of DNA repair kinetics by alkaline single-cell gel electrophoresis and γ-H2AX foci immunofluorescence indicate rapid resolution of DNA breaks in drug-treated cells. Study of DR-GFP transgene repair indicates GA facilitates homologous recombinational repair to establish a functional GFP gene. In contrast, inactivation of TLK1 or its shRNA knockdown suppressed resolution of radiation-induced DNA tails in NS–SV–AC, and homology directed repair in DR-GFP cells. Consistent with our results in culture, animals treated with GA after exposure to fractionated radiation showed better preservation of salivary function compared to saline-treated animals. Our results suggest that GA-mediated transient modulation of TLK1 activity promotes DNA repair and suppresses radiation cytoxicity in salivary gland cells.

Graphical abstract

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From pets to people? UC Davis vets' stem cell work gives humans hope - Sacramento Bee


Sacramento Bee

From pets to people? UC Davis vets' stem cell work gives humans hope
Sacramento Bee
That's what it feels like,” said the Marysville resident, who said she gets blood blisters inside her mouth and ulcers on her tongue and lips. She often ... Not only does it “diminish a patient's quality of life,” it also puts patients at greater risk ...



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Stimulation of the EAAT4 glutamate transporter by SGK protein kinase isoforms and PKB

The serum and glucocorticoid inducible kinase (SGK) 1 is expressed in brain tissue and upregulated by ischemia, neuronal excitation, and ...

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