Monthly News Roundup - December 2017

Luxturna Gene Therapy OK'd for Rare Form of Vision Loss A historic approval, Luxturna (voretigene neparvovec-rzyl) from Spark Therapeutics is the first directly administered gene therapy that targets a disease caused by specific gene...

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Oral Biofilm Sampling for Microbiome Analysis in Healthy Children

Changes in the oral microbiome throughout childhood are of growing interest. Comparison of different microbiome studies reveals a lack of standardized sampling protocols. Limited space makes sampling the sound subgingival sulcus of children challenging. Paper point sampling is presented here in detail as the method of choice for this area.

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SC restaurant offers free breakfast to first responders on New Year's Day

By Elise Franco Herald-Journal DUNCAN, S.C. — The Sialmas family is opening its arms, and it's kitchen, to the Upstate on New Year's Day. From 6 to 11 a.m. on Monday, Melissa and Christos Sialmas and their staff at Sialmas Family Restaurant will treat all emergency medical, safety and law enforcement personnel from Spartanburg and Greenville counties to free breakfast during the restaurant's ...

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An In Vivo Duo-color Method for Imaging Vascular Dynamics Following Contusive Spinal Cord Injury

We introduce an in vivo imaging method using two different fluorescent dyes to track dynamic spinal vascular changes following a contusive spinal cord injury in adult Sprague-Dawley rats.

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MicroRNA-155-5p Overexpression in Peripheral Blood Mononuclear Cells of Chronic Lymphocytic Leukemia Patients Is a Novel, Independent Molecular Biomarker of Poor Prognosis

MicroRNA-155-5p (miR-155-5p) is a proinflammatory, oncogenic miRNA, involved in various physiological processes, including hematopoiesis, immunity, inflammation, and cell lineage differentiation. It regulates important transcription factors, such as E2F2, hypoxia-inducible factor 1 (HIF1), and FOXO3. Recently, the dysregulation of miR-155-5p expression has been linked to chronic lymphocytic leukemia (CLL) pathogenesis. In this research study, we investigated the potential diagnostic and prognostic value of miR-155-5p in CLL. To achieve our goal, we isolated total RNA from peripheral blood mononuclear cells (PBMCs) collected from 88 CLL patients and 36 nonleukemic blood donors and performed polyadenylation of total RNA and reverse transcription. Next, we quantified miR-155-5p levels using an in-house-developed real-time quantitative PCR method, before proceeding to extensive biostatistical analysis. Thus, it appears that miR-155-5p is significantly overexpressed in PBMCs of CLL patients and can distinguish them from nonleukemic population. Kaplan-Meier OS analysis and bootstrap univariate Cox regression showed that high miR-155-5p expression predicts inferior OS for CLL patients (). Interestingly, miR-155-5p overexpression retains its unfavorable prognostic role in CLL patients stratified according to established prognostic factors [CD38 expression and mutational status of the immunoglobulin heavy chain variable region (IGHV)]. Thus, miR-155-5p appears as a promising, independent molecular biomarker of unfavorable prognosis in CLL.

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Use of Chinese Medicine Reduces the Development of Cervical Cancer from Pap Smear-Diagnosed Cervical Dysplasia: A Case-Control Study

The Pap test diagnosed cervical dysplasia, which could recover to normal or progress to cervical cancer (CC), is an early stage of cell abnormality before CC. This case-control study analyzed the differences in the risk to develop CC between Chinese medicine (CM) users and nonusers among women who had ever been diagnosed as having cervical dysplasia. A total of 750 CC patients with a cervical dysplasia history were collected between 1998 and 2011 from National Health Insurance Research Database, and controls were women with cervical dysplasia history but did not develop CC. Adjusted odds ratio (aOR) for developing CC was assessed using multivariable logistic regression after adjusting for age, urbanization of residence, and occupation. The proportion of using CM among CC patients was lower than that among CC nonpatients, with an aOR of 0.8. By analyzing the relationship between CC development and the frequency of CM usage, the trend test revealed a significant decreasing trend for developing CC among high-frequency CM users. Moreover, the most frequently used single herb high-frequency was Rheum palmatum (Da-Huang). The usage of CM might be an effective complementary method to prevent uterine cervix from progressing to CC after cervical dysplasia has occurred.

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Pharmacological Effect of Caulophyllum robustum on Collagen-Induced Arthritis and Regulation of Nitric Oxide, NF-κB, and Proinflammatory Cytokines In Vivo and In Vitro

Caulophyllum robustum Maxim (C. robustum) has commonly been used as traditional Chinese medicine for the treatment of rheumatic pain and rheumatoid arthritis (RA) in China. This paper first investigated the anti-inflammation effect of C. robustum extraction (CRME) on RAW264.7 cells stimulated by lipopolysaccharide (LPS) and gene expression levels of inflammatory factors. Moreover, we first evaluated the anti-RA effects of CRME using collagen-induced arthritis (CIA) in DBA/1J mice, and the incidence, clinical score, and joint histopathology were evaluated. The levels of IL-1, IL-6, TNF-α, and PGE2 inflammatory factors in sera of mice were detected by enzyme-linked immunosorbent assay. The expression of NF-κB p65 in the joint was tested by immune histochemical technique. The results showed that, compared with the model group, CRME significantly improved symptoms of the arthritis index, limb swelling, and histological findings by decreasing synovial membrane damage, the extent of inflammatory cell infiltration, and the expansion of capillaries in CIA mice. The results also showed that CRME can reduce the levels of IL-1, IL-6, TNF-α, and PGE2 and inhibit the expression of NF-κB p65. All these results indicated the anti-inflammatory efficacy of CRME as a novel botanical extraction for the treatment of RA.

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Wushenziye Formula Improves Skeletal Muscle Insulin Resistance in Type 2 Diabetes Mellitus via PTP1B-IRS1-Akt-GLUT4 Signaling Pathway

Background. Wushenziye formula (WSZYF) is an effective traditional Chinese medicine in the treatment of type 2 diabetes mellitus (T2DM). Aim. This study aimed to identify the effects and underlying mechanisms of WSZYF on improving skeletal muscle insulin resistance in T2DM. Methods. An animal model of T2DM was induced by Goto-Kakizaki diabetes prone rats fed with high fat and sugar for 4 weeks. Insulin resistance model was induced in skeletal muscle cell. Results. In vivo, WSZYF improved general conditions and decreased significantly fasting blood glucose, glycosylated serum protein, glycosylated hemoglobin, insulin concentration, and insulin resistance index of T2DM rats. In vitro, WSZYF enhanced glucose consumption in insulin resistance model of skeletal muscle cell. Furthermore, WSZYF affected the expressions of molecules in regulating T2DM, including increasing the expressions of p-IRS1, p-Akt, and GLUT4, reducing PTP1B expression. Conclusion. These findings displayed the potential of WSZYF as a new drug candidate in the treatment of T2DM and the antidiabetic mechanism of WSZYF is probably mediated through modulating the PTP1B-IRS1-Akt-GLUT4 signaling pathway.

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Antibiotic-Related Adverse Drug Reactions at a Tertiary Care Hospital in South Korea

Background. Adverse drug reactions (ADRs) are any unwanted/uncomfortable effects from medication resulting in physical, mental, and functional injuries. Antibiotics account for up to 40.9% of ADRs and are associated with several serious outcomes. However, few reports on ADRs have evaluated only antimicrobial agents. In this study, we investigated antibiotic-related ADRs at a tertiary care hospital in South Korea. Methods. This is a retrospective cohort study that evaluated ADRs to antibiotics that were reported at a 2400-bed tertiary care hospital in 2015. ADRs reported by physicians, pharmacists, and nurses were reviewed. Clinical information reported ADRs, type of antibiotic, causality assessment, and complications were evaluated. Results. 1,277 (62.8%) patients were considered antibiotic-related ADRs based on the World Health Organization-Uppsala Monitoring Center criteria (certain, 2.2%; probable, 35.7%; and possible, 62.1%). Totally, 44 (3.4%) patients experienced serious ADRs. Penicillin and quinolones were the most common drugs reported to induce ADRs (both 16.0%), followed by third-generation cephalosporins (14.9%). The most frequently experienced side effects were skin manifestations (45.1%) followed by gastrointestinal disorders (32.6%). Conclusion. Penicillin and quinolones are the most common causative antibiotics for ADRs and skin manifestations were the most frequently experienced symptom.

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Oxidative Modification of Biomolecules in the Nonstimulated and Stimulated Saliva of Patients with Morbid Obesity Treated with Bariatric Surgery

Morbid obesity leads to progressive failure of many human organs and systems; however, the role of oxidative damage to salivary composition is still unknown in the obese patients. In this study, we assessed the effect of bariatric surgery on oxidative damage in nonstimulated (NS) and stimulated (S) whole saliva. The study included 47 subjects with morbid obesity as well as 47 age- and gender-matched healthy volunteers. Oxidative modifications to lipids (4-hydroxynonenal (4-HNE) and 8-isoprostanes (8-isoP)), proteins (advanced oxidation protein products (AOPP) and protein carbonyl groups (PC)), and DNA (8-hydroxy-D-guanosine (8-OHdG)) were analyzed in morbidly obese patients before and after bariatric surgery as well as in the healthy controls. The concentrations of 8-isoP, AOPP, PC, and 8-OHdG were significantly higher in both NS and S of patients with morbid obesity than in the control patients and compared to the results obtained 6 months after bariatric surgery. The levels of oxidative damage markers were also higher in S versus NS of morbidly obese patients. In summary, morbid obesity is associated with oxidative damage to salivary proteins, lipids, and DNA, while bariatric treatment generally lowers the levels of salivary oxidative damage.

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Impact of Elevated Circulating Histones on Systemic Inflammation after Radiofrequency Ablation in Lung Cancer Patients

Background. This study investigated the changes of circulating histones following radiofrequency ablation (RFA) in lung cancer patients and their impact on systemic inflammation. Methods. Serial blood samples were obtained from a total of 65 primary and metastatic lung cancer patients undergoing RFA at 2 time points: pre-RFA and post-RFA within 48 h. Circulating histones, myeloperoxidase (MPO), and multiple inflammatory cytokines were measured. Moreover, the patient's sera were incubated overnight with human monocytic U937 cells in the presence or absence of anti-histone antibody, and cytokine production was evaluated. Results. Compared to pre-RFA, there was a significant increase in circulating histones within 48 h after RFA, along with an elevation of MPO and several canonical inflammatory cytokines. Circulating histones were correlated with these inflammatory markers. Notably, compared to the sera obtained before RFA, the patients' post-RFA sera significantly stimulated cytokine production in the supernatant of U937 cells, which could be prevented by anti-histone antibody, thereby confirming a cause-effect relationship between circulating histones and systemic inflammation. Conclusions. This study showed that circulating histones may serve as a marker indicating RFA-related systemic inflammation as well as represent a therapeutic target for resolution of inflammation.

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Silencing Chitinase Genes Increases Susceptibility of Tetranychus cinnabarinus (Boisduval) to Scopoletin

The carmine spider mite Tetranychus cinnabarinus is a major pest of crop and vegetable plants worldwide. Previous studies have shown that scopoletin is a promising acaricidal compound against Tetranychus cinnabarinus. However, the acaricidal mechanism of scopoletin remains unclear. In the present study, 12 full-length cDNAs of chitinase (CHIT) genes from Tetranychus cinnabarinus (designated TcCHITs) were cloned and characterized. Although TcCHITs were expressed throughout all life stages, their expression levels were significantly upregulated during the larval and nymphal stages. TcCHITs were downregulated 24 h after treatment with scopoletin and upregulated 24 h after treatment with diflubenzuron (DFB, a chitin synthesis inhibitor). Feeding double-stranded RNA effectively silenced TcCHIT transcription in Tetranychus cinnabarinus, thus increasing its susceptibility to scopoletin but reducing that to DFB. Meanwhile, TcCHIT silencing in larvae and adult resulted in an extremely low molting rate (7.3%) and high mortality rate (53.3%), respectively, compared with those in the control group. CHIT genes are closely related to arthropod survival, molting, and development in Tetranychus cinnabarinus, suggesting that acaricidal mechanisms of scopoletin and DFB may occur by inhibition and activation of CHIT gene expression, respectively. TcCHIT constitutes a possible target of scopoletin and DFB in Tetranychus cinnabarinus.

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Role of FGF23 in Pediatric Hypercalciuria

Background. This study explored the possible role of FGF23 in pediatric hypercalciuria. Methods. Plasma FGF23 was measured in 29 controls and 58 children and adolescents with hypercalciuria: 24 before treatment (Pre-Treated) and 34 after 6 months of treatment (Treated). Hypercalciuric patients also measured serum PTH hormone, 25(OH)vitD, phosphate, calcium, creatinine, and 24 h urine calcium, phosphate, and creatinine. Results. There were no differences in age, gender, ethnicity, or body mass index either between controls and patients, or between Pre-Treated and Treated patients. Median plasma FGF23 in controls was 72 compared with all patients, 58 RU/mL (). However, whereas FGF23 in Pre-Treated patients, 73 RU/mL, was not different from controls, in Treated patients it was 50 RU/mL, significantly lower than in both controls () and Pre-Treated patients (). In all patients, there was a correlation between FGF23 and urinary calcium (; ). Treated patients had significantly lower urinary calcium (), higher TP/GFR (), and higher serum phosphate () versus Pre-Treated patients. Conclusions. Pharmacological treatment of hypercalciuric patients resulted in significantly lower urinary calcium excretion, lower serum FGF23, and elevated TP/GFR and serum phosphate concentration, without significant changes in PTH. Further studies are indicated. This trial is registered with Clinical Registration Number RBR 8W27X5.

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Corrigendum to “Preservation of Myocardial Perfusion and Function by Keeping Hypertrophied Heart Empty and Beating for Valve Surgery: An In Vivo MR Study of Pig Hearts”

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Preventive Effect of Cashew-Derived Protein Hydrolysate with High Fiber on Cerebral Ischemia

This study aimed to determine the protective effect of cashew nut-derived protein hydrolysate with high dietary fiber (AO) in cerebral ischemic rats induced by the occlusion of right middle cerebral artery (Rt.MCAO). Acute toxicity was determined and data showed that LD50 of AO > 5000 mg/kg BW. To determine the cerebroprotective effect of AO, male Wistar rats were orally given AO at doses of 2, 10, and 50 mg/kg for 14 days and subjected to Rt.MCAO. Brain infarction volume, neurological score, spatial memory, serum lipid profiles, and C-reactive protein together with the brain oxidative stress status were assessed. All doses of AO significantly decreased brain infarction in cortex, hippocampus, and striatum together with the decreased oxidative stress status. The improvement of spatial memory and serum C-reactive protein were also observed in MCAO rats which received AO at all doses. In addition, the decreased serum cholesterol, TG, and LDL but increased HDL were observed in MCAO rats which received high dose of AO. Taken all together, AO is the potential protectant against cerebral ischemia. The improvement of oxidative stress, inflammation, and dyslipidemia might play roles in the actions. However, further researches are required to understand the precise underlying mechanism.

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A Peculiar Case of Invasive Streptococcus pneumoniae

Patients commonly present to the emergency department with acute respiratory distress; however, the differentials are broad and at times difficult to distinguish. We describe a case of severe community-acquired pneumonia (CAP) secondary to invasive Streptococcus pneumoniae. The patient was intubated within 3 h of presentation and suffered multiorgan failure within 72 h of intensive care unit (ICU) admission. This case is a stark illustration of how the most common bacteria associated with CAP can be fatal and highlights the associated markers of severity. It also outlines other potential complications including a very rare phenomenon of cardiomyopathy with myocarditis associated with S. pneumoniae bacteraemia.

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The Root Aqueous Extract of Entada africana Guill. et Perr. (Mimosaceae) Inhibits Implant Growth, Alleviates Dysmenorrhea, and Restores Ovarian Dynamic in a Rat Model of Endometriosis

Entada africana (Mimosaceae) was reported to have analgesic and antioxidant properties. The present study is aimed at investigating the effects of the root aqueous extract of Entada africana (EA) on an experimental model of endometriosis. The study was performed in rats orally treated with EA at doses of 127.5, 255, and 510 mg/kg. Microgynon® 30 served as the reference substance. Estradiol valerate and oxytocin were used to induce dysmenorrhea. Endometrial implant levels of catalase and malondialdehyde (MDA) allowed estimating tissue oxidative status. Ovarian dynamic and rat sexual behavior were assessed through histological analysis of ovaries, uterus, and vagina. EA decreased dysmenorrhea at tested doses following a 7-day treatment (). Endometrial implant volume decreased following the three treatment periods (). Catalase activity () and MDA level () increased only following a 3-day treatment. EA also increased antral follicles, reduced luteinized unruptured follicle number (), and induced animals to be in the estrus phase. In conclusion, EA prevented the progress of endometriosis, reduced dysmenorrhea, promoted ovarian follicle growth, prevented anovulation, and stimulated the special period of rat sexual desire. These results suggest that Entada africana could be a promising alternative option for the treatment of endometriosis.

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The Relationship of Motor Coordination, Visual Perception, and Executive Function to the Development of 4–6-Year-Old Chinese Preschoolers’ Visual Motor Integration Skills

Visual motor integration (VMI) is a vital ability in childhood development, which is associated with the performance of many functional skills. By using the Beery Developmental Test Package and Executive Function Tasks, the present study explored the VMI development and its factors (visual perception, motor coordination, and executive function) among 151 Chinese preschoolers from 4 to 6 years. Results indicated that the VMI skills of children increased quickly at 4 years and peaked at 5 years and decreased at around 5 to 6 years. Motor coordination and cognitive flexibility were related to the VMI development of children from 4 to 6 years. Visual perception was associated with the VMI development at early 4 years and inhibitory control was also associated with it among 4-year-old and the beginning of 5-year-old children. Working memory had no impact on the VMI. In conclusion, the development of VMI skills among children in preschool was not stable but changed dynamically in this study. Meanwhile the factors of the VMI worked in different age range for preschoolers. These findings may give some guidance to researchers or health professionals on improving children's VMI skills in their early childhood.

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Zoledronic Acid Regulates Autophagy and Induces Apoptosis in Colon Cancer Cell Line CT26

Zoledronic acid (ZOL) is the third generation of bisphosphonates, which can inhibit many tumors growth, especially to inhibit the growth of colon cancer. However, the molecular mechanism is still very mysterious. In this study, we observed that ZOL could regulate CT26 colon cancer cells autophagy, promote CT26 cells apoptosis, and inhibit CT26 cells proliferation. Western blotting analysis showed that proapoptosis protein caspase-3 was basically unchanged, whereas the expression of the activated caspase-3 was significantly increased, after CT26 cells were treated with different doses of zoledronic acid. Western blot also showed that ZOL could significantly affect the expression of p-p53 and autophagy-related proteins beclin-1 and p62. In conclusion, the antitumor effect of ZOL on CT26 colon cancer cells in vitro is achieved by apoptosis induction and autophagy regulation, resulting in inhibition of cell proliferation.

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Effect of Dietary Chestnut or Quebracho Tannin Supplementation on Microbial Community and Fatty Acid Profile in the Rumen of Dairy Ewes

Ruminants derived products have a prominent role in diets and economy worldwide; therefore, the capability to control the rumen microbial ecosystem, for ameliorating their quality, is of fundamental importance in the livestock sector. The aim of this study was to evaluate the effect of dietary supplementation with chestnut and quebracho tannins on microbial community and fatty acid profile, in the rumen fluid of dairy ewes. Multivariate analysis of PCR-DGGE profiles of rumen microbial communities showed a correlation among the presence of chestnut or quebracho in the diet, the specific Butyrivibrio group DGGE profiles, the increase in 18:3 cis9, cis12, and cis15; 18:2 cis9 and cis12; 18:2 cis9 and trans11; 18:2 trans11 and cis15; and 18:1 trans11 content, and the decrease in 18:0 concentration. Phylogenetic analysis of DGGE band sequences revealed the presence of bacteria representatives related to the genera Hungatella, Ruminococcus, and Eubacterium and unclassified Lachnospiraceae family members, suggesting that these taxa could be affected by tannins presence in the diets. The results of this study showed that tannins from chestnut and quebracho can reduce the biohydrogenation of unsaturated fatty acids through changes in rumen microbial communities.

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Diagnostic Value of the lncRNA NEAT1 in Peripheral Blood Mononuclear Cells of Patients with Sepsis

Background. This study aims to evaluate the diagnostic value of nuclear-enriched abundant transcript 1 (NEAT1) expression in peripheral blood mononuclear cells (PBMCs) for the early diagnosis of sepsis. Methods. A total of 59 patients with sepsis, 52 noninfectious SIRS patients, and 56 healthy controls were recruited fort this study. The levels of NEAT1 expression in PBMCs were measured using quantitative real-time polymerase chain reaction (qRT-PCR). Results. Compared with healthy controls, NEAT1 expression of PBMCs in sepsis and SIRS groups were significantly increased (3.76 ± 0.71- and 1.64 ± 0.43-fold, resp.) (), but NEAT1 levels are significantly lower in the SIRS group than in the sepsis group, and there was no statistical significant relevance between survivors and nonsurvivors in patients with sepsis. NEAT1 with an area under the curve (AUC) of 0.851 (95% CI: 0.812–0.935) indicated sensitivity (67.85%) and specificity (87.27%) for the diagnosis for sepsis, the positive predictive value (PPV) was 83.3%, and the negative predictive value (NPV) was 71.6%. The AUC for NEAT1 in the diagnosis of SIRS versus healthy controls was 0.755 (95% CI: 0.664–0.847), with 69.23% sensitivity and 70.91% specificity, the PPV was 72.3%, and the NPV was 72.49%. Conclusion. Measurement of NEAT1 expression in PBMCs could be considered as a good additive marker for the diagnosis of sepsis.

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Resveratrol Ameliorates Experimental Alcoholic Liver Disease by Modulating Oxidative Stress

The aim of this study was to investigate the hepatoprotective effects of resveratrol in alcoholic liver disease (ALD). Alcohol was administered to healthy female rats starting from 6% (v/v) and gradually increased to 20% (v/v) by the fifth week. After 16 weeks of intervention, liver enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) were analyzed using a chemistry analyzer, while hepatic antioxidant enzymes, oxidative stress markers, and caspase 3 activity were assessed using ELISA kits. Furthermore, hepatic CYP2E1 protein levels and mRNA levels of antioxidant and inflammation-related genes were determined using western blotting and RT-PCR, respectively. The results showed that resveratrol significantly attenuated alcohol-induced elevation of liver enzymes and improved hepatic antioxidant enzymes. Resveratrol also attenuated alcohol-induced CYP2E1 increase, oxidative stress, and apoptosis (caspase 3 activity). Moreover, genes associated with oxidative stress and inflammation were regulated by resveratrol supplementation. Taken together, the results suggested that resveratrol alleviated ALD through regulation of oxidative stress, apoptosis, and inflammation, which was mediated at the transcriptional level. The data suggests that resveratrol is a promising natural therapeutic agent against chronic ALD.

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Unilateral Arm Crank Exercise Test for Assessing Cardiorespiratory Fitness in Individuals with Hemiparetic Stroke

Cardiorespiratory fitness assessment with leg cycle exercise testing may be influenced by motor impairments in the paretic lower extremity. Hence, this study examined the usefulness of a unilateral arm crank exercise test to assess cardiorespiratory fitness in individuals with stroke, including sixteen individuals with hemiparetic stroke (mean ± SD age, years) and 12 age- and sex-matched healthy controls. Participants performed the unilateral arm crank and leg cycle exercise tests to measure oxygen consumption (O2) and heart rate at peak exercise. The O2 at peak exercise during the unilateral arm crank exercise test was significantly lower in the stroke group than in the control group (). In the stroke group, the heart rate at peak exercise during the unilateral arm crank exercise test did not significantly correlate with the Brunnstrom recovery stages of the lower extremity (), whereas there was a significant correlation during the leg cycle exercise test (rho = 0.775, ). The unilateral arm crank exercise test can detect the deterioration of cardiorespiratory fitness independently of lower extremity motor impairment severity in individuals with hemiparetic stroke. This study is registered with UMIN000014733.

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LPA Gene Polymorphisms and Gene Expression Associated with Coronary Artery Disease

The aim of our study was to investigate the influence of LPA gene polymorphisms for CAD risk and Lp(a) in a case-control study of Chinese Han population. In addition, we further analyzed the effect of LPA gene expression on plasma levels of Lp(a) and CAD risk. First, five SNPs (rs1367211, rs3127596, rs6415085, rs9347438, and rs9364559) in LPA gene were genotyped using the SEQUENOM Mass-ARRAY system in two groups. Second, we used quantitative real-time PCR to examine the mRNA expression levels of LPA gene in 92 cases and 32 controls. Results showed that the frequency of rs6415085-T allele was significantly higher in case group than that in control group (). Haplotypes were not associated with CAD risk (). And cases with the TT/TG genotype had significantly higher plasma Lp(a) levels compared with those that have the rs6415085 GG genotype (). Additionally, the mRNA expression levels in case group are significantly higher than that in control group (). Our study confirmed that rs6415085 was associated with CAD and increased plasma Lp(a) levels. And increased mRNA expression level of LPA gene may be a mechanism in development of CAD.

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Decreased Expression of Semaphorin3A/Neuropilin-1 Signaling Axis in Apical Periodontitis

Apical periodontitis (AP) is a chronic infection of endodontic origin accompanied with bone destruction around the apical region. Semaphorin3A (Sema3A) and neuropilin-1 (Nrp1) are regarded as a pair of immune regulators in bone metabolism. In this study, we firstly investigated the expression pattern of Sema3A/Nrp1 in apical periodontitis and its correlation with bone destruction. Using rat animal model, we analysed the level of mandibular bone destruction and the expression of Sema3A/Nrp1 on days 0, 7, 14, 21, 28, and 35 after pulp exposure. In addition, clinical samples from apical periodontitis patients were obtained to analyse the expression of Sema3A/Nrp1. These results indicated that the bone destruction level expanded from days 7 to 35. The number of positive cells and level of mRNA expression of Sema3A/Nrp1 were significantly decreased from days 7 to 35, with a negative correlation with bone destruction. Moreover, expression of Sema3A/Nrp1 in the AP group was reduced compared to the control group of clinical samples. In conclusion, decreased expression of Sema3A/Nrp1 was observed in periapical lesions and is potentially involved in the bone resorption of the periapical area, suggesting that Sema3A/Nrp1 may contribute to the pathological development of apical periodontitis.

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The Tubular Penetration Depth and Adaption of Four Sealers: A Scanning Electron Microscopic Study

Background. The tubular penetration and adaptation of the sealer are important factors for successful root canal filling. The aim of this study was to evaluate the tubular penetration depth of four different sealers in the coronal, middle, and apical third of root canals as well as the adaptation of these sealers to root canal walls. Materials and Methods. 50 single-rooted teeth were prepared in this study. Forty-eight of them were filled with different sealers (Cortisomol, iRoot SP, AH-Plus, and RealSeal SE) and respective core filling materials. Then the specimens were sectioned and scanning electron microscopy was employed to assess the tubular penetration and adaptation of the sealers. Results. Our results demonstrated that the maximum penetration was exhibited by RealSeal SE, followed by AH-Plus, iRoot SP, and Cortisomol. As regards the adaptation property to root canal walls, AH-Plus has best adaptation capacity followed by iRoot SP, RealSeal SE, and Cortisomol. Conclusion. The tubular penetration and adaptation vary with the different sealers investigated. RealSeal SE showed the most optimal tubular penetration, whereas AH-Plus presented the best adaptation to the root canal walls.

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Effect of Zinc Supplementation on Maintenance Hemodialysis Patients: A Systematic Review and Meta-Analysis of 15 Randomized Controlled Trials

We aimed to examine the effects of zinc supplementation on nutritional status, lipid profile, and antioxidant and anti-inflammatory therapies in maintenance hemodialysis (MHD) patients. We performed a systematic review and meta-analysis of randomized, controlled clinical trials of zinc supplementation. Metaregression analyses were utilized to determine the cause of discrepancy. Begg and Egger tests were performed to assess publication bias. Subgroup analysis was utilized to investigate the effects of zinc supplementation in certain conditions. In the crude pooled results, we found that zinc supplementation resulted in higher serum zinc levels (weighted mean difference [WMD] = 28.489; ), higher dietary protein intake (WMD = 8.012; ), higher superoxide dismutase levels (WMD = 357.568; ), and lower levels of C-reactive protein (WMD = −8.618; ) and malondialdehyde (WMD = −1.275; ). The results showed no differences in lipid profile. In the metaregression analysis, we found that serum zinc levels correlated positively with intervention time (; ) and varied greatly by ethnicity (). Results from Begg and Egger tests showed that there was no significant bias in our meta-analysis (). Results of subgroup analysis supported the above results. Our analysis shows that zinc supplementation may benefit the nutritional status of MHD patients and show a time-effect relationship.

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Insulin Resistance and Its Association with Metabolic Syndrome in Korean Children

Background. This study investigated the association between insulin resistance (IR) and metabolic syndrome (MetS) in children. Methods. A cross-sectional study involving 1036 healthy children aged between 7 and 13 years was conducted. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated as an index of IR. Participants were classified according to the HOMA-IR quartiles. Results. Incremental, linear trends were found in age (), body mass index (BMI) (), body fat (), waist circumference (), resting blood pressures (BP) (), triglycerides (TG) (), total cholesterol (TC) (), high density lipoprotein-cholesterol (HDL-C) (), FBG (), and insulin (

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Measurement of Gender Differences of Gastrocnemius Muscle and Tendon Using Sonomyography during Calf Raises: A Pilot Study

Skeletal muscles are essential to the gender-specific characteristics of human movements. Sonomyography, a new signal for quantifying muscle activation, is of great benefit to understand muscle function through monitoring the real-time muscle architectural changes. The purpose of this pilot study was to investigate gender differences in the architectural changes of gastronomies muscle and tendon by using sonomyography during performing two-legged calf raising exercises. A motion analysis system was developed to extract sonomyography from ultrasound images together with kinematic and kinetic measurements. Tiny fascicle length changes among seven male subjects were observed at the initial part of calf raising, whereas the fascicle of seven female subjects shortened immediately. This result suggested that men would generate higher mechanical power output of plantar flexors to regulate their heavier body mass. In addition, the larger regression coefficient between the fascicle length and muscle force for the male subjects implied that higher muscle stiffness for the men was required in demand of maintaining their heavier body economically. The findings from the current study suggested that the body mass might play a factor in the gender difference in structural changes of muscle and tendon during motion. The sonomyography may provide valuable information in the understanding of the gender difference in human movements.

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Structural insights into simocyclinone as an antibiotic, effector ligand and substrate

Abstract

Simocyclinones are antibiotics produced by Streptomyces and Kitasatospora species that inhibit the validated drug target DNA gyrase in a unique way, and they are thus of therapeutic interest. Structural approaches have revealed their mode of action, the inducible-efflux mechanism in the producing organism, and given insight into one step in their biosynthesis. The crystal structures of simocyclinones bound to their target (gyrase), the transcriptional repressor SimR and the biosynthetic enzyme SimC7 reveal fascinating insight into how molecular recognition is achieved with these three unrelated proteins.

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Use of genetic and chemical synthetic lethality as probes of complexity in bacterial cell systems

Abstract

Different conditions and genomic contexts are known to have an impact on gene essentiality and interactions. Synthetic lethal interactions occur when a combination of perturbations, either genetic or chemical, result in a more profound fitness defect than expected based on the effect of each perturbation alone. Synthetic lethality in bacterial systems has long been studied; however, during the past decade, the emerging fields of genomics and chemical genomics have led to an increase in the scale and throughput of these studies. Here, we review the concepts of genomics and chemical genomics in the context of synthetic lethality and their revolutionary roles in uncovering novel biology such as the characterization of genes of unknown function and in antibacterial drug discovery. We provide an overview of the methodologies, examples and challenges of both genetic and chemical synthetic lethal screening platforms. Finally, we discuss how to apply genetic and chemical synthetic lethal approaches to rationalize the synergies of drugs, screen for new and improved antibacterial therapies and predict drug mechanism of action.

http://ift.tt/2q22x2V

Environmental factors influencing the development and spread of antibiotic resistance

Abstract

Antibiotic resistance and its wider implications present us with a growing healthcare crisis. Recent research points to the environment as an important component for the transmission of resistant bacteria and in the emergence of resistant pathogens. However, a deeper understanding of the evolutionary and ecological processes that lead to clinical appearance of resistance genes is still lacking, as is knowledge of environmental dispersal barriers. This calls for better models of how resistance genes evolve, are mobilized, transferred and disseminated in the environment. Here, we attempt to define the ecological and evolutionary environmental factors that contribute to resistance development and transmission. Although mobilization of resistance genes likely occurs continuously, the great majority of such genetic events do not lead to the establishment of novel resistance factors in bacterial populations, unless there is a selection pressure for maintaining them or their fitness costs are negligible. To enable preventative measures it is therefore critical to investigate under what conditions and to what extent environmental selection for resistance takes place. In addition, understanding dispersal barriers is not only key to evaluate risks, but also to prevent resistant pathogens, as well as novel resistance genes, from reaching humans.

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The effect of bacterial chemotaxis on host infection and pathogenicity

Abstract

Chemotaxis enables microorganisms to move according to chemical gradients. Although this process requires substantial cellular energy, it also affords key physiological benefits, including enhanced access to growth substrates. Another important implication of chemotaxis is that it also plays an important role in infection and disease, as chemotaxis signalling pathways are broadly distributed across a variety of pathogenic bacteria. Furthermore, current research indicates that chemotaxis is essential for the initial stages of infection in different human, animal and plant pathogens. This review focuses on recent findings that have identified specific bacterial chemoreceptors and corresponding chemoeffectors associated with pathogenicity. Pathogenicity-related chemoeffectors are either host and niche-specific signals or intermediates of the host general metabolism. Plant pathogens were found to contain an elevated number of chemotaxis signalling genes and functional studies demonstrate that these genes are critical for their ability to enter the host. The expanding body of knowledge of the mechanisms underlying chemotaxis in pathogens provides a foundation for the development of new therapeutic strategies capable of blocking infection and preventing disease by interfering with chemotactic signalling pathways.

http://ift.tt/2EixHpT

Metals in fungal virulence

Abstract

Metals are essential for life, and they play a central role in the struggle between infecting microbes and their hosts. In fact, an important aspect of microbial pathogenesis is the 'nutritional immunity', in which metals are actively restricted (or, in an extended definition of the term, locally enriched) by the host to hinder microbial growth and virulence. Consequently, fungi have evolved often complex regulatory networks, uptake and detoxification systems for essential metals such as iron, zinc, copper, nickel and manganese. These systems often differ fundamentally from their bacterial counterparts, but even within the fungal pathogens we can find common and unique solutions to maintain metal homeostasis. Thus, we here compare the common and species-specific mechanisms used for different metals among different fungal species—focusing on important human pathogens such as Candida albicans, Aspergillus fumigatus or Cryptococcus neoformans, but also looking at model fungi such as Saccharomyces cerevisiae or A. nidulans as well-studied examples for the underlying principles. These direct comparisons of our current knowledge reveal that we have a good understanding how model fungal pathogens take up iron or zinc, but that much is still to learn about other metals and specific adaptations of individual species—not the least to exploit this knowledge for new antifungal strategies.

http://ift.tt/2q13kkH

Protein kinase C in fungi—more than just cell wall integrity

Abstract

Human protein kinase C (PKC) isoforms have been implicated in diseases such as Alzheimer's, diabetes and cancers. In contrast to mammals, which have at least nine genes, fungi have only one or two. The yeast Saccharomyces cerevisiae produces only a single Pkc1 and is employed in the study of specific human isozymes, including their susceptibility to pharmacological drugs. Vice versa, the domain structure and regulation of yeast and other fungal PKCs yield insights into the function of human isozymes. Therefore, human PKCs are briefly reviewed herein and related to the yeast enzyme. The latter was originally implicated in the regulation of cell wall synthesis through a conserved MAP kinase pathway, but many more targets have now been described in S. cerevisiae and other fungi. These implicate PKC in the control of such diverse processes as the organization of the actin cytoskeleton, autophagy and apoptosis, nutrient sensing and ribosome biogenesis, cell cycle control, cytokinesis and genetic stability. PKC is a promising target for the development of antifungal drugs against pathogenic fungi such as Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus. Thus, fungal PKCs are drawing increased attention and the accumulating literature on the enzymes from different species is summarized herein.

http://ift.tt/2Ejnk56

Thalassemia

Over the years, an increase in understanding of the underlying molecular and cellular mechanisms as well as the pathophysiology of thalassemia has caused a paradigm shift in diagnosis and treatment.

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Aspirin versus placebo in stage III or high-risk stage II colon cancer with PIK3CA mutation: a French randomised double-blind phase III trial (PRODIGE 50-ASPIK)

Oxaliplatin-based adjuvant chemotherapy is standard of care for radically resected stage III colon cancer and an accepted option for high-risk stage II. Two recent retrospective studies strongly suggested that low-dose aspirin used (100 mg/d) after surgical resection of colorectal cancer with a PIK3CA mutation could act as a targeted therapy with a major protective effect on the risk of recurrence.We propose a double-blind randomized phase III study to evaluate aspirin (100 mg/d during 3 years or until recurrence) versus placebo.

http://ift.tt/2Cr7Hbd

ACCURACY OF FECAL CALPROTECTIN FOR THE PREDICTION OF ENDOSCOPIC ACTIVITY IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE

Fecal calprotectin is a noninvasive marker of inflammatory bowel disease.

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Duodenal invasion of hepatocellular carcinoma following transarterial chemoembolization

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A Review on Ethnopharmacological Applications, Pharmacological Activities, and Bioactive Compounds of Mangifera indica (Mango)

Mangifera indica (family Anacardiaceae), commonly known as mango, is a pharmacologically, ethnomedically, and phytochemically diverse plant. Various parts of M. indica tree have been used in traditional medicine for the treatment of different ailments, and a number of bioactive phytochemical constituents of M. indica have been reported, namely, polyphenols, terpenes, sterols, carotenoids, vitamins, and amino acids, and so forth. Several studies have proven the pharmacological potential of different parts of mango trees such as leaves, bark, fruit peel and flesh, roots, and flowers as anticancer, anti-inflammatory, antidiabetic, antioxidant, antibacterial, antifungal, anthelmintic, gastroprotective, hepatoprotective, immunomodulatory, antiplasmodial, and antihyperlipemic. In the present review, a comprehensive study on ethnopharmacological applications, pharmacological activities, and bioactive compounds of M. indica has been described.

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Integrative Approach to Facilitate Fracture Healing: Topical Chinese Herbal Paste with Oral Strontium Ranelate

Strontium ranelate (SrR) is one of the pharmaceutical agents reported to be effective on the promotion of fracture healing. This study aimed to evaluate the integrative effect of the oral SrR with a topical Chinese herbal paste, namely, CDR, on facilitation of bone healing. The in vivo efficacy was evaluated using rats with tibial fracture. They were treated with either CDR topically, or SrR orally, or their combined treatments. The in vivo results illustrated a significant additive effect of CDR on SrR in increasing the yield load of the fractured tibia. The in vitro results showed that neither SrR nor CDR exhibited a cytotoxic effect on UMR106 and bone-marrow stem cell (BMSC), but both of them increased the proliferation of BMSC at low concentrations. The combination of CDR at 200 μg/mL with SrR at 200 or 400 μg/ml also showed an additive effect on increasing the ALP activity of BMSC. Both SrR and CDR alone reduced osteoclast formation, and the effective concentration of SrR to inhibit osteoclastogenesis was reduced in the presence of CDR. This integrative approach by combining oral SrR and topical CDR is effective in promoting fracture healing properly due to their additive effects on proosteogenic and antiosteoclastogenic properties.

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In Vitro Phagocytosis of Myelin Debris by Bone Marrow-Derived Macrophages

We present methods to assess the phagocytic capacity of primary murine bone marrow-derived macrophages using fluorescently labeled myelin debris and intracellular lipid droplet staining.

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A Rapid and Efficient Method to Dissect Pupal Wings of Drosophila Suitable for Immunodetections or PCR Assays

The ability to accurately detect transcripts or proteins in Drosophila tissues is critical for studying their abundance and localization related to the development process. Here is the description of a straightforward procedure to dissect pupal wings. These wings can be used as samples in several techniques (immunohistochemistry, PCR assay, etc.).

http://ift.tt/2Ej1uyD

Texas college aims to bring medical students of different fields together

By Ruth Campbell Odessa American ODESSA, Texas — Odessa College's Health Sciences Building is being renovated to allow everyone from emergency medical services students to nursing and radiologic technology pupils to mingle and cooperate. Vice President for Business Affairs Virginia Chisum said the two-story, 57,000-square-foot building is being remodeled in stages. Chisum said they started ...

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Effect of Telemedicine Education and Telemonitoring on Continuous Positive Airway Pressure Adherence. The Tele-OSA Randomized Trial

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 1, Page 117-126, January 1, 2018.


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The Impact of the ASAP Trial: Maybe We Shouldn’t Act So Quickly

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 1, Page 142-143, January 1, 2018.


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We Have to Learn to Do without Knowing Enough: Antieosinophilic Treatments for Severe Asthma

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 1, Page 1-2, January 1, 2018.


http://ift.tt/2Elzhr1

Mesenchymal Stromal Cell Exosomes Ameliorate Experimental Bronchopulmonary Dysplasia and Restore Lung Function through Macrophage Immunomodulation

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 1, Page 104-116, January 1, 2018.


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Diagnosis of peritoneal tuberculosis via endosonography assisted through the needle forceps biopsy of peritoneum: First case in the literature (with video)

Abstract

Ascites can pose a difficult problem in diagnosis of peritoneal tuberculosis, and diagnostic laparoscopy or laparotomy is eventually required in some patients. Herein, we reported the diagnosis of peritoneal tuberculosis in a patient with ascites by using endosonography (EUS) assisted through the needle biopsy forceps (TTNB). The patient was immediately started on the tuberculosis treatment.

This article is protected by copyright. All rights reserved.

http://ift.tt/2Ej9kbG

Phase I trial to evaluate the addition of alisertib to fulvestrant in women with endocrine-resistant, ER+ metastatic breast cancer

Abstract

Purpose

In estrogen receptor-positive (ER+) breast cancer models, activation of Aurora A kinase (AURKA) is associated with downregulation of ERα expression and resistance to endocrine therapy. Alisertib is an oral selective inhibitor of AURKA. The primary objectives of this phase I trial were to determine the recommended phase II dose (RP2D) and evaluate the toxicities and clinical activity of alisertib combined with fulvestrant in patients with ER+ metastatic breast cancer (MBC).

Methods

In this standard 3 + 3 dose-escalation phase I study, postmenopausal patients with endocrine-resistant, ER+ MBC previously treated with endocrine therapy were assigned to one of two dose levels of alisertib (40 or 50 mg) in combination with fixed-dose fulvestrant.

Results

Ten patients enrolled, of which nine were evaluable for the primary endpoint. The median patient age was 59. All patients had secondary (acquired) endocrine resistance, and all had received prior aromatase inhibitor. Six had experienced disease progression on fulvestrant. There were no severe (grade 3+) toxicities reported during cycle 1 at either dose level. The median progression-free survival time was 12.4 months (95% CI 5.3–not met), and the 6-month clinical benefit rate was 77.8% (95% CI 40.0–87.2%).

Conclusions

In patients with endocrine-resistant, ER+ MBC, alisertib in combination with fulvestrant was well tolerated. A favorable safety profile was observed. The RP2D is 50 mg twice daily on days 1–3, 8–10, and 15–17 of a 28-day cycle with standard dose fulvestrant. Promising antitumor activity was observed, including activity among patients with prior progression on fulvestrant.

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The large mouth of largemouth bass is of interest to scientists trying to understand how joints work

Inside the bass's mouth is a system of linked muscle and bone that resembles the mechanism of an oil rig. NYTimes:



Read more here: http://ift.tt/2DAmX4W

Posted at Clinical Cases and Images. Stay updated and subscribe, follow us on Twitter and connect on Facebook.

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Introduction: Antibody-Mediated Therapy Special Issue Part 2

Antibodies have been used therapeutically for well over a century but the breadth and depth of their applications are increasing so rapidly and successfully that clinical studies are informing mechanistic questions while basic research continues to interrogate how antibodies are made and function, so their properties can be further refined. The first part of this Special Issue comprised five review articles (1); this second part includes four more reviews. Once again, we thank the authors for their excellent contributions. This issue also includes an original research article that builds on observations from patients with hyper-IgM syndrome to further define the mechanism for antibody class-switch recombination (CSR).

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Cover

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Table of Contents

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A pro-inflammatory role of Fcα/μR on marginal zone B cells in sepsis

Abstract

Fc receptors play important roles for a wide array of immune responses. In contrast to the well-defined Fcγ and Fcε receptors, the molecular and functional characteristics of Fc receptors for IgA and IgM have remained incompletely understood for years. Recent progress has unveiled the characteristics of Fc receptors for IgA and IgM, including Fcα/μ receptor (Fcα/μR) (CD351), polymeric immunoglobulin receptor (poly-IgR), Fcα receptor (FcαRI) (CD89) and Fcμ receptor (FcμR). In this review, we summarize the molecular and functional characteristics of Fcα/μR in comparison with poly-IgR, FcμR and FcαRI, and focus particularly on the pro-inflammatory function of Fcα/μR expressed on marginal zone B cells in sepsis.

http://ift.tt/2lu5Pqj

Depletion of recombination-specific cofactors by the C-terminal mutant of the activation-induced cytidine deaminase causes the dominant negative effect on class switch recombination

Abstract

Activation-induced cytidine deaminase (AID) is essential for class-switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin genes. Studies on in vitro mutagenized AID as well as its mutations in human patients with hyper-IgM (HIGM)-syndrome type II revealed that C-terminal AID mutations were defective in CSR whereas their DNA cleavage and SHM activities remained intact. The C-terminal mutants of AID were speculated to exert the dominant negative effect on wild-type (WT) AID whereas its mechanism remains unknown. We generated the JP41 (R190X) mutation in one allele and a null mutation on the other allele in a mouse B cell line (CH12F3-2A) using CRISPR/Cas9 genome-editing tools and studied the effect of JP41 expression on the function of exogenously introduced WT AID fused with estrogen receptor (AIDER) in AID^JP41/∆/AIDER CH12F3-2A cells. We found that JP41 expression strongly suppressed not only CSR but also Igh/c-Myc chromosomal translocations by AIDER. We showed that the dominant negative effect is not evident at the DNA cleavage step but obvious at both deletional and inversional recombination steps. We also confirmed the dominant negative effect of other C-terminal mutants, JP8Bdel (R183X) and P20 (34-aa insertion at residue 182) in AID-deficient spleen B cells. Finally, we showed that the expression of JP41 reduced the binding of AIDER with its cofactors (hnRNP L, SERBP1 and hnRNP U). Together, these data indicate that dominant negative effect of JP41 on CSR is likely due to the depletion of the CSR-specific RNA-binding proteins from WT AID.

http://ift.tt/2lnxLwG

Targeted antibody therapy and relevant novel biomarkers for precision medicine for rheumatoid arthritis

Abstract

Over the past two decades, the management of rheumatoid arthritis (RA) has progressed remarkably, encompassing the development of new diagnostic tools and efficacious biological agents, such as monoclonal antibodies against inflammatory cytokines and surface markers on immune cells. In addition to the significant efficacy of these biological agents, biomarkers for RA are under consideration for their potential to classify heterogeneous patients into several groups based on clinical and immunological phenotypes for the prediction of clinical course and prognosis and the facilitation of appropriate and precise treatment with the appropriate therapeutic monoclonal antibodies. Biomarkers, particularly those for the prediction and monitoring of the responses to therapeutic monoclonal antibodies for RA, are in demand, with many approaches examined in recent years. In this article, we have summarized the background research on biomarkers and introduced recent topics in the field that enable the possible clinical applications of biomarkers, especially those related to pathogenic cytokines, to guide the treatment of RA.

http://ift.tt/2lwKn46

Sweet SIGNs: IgG glycosylation leads the way in IVIG-mediated resolution of inflammation

Abstract

A hallmark of many chronic inflammatory and autoimmune diseases is that there is an impaired resolution of inflammation and return to the steady state. The infusion of high doses of pooled serum IgG preparations from thousands of donors [intravenous immunoglobulin (IVIG) therapy] has been shown to induce resolution of inflammation in a variety of chronic inflammatory and autoimmune diseases, suggesting that IgG molecules can instruct the immune system to stop inflammatory processes and initiate the return to the steady state. The aim of this review is to discuss how insights into the mechanism of IVIG activity may help to understand the molecular and cellular pathways underlying resolution of inflammation. We will put a special emphasis on pathways dependent on the IgG F_C domain and IgG sialylation, as several recent studies have provided new insights into how this glycosylation-dependent pathway modulates innate and adaptive immune responses through different sets of C-type or I-type lectins.

http://ift.tt/2lnWNf4

IVIG-mediated effector functions in autoimmune and inflammatory diseases

Abstract

Intravenous immunoglobulin (IVIG) is a pooled preparation of normal IgG obtained from several thousand healthy donors. It is widely used in the immunotherapy of a large number of autoimmune and inflammatory diseases. The mechanisms of action of IVIG are complex and, as discussed in this review, experimental and clinical data provide an indicator that the therapeutic benefit of IVIG therapy is due to several mutually non-exclusive mechanisms affecting soluble mediators as well as cellular components of the immune system. These mechanisms depend on Fc and/or F(ab′)₂ fragments. A better understanding of the effector functions of IVIG should help in identification of biomarkers of responses to IVIG in autoimmune patients.

http://ift.tt/2ltQy8N

Incidence, risk and prognostic role of anti-epidermal growth factor receptor-induced skin rash in biliary cancer: a meta-analysis

Abstract

Background

Anti-epidermal growth factor receptor (EGFR)-induced skin rash is a common adverse event and is considered a prognostic factor of various cancers. However, the role of rash is rarely known in biliary cancer, possibly owing to the low incidence of this frequently fatal malignancy. We thus performed a meta-analysis to investigate the incidence, risk and prognostic significance of skin rash related to anti-EGFR treatment for biliary cancer.

Methods

Eligible studies were enrolled after a systematic search of electronic databases. A fixed-effects or random-effects model was utilized according to the heterogeneity.

Results

Fourteen clinical trials published between 2006 and 2017 comprising 1,106 patients with advanced biliary cancer were included. The overall incidence of all-grade and high-grade (grade ≥3) rash was 78.2% [95% confidence interval (CI) 70.4–84.3] and 11.3% (7.6–16.5), respectively. Anti-EGFR treatment correlates with a significantly increased risk of all-grade [risk ratio (RR) 7.37, 95% CI 5.11–10.64, p < 0.0001] and high-grade (RR 6.94, 95% CI 1.89–25.45, p = 0.0035) rash compared with control medication. Higher grades of skin rash correlate with a higher objective response rate (RR 3.50, 95% CI 1.47–8.33, p = 0.0048), and a longer overall [hazard ratio (HR) 0.47, 95% CI 0.31–0.71, p = 0.0003) and progression-free survival (HR 0.51, 95% CI 0.36–0.72, p = 0.0001) compared with lower grades or no rash in patients who received anti-EGFR treatment.

Conclusions

Anti-EGFR treatment correlates with an increased risk of skin rash in advanced biliary cancer. Stratifying patients by the severity of rash may have major implications for survival benefit regarding anti-EGFR treatment for biliary cancer.

http://ift.tt/2CclN3E

Development of a Patient Decision Aid for Syncope in the Emergency Department: the SynDA tool

Abstract

Objectives

To develop a patient decision aid to promote shared decision-making for stable, alert patients who present to the emergency department (ED) with syncope.

Methods

Using input from patients, clinicians, and experts in the field of syncope, health care design, and shared decision-making, we created a prototype of a paper-based decision aid to engage patients in the disposition decision (admission vs. discharge) after an unremarkable ED evaluation for syncope. In phase 1, we conducted 1-on-1 semi-structured exploratory interviews with 10 emergency physicians and 10 ED syncope patients. In phase 2, we conducted 1-on-1 directed interviews with 15 emergency care clinicians, 5 cardiologists, and 12 ED syncope patients to get detailed feedback on decision aid content and design. We iteratively modified the aid using feedback from each interviewee until clarity and usability had been optimized.

Results

The 11- x 17-inch, paper-based decision aid, titled SynDA, includes 4 sections: 1) Explanation of syncope, 2) Explanation of future risks, 3) Personalized 30-day risk estimate, and 4) Disposition options. The personalized risk estimate is calculated using a recently published syncope risk-stratification tool. This risk estimate is stated in natural frequency and graphically displayed using a 100-person color-coded pictogram. Patient-oriented questions are included to stimulate dialogue between patient and clinician. At the end of the development process, patient and physician participants expressed satisfaction with the clarity and usability of the decision aid.

Conclusions

We iteratively developed an evidence-based decision aid to facilitate shared decision-making for alert syncope patients after an unremarkable ED evaluation. Further testing is required to determine its effects on patient care. This decision aid has the potential to improve care for syncope patients and promote patient-centered care in emergency medicine.

This article is protected by copyright. All rights reserved.

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Different applicabilities of the etch-bleach-seal technique for treating opacities on permanent incisor damage by molar incisor hypomineralisation in three young patients

Enamel opacity on anterior teeth can be prejudicial for the aesthetic appearance of affected patients. Patients with molar incisor hypomineralisation, for example, present opacities that can range from discrete white mottling to extensive yellow-brown discolourations. They can request a treatment to improve their aesthetic conditions. Many techniques have been considered to manage this condition. Wright developed a technique called etch–bleach–seal, which showed promising results for the management of anterior enamel opacities. The aims of this report are to present this technique and to analyse its benefits and inconveniences.

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Immunopharmacogenomics towards personalized cancer immunotherapy targeting neoantigens

Summary

Utilizing the host immune system to eradicate cancer cells has been the most investigated subject in the cancer research field in recent years. However, most of the studies have focused on highly variable responses from immunotherapies such as immune checkpoint inhibitors, where the majority of patients experienced no or minimum clinical benefits. Advances in genomic sequencing technologies have improved our understanding of immunopharmacogenomics and allowed us to identify novel cancer-specific immune targets. Highly tumor-specific antigens, neoantigens, are generated by somatic mutations which are not present in normal cells. It is plausible that by targeting antigens with high tumor-specificity such as neoantigens, the likelihood of toxic effects is likely to be very limited. However, understanding the interaction between neoantigens and the host immune system has remained to be a big challenge. This review focuses on the potential use of neoantigen-targeted immunotherapies in cancer treatment and the recent progresses of the different strategies in predicting, identifying and validating neoantigens. Successful identification of highly tumor-specific antigens accelerates the development of personalized immunotherapy with no or minimum adverse effects and with a broader coverage of patients.

This article is protected by copyright. All rights reserved.

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Pretreatment of Probiotic Bifico Ameliorates Colitis-Associated Cancer in Mice: Transcriptome and Gut Flora Profiling

Abstract

Individuals with inflammatory bowel disease (IBD) are at a high risk for developing colitis-associated cancer (CAC). Strategies to block the process from IBD to CAC should be considered. In the experiment, we aim to explore the chemopreventive efficacy of the probiotic cocktail Bifico and its potential mechanism in azoxymethane (AOM) and dextran sodium sulphate (DSS) induced colitis-associated cancer in mice. Oral pretreatment of Bifico was adopted to evaluate its protective effect. The colorectums of thirty-five C57BL/6 mice were collected and examined for degree of inflammation and tumorigenesis. Methods of cDNA microarray, comparative 16S rRNA sequencing were performed to observe Bifico-target alterations in gene expression and microbiota structure. We found pretreatment of Bifico alleviated intestinal inflammation and reduced tumor formation. Furthermore, we identified a subset of genes as potential targets of Bifico treatment, including chemokine C-X-C motif ligand 1 (CXCL1), CXCL2, CXCL3, and CXCL5, which were all ligands of C-X-C motif receptor 2 (CXCR2). 16S rRNA sequencing demonstrated that Bifico decreased the abundance of genus Desulfovibrio, Mucispirillum and Odoribacter, while a bloom of genus Lactobacillus was detected. Notably, we found abundance of these Bifico-target taxa was significantly associated with the expression of CXCR2 ligand genes. Our studies demonstrate that oral administration of Bifico can ameliorate CAC in mice through intervening with the possible link between Desulfovibrio, Mucispirillum, Odoribacter, Lactobacillus and CXCR2 signaling.

This article is protected by copyright. All rights reserved.

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Cdc37 facilitates cell survival of colorectal carcinoma via activating the CDK4 signaling pathway

Abstract

Cdc37 is an important partner for HSP90, assisting in molecular chaperone activities, particularly with regard to the regulation of protein kinases. Given its influence on cell growth pathways, Cdc37 has been discussed as a potential intermediate in carcinogenesis. However, to date, the potential functional roles and molecular mechanisms by which Cdc37 regulated cell survival remained unclear in colorectal carcinoma. Here, we investigated the expression of Cdc37 and its clinical significance in colorectal carcinoma, and systematically explored the role of Cdc37 in colorectal carcinoma cell survival both in vitro and in vivo and the underlying mechanism. Our results showed that Cdc37 was remarkably up-regulated in colorectal carcinoma, which facilitated cell survival mainly by promoting cell proliferation, G1-S transition, and inhibiting cell apoptosis. Our data further indicated that Cdc37 increased the stability of CDK4 to activate the RB1 signaling pathway, followed by the increased expression of Bcl-2 and Bcl-xL, which ultimately promoted the cell survival in colorectal carcinoma. Moreover, knockdown of CDK4 reversed the Cdc37-mediated effect in promoting the progression of CRC. Our findings demonstrated that Cdc37 played a critical role in promoting colorectal carcinoma cell survival by increasing CDK4 stability to activate the RB1 signaling pathway. Thereby, Cdc37 might serve as a potential therapeutic target in CRC patient.

This article is protected by copyright. All rights reserved.

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Dietary acrylamide intake and risk of breast cancer: the Japan Public Health Center-based Prospective Study

Abstract

Acrylamide forms during cooking and is classified as a probable carcinogen in humans, mandating the need for epidemiological studies of dietary acrylamide and cancers. However, the risk of dietary acrylamide exposure to breast cancer in Japanese women has not been assessed. We investigated the association between dietary acrylamide intake and risk of breast cancer in the Japan Public Health Center-based Prospective Study. The present study included 48,910 women aged 45-74 years who responded to a 5-year follow-up survey questionnaire. Dietary acrylamide intake was assessed using a validated food frequency questionnaire. Cox proportional hazards regression models were used to estimate hazard ratios and 95% confidence intervals. During an average of 15.4 years of follow up, 792 breast cancers were diagnosed. Energy-adjusted dietary acrylamide intake was not associated with the risk of breast cancer (adjusted hazard ratio for highest versus lowest tertile=0.95, 95% confidence intervals: 0.79-1.14, p-trend=0.58). Further, no significant associations were observed when stratified analyses were conducted by smoking status, coffee consumption, alcohol consumption, body mass index, menopausal status, estrogen receptor status, and progesterone receptor status. In conclusion, dietary acrylamide intake was not associated with the risk of breast cancer in this population-based prospective cohort study of Japanese women.

This article is protected by copyright. All rights reserved.

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CCL5 promotes migration of prostate cancer cells in the prostate cancer bone metastasis microenvironment

Summary

Chemokines and their receptors have key roles in cancer progression. This study investigated chemokine activity in the prostate cancer bone metastasis microenvironment. Growth and migration of human prostate cancer cells were assayed in cocultures with bone stromal cells. The migration of LNCaP cells significantly increased when co-cultured with bone stromal cells isolated from prostate cancer bone metastases. Cytokine array analysis of conditioned medium from bone stromal cell cultures identified CCL5 as a concentration-dependent promoter of LNCaP cell migration. The migration of LNCaP cells was suppressed when CCL5 neutralizing antibody was added to cocultures with bone stromal cells. Knockdown of androgen receptor with small interfering RNA increased the migration of LNCaP cells compared with control cells, and CCL5 did not promote the migration of androgen receptor knockdown LNCaP. Elevated CCL5 secretion in bone stromal cells from metastatic lesions induced prostate cancer cell migration by a mechanism consistent with CCL5 activity upstream of androgen receptor signaling.

This article is protected by copyright. All rights reserved.

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IL-6/STAT3 promotes prostate cancer resistance to androgen deprivation therapy via regulating PTTG1 expression

Summary

Prostate cancer can progress from androgen dependence to androgen deprivation resistance with some unknown mechanisms. The current study aims to explore the possible role of pituitary tumor transforming gene1 (PTTG1) in castration-resistant prostate cancer (CRPC). Initially, we found that PTTG1 expression was significantly increased in androgen-independent prostate cancer cell lines PC3, DU145 and CRPC specimens compared with that in androgen-dependent prostate cancer cell line LNCaP and initial prostate cancer specimens. PTTG1 overexpression significantly enhanced the cell survival rate, clonality and tumorigenicity in LNCaP cells upon androgen-deprivation therapy (ADT). While knockdown of PTTG1 expression significantly elevated the sensitivity of DU145 cells to ADT. The effects of PTTG1 overexpression on LNCaP cells may be ascribed to the induced EMT and increased CD44⁺CD24^- cancer stem cell population. Furthermore, we detected that PTTG1 expression was regulated by IL-6 via activated STAT3 directly binding to the region -500 to +1 of PTTG1 promoter in LNCaP cells. In conclusion, our results elucidate that IL-6/STAT3 activation can increase PTTG1 expression and consequently promote the resistance to ADT in CRPC via inducing EMT and increasing the cancer stem cell population, suggesting that PTTG1 may be a novel therapeutic target for CRPC.

This article is protected by copyright. All rights reserved.

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A third-generation oncolytic herpes simplex virus inhibits the growth of liver tumors in mice

Summary

Multimodality therapies are used to manage patients with hepatocellular carcinoma (HCC), although advanced HCC is incurable. Oncolytic virus therapy is probably the next major breakthrough in cancer treatment. The third-generation oncolytic herpes simplex virus type 1 (HSV-1) T-01 kills tumor cells without damaging the surrounding normal tissues. Here we investigated the antitumor effects of T-01 on HCC and the host's immune response to HCC cells. The cytopathic activities of T-01 were tested in 14 human and one murine hepatoma cell lines in vitro. In mouse various xenograft models, HuH-7, KYN-2, PLC/PRF/5 and HepG2 human cells and Hepa1-6 murine cells were used to investigate the in vivo efficacy of T-01. T-01 was cytotoxic to 13 cell lines (in vitro). In mouse xenograft models of subcutaneous, orthotopic and peritoneal tumor metastasis in athymic mice (BALB/c nu/nu), the growth of tumors formed by the human HCC cell lines and hepatoblastoma cell line was inhibited by T-01 compared with that of mock-inoculated tumors. In a bilateral Hepa1-6 subcutaneous tumor model in C57BL/6 mice, the growth of tumors inoculated with T-01 was inhibited and, in the contralateral tumors. T-01 also significantly reduced tumor growth. T-01 infection significantly enhanced antitumor efficacy via T cell-mediated immune responses. Results demonstrate that a third-generation oncolytic HSV-1 may serve as a novel treatment for patients with HCC.

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Expansion of human γδ T cells for adoptive immunotherapy using a bisphosphonate prodrug

Summary

Cancer immunotherapy with human γδ T cells expressing Vγ2Vδ2 T cell receptor (also termed Vγ9Vδ2) has shown promise because of their ability to recognize and kill most types of tumors in an MHC-unrestricted fashion that is independent of the number of tumor mutations. In clinical trials, adoptive transfer of Vγ2Vδ2 T cells has been shown to be safe and does not require preconditioning. In this report, we describe a method for preparing highly enriched human Vγ2Vδ2 T cells using the bisphosphonate prodrug, tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1-bisphosphonate (PTA). PTA stimulated the expansion of Vγ2Vδ2 cells to purities up to 99%. These levels were consistently higher than those observed after expansion with zoledronic acid, the most commonly used stimulator for clinical trials. Cell numbers also averaged more than those obtained with zoledronic acid and the expanded Vγ2Vδ2 cells exhibited high cytotoxicity against tumor cells. The high purity of Vγ2Vδ2 cells expanded by PTA increased engraftment success in immunodeficient NOG mice. Even low levels of contaminating αβ T cells resulted in some mice with circulating human αβ T cells rather than Vγ2Vδ2 cells. Vγ2Vδ2 cells from engrafted NOG mice upregulated CD25 and secreted tumor necrosis factor-α and interferon-γ in response to PTA-treated tumor cells. Thus, PTA expands Vγ2Vδ2 T cells to higher purity than zoledronic acid. The high purities allow the successful engraftment of immunodeficient mice without further purification and may speed the development of allogeneic Vγ2Vδ2 T cell therapies derived from HLA-matched normal donors for patients with poor autologous Vγ2Vδ2 T cell responses.

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Anti-PD-1-induced high-grade hepatitis associated with corticosteroid-resistant T cells: a case report

Abstract

Effective treatment or prevention of immune side effects associated with checkpoint inhibitor therapy of cancer is an important goal in this new era of immunotherapy. Hepatitis due to immunotherapy with antibodies against PD-1 is uncommon and generally of low severity. We present an unusually severe case arising in a melanoma patient after more than 6 months uncomplicated treatment with anti-PD-1 in an adjuvant setting. The hepatitis rapidly developed resistance to high-dose steroids, requiring anti-thymocyte globulin (ATG) to achieve control. Mass cytometry allowed comprehensive phenotyping of circulating lymphocytes and revealed that CD4⁺ T cells were profoundly depleted by ATG, while CD8⁺ T cells, B cells, NK cells and monocytes were relatively spared. Multiple abnormalities in CD4⁺ T cell phenotype were stably present in the patient before disease onset. These included a population of CCR4⁻CCR6⁻ effector/memory CD4⁺ T cells expressing intermediate levels of the Th1-related chemokine receptor CXCR3 and abnormally high multi-drug resistance type 1 transporter (MDR1) activity as assessed by a rhodamine 123 excretion assay. Expression of MDR1 has been implicated in steroid resistance and may have contributed to the severity and lack of a sustained steroid response in this patient. The number of CD4⁺ rhodamine 123-excreting cells was reduced > 3.5-fold after steroid and ATG treatment. This case illustrates the need to consider this form of steroid resistance in patients failing treatment with corticosteroids. It also highlights the need for both better identification of patients at risk and the development of treatments that involve more specific immune suppression.

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FDA Permits Marketing of Device to Treat Diabetic Foot Ulcers

December 28, 2017 -- Today, the U.S. Food and Drug Administration permitted the marketing of the Dermapace System, the first shock wave device intended to treat diabetic foot ulcers. "Diabetes is the leading cause of lower limb amputations,"...

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Bone response to functionally loaded, two-piece zirconia implants: A preclinical histometric study

Abstract

Objective

To evaluate the bone response to a two-piece zirconia implant in comparison with a control titanium implant in the canine mandible 4 and 16 weeks after restoration.

Material and Methods

Zirconia and titanium implants were alternately placed bilaterally in healed mandibular molar and premolar sites of five canines. Full-ceramic single-tooth restorations were cemented after 6 weeks of transmucosal healing, allowing for full functional loading of the implants. Histologic and histometric analyses were performed on orofacial and mesiodistal undecalcified sections of the specimens obtained upon sacrifice after 4 and 16 weeks of functional loading. Bone-to-implant contact (BIC), multinucleated giant cells-to-implant contact (MIC), crestal bone level, and peri-implant bone density were histometrically assessed.

Results

All 60 implants and 60 restorations were still in function after 4 and 16 weeks of loading in both test and control groups. No implant loss, no implant or abutment fracture, and no chipping of the restorations could be detected. Histometric analysis showed no statistically significant differences between zirconia and titanium implants in BIC, crestal bone level, and peri-implant bone density at both time points. Between 4 and 16 weeks, the crestal bone level around zirconia implants showed a small but statistically significant increase in its distance from the implant shoulder. MIC was very low on both implant types and both time points and decreased statistically significantly overtime.

Conclusion

The present two-piece zirconia implant showed a similar bone integration compared to the titanium implant with similar surface morphology after 4 and 16 weeks of loading.

http://ift.tt/2EfTIpn

Anti-PD-1-induced high-grade hepatitis associated with corticosteroid-resistant T cells: a case report

Abstract

Effective treatment or prevention of immune side effects associated with checkpoint inhibitor therapy of cancer is an important goal in this new era of immunotherapy. Hepatitis due to immunotherapy with antibodies against PD-1 is uncommon and generally of low severity. We present an unusually severe case arising in a melanoma patient after more than 6 months uncomplicated treatment with anti-PD-1 in an adjuvant setting. The hepatitis rapidly developed resistance to high-dose steroids, requiring anti-thymocyte globulin (ATG) to achieve control. Mass cytometry allowed comprehensive phenotyping of circulating lymphocytes and revealed that CD4⁺ T cells were profoundly depleted by ATG, while CD8⁺ T cells, B cells, NK cells and monocytes were relatively spared. Multiple abnormalities in CD4⁺ T cell phenotype were stably present in the patient before disease onset. These included a population of CCR4⁻CCR6⁻ effector/memory CD4⁺ T cells expressing intermediate levels of the Th1-related chemokine receptor CXCR3 and abnormally high multi-drug resistance type 1 transporter (MDR1) activity as assessed by a rhodamine 123 excretion assay. Expression of MDR1 has been implicated in steroid resistance and may have contributed to the severity and lack of a sustained steroid response in this patient. The number of CD4⁺ rhodamine 123-excreting cells was reduced > 3.5-fold after steroid and ATG treatment. This case illustrates the need to consider this form of steroid resistance in patients failing treatment with corticosteroids. It also highlights the need for both better identification of patients at risk and the development of treatments that involve more specific immune suppression.

http://ift.tt/2lkucHJ

Immunological hallmarks of cis -DDP-resistant Lewis lung carcinoma cells

Abstract

Purpose

Tumor cell resistance to platinum-based chemotherapeutic agents is one of the major hurdles to successful cancer treatment with these drugs, and is associated with alterations in tumor cell immune evasion and immunomodulatory properties. Immunocyte targeting is considered as a relevant approach to fight drug-resistant cancer. In this study, immunological hallmarks of cis-DDP-resistant Lewis lung carcinoma cells (LLC/R9) were investigated.

Methods

Immunological features of LLC/R9 cells cultured in vitro in normoxic and hypoxic conditions as well as of those that were grown in vivo were examined. The expression of immunologically relevant genes was evaluated by RT-PCR. Tumor cell susceptibility to the macrophage contact tumoricidal activity and NK-mediated cytolysis was investigated in MTT test. TNF-α-mediated tumor cell apoptosis as well as macrophage phagocytosis, oxidative metabolism, and CD206 expression after the treatment with conditioned media from normoxic and hypoxic tumor cells were studied by flow cytometry. Flow cytometry was also used to characterize dendritic cell maturity.

Results

When growing in vitro, LLC/R9 were characterized by slightly increased immunosuppressive cytokine gene expression. Transition to in vivo growth was associated with the enhancement of transcription of these genes in tumor cells. LLC/R9 cells had lowered sensitivity to contact-dependent macrophage-mediated cytotoxicity and to the TNFα-mediated apoptosis in vitro. Conditioned media from hypoxic LLC/R9 cells stimulated reactive oxygen species generation and CD206 expression in non-sensitized macrophages. Acquisition of drug resistance by LLC/R9 cells was associated with their increased sensitivity to NK-cell-mediated cytolysis. Meanwhile, the treatment of LLCR/9-bearing animals with generated ex vivo and loaded with LLC/R9 cell-lysate dendritic cells (DCs) resulted in profoundly enhanced tumor metastasizing.

Conclusion

Decreased sensitivity to macrophage cytolysis, polarizing effect on DCs maturation along with increased susceptibility to NK-cell cytotoxic action promote extensive local growth of chemoresistant LLC/R9 tumors in vivo, but hamper their metastasizing.

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Progression to bone-marrow carcinomatosis and extraosseous legion during treatment with radium-223 for multiple bone metastases

Abstract

A 67-year-old man with metastatic prostate cancer presented with progression to castration-resistant prostate cancer. After sequential therapies with flutamide, estramustine phosphate, docetaxel, enzalutamide, and cabazitaxel for castration-resistant prostate cancer, radium-223 was initiated and continued up to 4 cycles. However, concurrently with radiological and clinical progressions, pancytopenia was observed due to bone-marrow carcinomatosis by prostatic adenocarcinoma. This case suggested that radium-223 should be employed at appropriated timing before appearances of extraosseous and bone-marrow lesions in addition to visceral metastasis.

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The Focused History and Physical - circa 100 BCE

Abstract

When modern physicians reflect on 'ancient medicine' or 'Greek medicine,' they typically think of Hippocrates and Galen. Few know of the raging, centuries-long intellectual debates among physicians about what exactly mattered in the treatment of illness, or about a group of physicians whose pattern-based, systematized approach to health and disease was a forerunner of how today's emergency medicine physicians evaluate and treat their patients.Methodist physicians (c. 100 BCE to 500 CE, active mostly in Rome but present throughout the Mediterranean world) were named after their "method" of healing.

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An overview on Vadimezan (DMXAA), the vascular disrupting agent

Abstract

Vascular disrupting agents (VDAs), a group of cancer remedies, can cause a specific and irreversible destruction of established tumor vessels, and the complete halt of blood flow in the tumor. DMXAA(ASA404) or Vadimezan, a flavone-acetic acid-based drug is the most promising VDAs that induces a rapid shutdown of blood flow in tumors but not in normal tissue. The exact mechanism of vascular disruption is unknown; however proposed direct and indirect mechanisms of action for DMXAA comprises: i) inducing apoptosis in endothelial cells; ii) hemorrhagic necrosis and ischemia in tumor; iii) release of serotonin (5-HT); vi) stimulation of innate immune system; v) production of inflammatory cytokines e.g. TNF, IL-6, GCSF, KC, IP-10, and MCP-1; vi) activation of NFκB and p38 (MAPK); vii) production of nitric oxide and viii) reducing tumor energetics and membrane turnover. Despite the remarkable results from preclinical and Phase I/II, DMXAA has failed in phase III clinical trials. The reason for this surprising discrepancy, among others, was discovered to be STING receptor variations between mice and humans. In this review, the development, the mechanisms of DMXAA action, the clinical trials, the combination therapy, and the future of this drug will be discussed.

This article is protected by copyright. All rights reserved.

This review highlights the characteristics of clinically used vascular disrupting agent drug, vadimezan, DMXAA (ASA404). Also development, and mechanisms of DMXAA action, and also the clinical trials, the combination therapy and the future of this drug is discussed.

http://ift.tt/2EggXzL

FDA Clears Stereotactic Radiotherapy System for Use in Treating Breast Cancer

December 22, 2017 -- Today, the U.S. Food and Drug Administration cleared a new noninvasive stereotactic radiotherapy system intended for use in treating cancer in breast tissue. "With today's clearance, patients will have access to a treatment...

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Difference in causes and prognostic factors of early death between cohorts with de novo and relapsed acute promyelocytic leukemia

Abstract

Early death (ED) remains the most critical issue in the current care of patients with acute promyelocytic leukemia (APL). Very limited data are available regarding ED in patients with relapsed APL. In this retrospective study, 285 de novo and 79 relapsed patients were included. All patients received single-agent arsenic trioxide as induction therapy. The differences in baseline clinical features, incidence, causes, and prognostic factors of ED were compared between the two patient cohorts. The relapse cohort exhibited a better overall condition than the de novo cohort upon hospital admission. The ED rate in the relapsed patients (24.1%) was somewhat higher than that in the de novo patients (17.9%), although the difference was not significant (P = 0.219). For both cohorts, hemorrhage was the main cause of ED, followed by differentiation syndrome, infection, and other causes. Increased serum creatinine level, older age, male sex, white blood cell (WBC) count > 10 × 10⁹/L, and fibrinogen < 1 g/L were independently risk factors for ED in the de novo patients, whereas WBC count > 10 × 10⁹/L, elevated serum uric acid level, and D-dimer > 4 mg/L were independent risk factors for ED in the relapsed patients. These data furnish clinically relevant information that might be useful for designing more appropriate risk-adapted treatment protocols aimed at reducing ED rate in patients with relapsed APL.

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Association between hemorrhagic transformation after endovascular therapy and poststroke seizures

Summary

Objective

Endovascular therapy has recently become standard therapy for select patients with acute ischemic stroke. Infarcted brain tissue may undergo hemorrhagic transformation (HT) after endovascular therapy. We investigated the association between HT and occurrence of poststroke seizures in patients treated with endovascular therapy.

Methods

Consecutive patients treated with endovascular therapy for acute anterior circulation ischemic stroke were included. HT was assessed with computed tomography/magnetic resonance imaging (CT/MRI) at 24 h after stroke onset. Patients were followed for up to 2 years for seizure occurrence.

Results

A total of 205 (57.1% male) patients were analyzed. Median age was 69 years (interquartile range [IQR] 57-78). Among patients with HT, 17.9% (10/56) developed poststroke seizures compared with 4.0% (6/149) among those without HT (hazard ratio [HR] 5.52; 95% confidence interval [CI] 2.00-15.22; P = .001). The association remained significant after adjustment for cortical involvement, baseline National Institutes of Health Stroke Scale score, age and use of intravenous tissue plasminogen activator and clot retrieval (HR 4.85; 95% CI 1.60-14.76; P = .005). In patients who developed seizures within the follow-up period, median time to first seizure was 111 days (IQR 28-369) in patients with HT and 36 days (IQR 0.5-183) in patients without HT.

Significance

A patient who develops HT following endovascular therapy for acute ischemic stroke had a nearly 5 times higher rate of developing poststroke seizures within 2 years. HT may be used as an imaging biomarker for poststroke seizures.

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Cover, Ed Board and TOC

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Study protocol for a multicentre, randomised, controlled trial to assess the effectiveness of antimicrobial central venous catheters versus ordinary central venous catheters at reducing catheter related infections in critically ill Chinese patients

Introduction

Catheter use is associated with many complications and is an iatrogenic source of morbidity and mortality in intensive care units (ICU). The catheter being studied (Certofix Protect) was developed to reduce the risk of catheter related infections. This clinical trial will compare the safety and efficiency of Certofix Protect with that of an ordinary Certofix catheter.

Methods and analysis

In this multicentre trial, we will randomly assigned dual lumen central venous catheterisation (≥5 ds) in patients in the adult ICU to the antimicrobial central venous catheter (CVC) group or the ordinary CVC group. We plan to recruit 12–16 medical centres in China. Our main objective is to assess the effectiveness of antimicrobial CVCs in reducing catheter related bloodstream infection (CRBSI), all cause mortality, catheter colonisation, catheter related thrombosis and other catheter related complications. The primary outcome is the incidence of CRBSI.

Ethics and dissemination

The ethics committee of West China Hospital of Sichuan University has granted ethics approval for this study (27 January 2015). The results will be published in peer reviewed journals and presented at conferences.

Trial registration number

NCT02645682.

http://ift.tt/2Cqdn5A

Pneumonia diagnosis in childhood and incidence of leukaemia, lymphoma and brain cancer: a Danish nationwide cohort study

Objectives

There is an ongoing debate on the possible association between infections in early childhood and subsequent cancer risk, but it remains unclear if a hospital admission for infection is associated with risk of childhood cancer diagnosis. We examined if a hospital-based diagnosis of pneumonia was a clinical marker of the three most common childhood cancers.

Design

Population-based cohort study.

Setting

Denmark, hospital diagnoses, 1994–2013.

Methods

Using national health registries, we compared the observed incidence of leukaemia, lymphoma and brain cancer among 83 935 children with a hospital-based pneumonia diagnosis with that expected among children in the general population. We calculated absolute cancer risks and standardised incidence ratios (SIRs) as a measure of relative risk.

Results

The cancer SIRs were substantially increased during the first 6 months of follow-up; lymphoid leukaemia: 6.2 (95% CI 3.5 to 10.3); myeloid leukaemia: 14.8 (95% CI 6.0 to 30.6); Hodgkin's lymphoma: 60.8 (95% CI 26.2 to 120), non-Hodgkin's lymphoma: 15.9 (95% CI 5.2 to 37.2) and brain cancer: 4.4 (95% CI 1.9 to 8.7). The 6-month absolute risks of leukaemia, lymphoma and brain cancer were all low, reaching 0.05% when combined. An increased risk persisted beyond 5 years for non-Hodgkin's lymphoma and brain cancer. However, the 5-year absolute cancer risk was 0.14%.

Conclusions

The short-term incidence of leukaemia, lymphoma and brain cancer was higher than expected and persisted beyond 5 years for non-Hodgkin's lymphoma and brain cancer. However, the absolute cancer risk was low.

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Wait a minute? An observational cohort study comparing iron stores in healthy Swedish infants at 4 months of age after 10-, 60- and 180-second umbilical cord clamping

Background and objective

Umbilical cord blood (UCB) is a valuable stem cell source used for transplantation. Immediate umbilical cord (UC) clamping is widely practised, but delayed UC clamping is increasingly advocated to reduce possible infant anaemia. The aim of this study was to investigate an intermediate UC clamping time point and to evaluate iron status at the age of 4 months in infants who had the UC clamped after 60 s and compare the results with immediate and late UC clamping.

Design

Prospective observational study with two historical controls.

Setting

A university hospital in Stockholm, Sweden, and a county hospital in Halland, Sweden.

Methods

Iron status was assessed at 4 months in 200 prospectively recruited term infants whose UC was clamped 60 s after birth. The newborn baby was held below the uterine level for the first 30 s before placing the infant on the mother's abdomen for additional 30 s. The results were compared with data from a previously conducted randomised controlled trial including infants subjected to UC clamping at ≤10 s (n=200) or ≥180 s (n=200) after delivery.

Results

After adjustment for age differences at the time of follow-up, serum ferritin concentrations were 77, 103 and 114 µg/L in the 10, 60 and 180 s groups, respectively. The adjusted ferritin concentration was significantly higher in the 60 s group compared with the 10 s group (P=0.002), while the difference between the 60 and 180 s groups was not significant (P=0.29).

Conclusion

In this study of healthy term infants, 60 s UC clamping with 30 s lowering of the baby below the uterine level resulted in higher serum ferritin concentrations at 4 months compared with 10 s UC clamping. The results suggest that delaying the UC clamping for 60 s reduces the risk for iron deficiency.

Trial registration number

NCT01245296.

http://ift.tt/2DzQDiT

Azithromycin to prevent post-discharge morbidity and mortality in Kenyan children: a protocol for a randomised, double-blind, placebo-controlled trial (the Toto Bora trial)

Introduction

Child mortality due to infectious diseases remains unacceptably high in much of sub-Saharan Africa. Children who are hospitalised represent an accessible population at particularly high risk of death, both during and following hospitalisation. Hospital discharge may be a critical time point at which targeted use of antibiotics could reduce morbidity and mortality in high-risk children.

Methods and analysis

In this randomised, double-blind, placebo-controlled trial (Toto Bora Trial), 1400 children aged 1–59 months discharged from hospitals in Western Kenya, in Kisii and Homa Bay, will be randomised to either a 5-day course of azithromycin or placebo to determine whether a short course of azithromycin reduces rates of rehospitalisation and/or death in the subsequent 6-month period. The primary analysis will be modified intention-to-treat and will compare the rates of rehospitalisation or death in children treated with azithromycin or placebo using Cox proportional hazard regression. The trial will also evaluate the effect of a short course of azithromycin on enteric and nasopharyngeal infections and cause-specific morbidities. We will also identify risk factors for postdischarge morbidity and mortality and subpopulations most likely to benefit from postdischarge antibiotic use. Antibiotic resistance in Escherichia coli and Streptococcus pneumoniae among enrolled children and their primary caregivers will also be assessed, and cost-effectiveness analyses will be performed to inform policy decisions.

Ethics and dissemination

Study procedures were reviewed and approved by the institutional review boards of the Kenya Medical Research Institute, the University of Washington and the Kenyan Pharmacy and Poisons Board. The study is being externally monitored, and a data safety and monitoring committee has been assembled to monitor patient safety and to evaluate the efficacy of the intervention. The results of this trial will be published in peer-reviewed scientific journals and presented at relevant academic conferences and to key stakeholders.

Trial registration number

NCT02414399.

http://ift.tt/2Dz3vWm

Association between total dose of ritodrine hydrochloride and pulmonary oedema in twin pregnancy: a retrospective cohort study in Japan

Objective

Pulmonary oedema is recognised as a severe side effect of ritodrine hydrochloride. Recently, the number of twin pregnancies has been increasing. Few studies have reported the association between total dose of ritodrine hydrochloride prior to delivery and pulmonary oedema in twin pregnancy. We aimed to examine this association and determine the optimal cut-off threshold of total ritodrine hydrochloride dose to predict the incidence of pulmonary oedema in twin pregnancy based on obstetric records.

Design

Retrospective cohort study.

Setting

Yamanashi Prefectural Central Hospital, Japan.

Participants

Two hundred and twenty-six women with twin pregnancy who delivered at Yamanashi Prefectural Central Hospital between September 2009 and November 2016.

Methods

The obstetric records of the participants were analysed. We defined 1 unit of ritodrine hydrochloride as 72 mg per 24 hours continuous transfusion at 50 µg/min to calculate the dose of ritodrine used for tocolysis.

Outcome measures

Multivariable logistic regression analysis was performed to examine the association between total dose of ritodrine hydrochloride used for threatened preterm labour and pulmonary oedema, while controlling for potential confounding factors. Then, a receiver–operating characteristic curve was used to determine the optimal cut-off of total ritodrine dose to predict pulmonary oedema incidence.

Results

Mean maternal age was 32 (range, 18–46) years; 143 participants were nulliparous (63.3%), 109 had (48.2%) term deliveries and 194 (85.8%) had caesarean deliveries. The overall incidence of pulmonary oedema was 13.7% (31/226). Multivariable analysis showed that the total dose of ritodrine was significantly associated with pulmonary oedema (adjusted OR 1.02; 95% CI 1.004 to 1.03). The best cut-off point to predict the incidence of pulmonary oedema was 26 units (1872 mg) (sensitivity, 61.3%; specificity, 87.8%).

Conclusion

Our results suggest that consideration of the total dose of ritodrine hydrochloride is helpful in the management of patients with threatened preterm labour in twin pregnancy.

http://ift.tt/2DxjFQ0