Breast cancer survivorship: state of the science

Abstract

Purpose

Only recently has breast cancer survivorship earned formal recognition as a research discipline. Complicating survivorship research is the frequent overlap between aging and treatment sequelae. The ACS/ASCO 2016 Breast Cancer Survivorship Care Guideline (Guideline) reflects comprehensive literature review through April 2015, while the jointly sponsored, inaugural Cancer Survivorship Symposium in 2016 (Symposium) reflects ongoing research activity in the area. Together, these platforms provide an opportunity to examine the use of randomized trials and controlled studies in survivorship care research.

Methods

All 236 citations from the Guideline and all 250 abstracts from the Symposium were reviewed independently by two authors and assigned to prospectively determined categories.

Results

Guideline citations were most frequently reviews (n = 88, 37.3%) and non-randomized, non-controlled studies (n = 51, 21.6%). Thirty-seven (15.7%) randomized trials were cited. Only 9% of Guideline recommendations were based on randomized clinical trial evidence, while 64% were based on evidence level "0" (expert opinion, clinical practice, etc.). Symposium abstracts consisted largely of non-randomized, non-controlled studies (n = 113, 45.2%), with ten completed randomized trials (4%). Few Guideline citations or Symposium abstracts incorporated matched, cancer-free controls.

Conclusions

Based on the literature underlying the ASCO Guideline as well as a survey of the Cancer Survivorship Symposium abstracts, a significant proportion of the survivorship literature at least through 2015 consisted of non-randomized, non-controlled studies. To optimally address survivorship issues, cancer therapy sequelae need to be distinguished from normal aging in studies incorporating cancer-free controls, and randomized clinical trials are needed to inform intervention strategies.

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The Identity of “Chromium Malate”

Abstract

Recently, several studies on the effects of a compound named "chromium malate," with the proposed formula "Cr₂malate₃·xH₂O" where x = 3.5 or 5, on the health of healthy and diabetic rats have appeared. However, the compound is poorly characterized, and knowing the identity of this material could be important in the interpretation of the previous and of future studies on the effects of this compound in animals. Consequently, the synthesis, characterization, and identity of this material were explored. A combination of spectroscopic, magnetic, and elemental analyses and mass spectral studies reveal that the compound is probably a polymer, not a discrete molecule, and does not have the composition previously reported. The repeating unit of the polymer possesses an antiferromagnetically coupled trinuclear Cr(III) core. The current study suggests that previous reports on chromium malate and its effects in animals must be viewed with caution.

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Microenvironmental Scenario of the Bone Marrow of Inorganic Arsenic-Exposed Experimental Mice

Abstract

Exposure to arsenic on a regular basis, mainly through drinking water, agricultural pesticide, and sometimes therapeutic dose, results in various diseases of different tissues including the bone marrow hematopoietic system. Hematopoiesis is a dynamic process by which bone marrow (BM) hematopoietic stem/progenitor cells (HSPCs) generate a relatively constant pool of functionally mature blood cells by the support of microenvironmental components. The present study has been aimed to understand stem cell microenvironmental status during arsenic toxicity and the consequent reflection of dysregulation involving the hematopoietic machinery in experimental mice. Swiss albino mice were experimentally exposed to 10 μg arsenic trioxide/g body weight through oral gavage and 5 μg arsenic trioxide/g body weight intraperitoneally for a period of 30 days. Altered hemogram values in peripheral blood reflected the impaired hematopoiesis which was further validated by the reduced BM cellularity along with the deviated BM cell morphology as observed by scanning electron microscopy post arsenic exposure. The stromal cells were unable to establish a healthy matrix and the sustainability of hematopoietic progenitors was drastically affected in arsenic-exposed mouse groups, as observed in in vitro explant culture. The inability of stromal cells to establish supportive matrix was also explained by the decreased adherent colony formation in treated animals. Furthermore, the flow cytometric characterization of CXCR4⁺ and Sca-1⁺ CD44⁺ receptor expressions confirmed the dysregulation in the hematopoietic microenvironment. Thus, considering the importance of microenvironment in the maintenance of HSPC, it can be concluded that arsenic toxicity causes microenvironmental damage, leading to niche derangement and impaired hematopoiesis.

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Effect of the Zinc Oxide Nanoparticles and Thiamine for the Management of Diabetes in Alloxan-Induced Mice: a Stereological and Biochemical Study

Abstract

This research was carried out to evaluate the antidiabetic effects of zinc oxide nanoparticles (ZnO NPs) and thiamine following experimental diabetes. Fifty-six 6-week-old female mice were used and divided into seven groups of eight animals. Diabetes was induced in fasted mice by using intraperitoneal (IP) injection of alloxan (180 mg/kg). Groups included (I) non-diabetic control, (II) thiamine (30 mg/l, IP), (III) alloxan-induced diabetic mice, (IV) diabetes + ZnO NPs (0.1 mg/kg IP), (V) diabetes + ZnO NPs (0.5 mg/kg IP), (VI) diabetes + ZnO NPs (0.1 mg/kg IP) + thiamine (30 mg/l, IP), and (VII) diabetes + ZnO NPs (0.5 mg/kg IP) + thiamine (30 mg/l, IP). Coincident with pancreas recovery, in diabetic treated mice (groups IV to VII), the mean islet volume, islets per square micrometer, and volume density of the pancreas had increased than in alloxan-induced diabetic mice. ZnO NPs and thiamine induced a decreasing blood glucose, lower serum triglyceride (TG), LDL, and total cholesterol (TC) levels in alloxan-induced diabetic mice treated with ZnO NPs and thiamine, simultaneously increasing HDL as well. In conclusion, ZnO NPs and thiamine are potent antidiabetic factors, and that, these compound supplementation possesses hypoglycemic properties and have effect on serum lipid parameters in diabetes mice.

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Maternal Magnesium Restriction Elevates Glucocorticoid Stress and Inflammation in the Placenta and Fetus of WNIN Rat Dams

Abstract

Magnesium plays a major role in many vital functions in the body. We reported earlier that maternal magnesium restriction altered body composition, fat metabolism, and insulin resistance in WNIN rat offspring and was associated with increased glucocorticoid stress in the offspring in their later life. We hypothesize that increased glucocorticoid stress and inflammation which originate in Mg restricted rat dams is transmitted through placenta to the fetus and underlie the metabolic disturbances in the later life of the offspring. Female weanling WNIN rats received ad libitum, a control diet (MgC) or the same with 62% restriction of Mg (MgR) for 3 months, and their plasma magnesium, inflammatory cytokines, and corticosterone were determined (n = 6 per group) before mating. Following mating with control males, placentae, and fetuses were collected on gestational day 15 (GD 15) from MgC and MgR dams (eight dams from each group and three samples from each dam) and used to determine the levels of inflammatory cytokines, corticosterone, and expression of relevant genes. MgR placentae and fetuses had higher (than MgC) levels of corticosterone and proinflammatory cytokines. Expression of Hsd11b1 was increased (sixfold, p < 0.05), while that of Hsd11b2 was decreased (0.4-fold, p < 0.05) in MgR (than MgC) placenta, whereas expression of Hsd11b1was increased (3.4-fold, p < 0.05) in MgR fetus. Chronic dietary magnesium restriction in WNIN female rats increased their levels of corticosterone, leptin, and proinflammatory cytokines which appeared to be transmitted through placenta to the fetus and could thus be associated with increased stress, altered body composition, fat metabolism, and insulin resistance in the later life of the offspring.

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Effects of Different Selenium Sources on Growth Performance, Antioxidant Capacity and Meat Quality of Local Chinese Subei Chickens

Abstract

Despite increasing evidence indicating the essential involvement of selenium (Se) on growth performance, antioxidant capacity, and meat quality of commercial broilers, the effects of different Se sources on local Chinese Subei chickens is unclear. A total of 360 50-day-old male chickens were individually weighed and randomly allocated to four treatment groups. Chickens in each of the four groups were fed diets supplemented with 0.3 mg Se/kg as sodium Se (SS), Se-enriched yeast (SY), selenomethionine (Met-Se), or nano red element Se (Nano-Se) for 40 days. At the end of the experiment, one bird of approximately average weight from each cage was selected and slaughtered, and blood and breast muscles samples were collected. The results showed that there was no significant difference in feed intake, body weight gain, or feed to gain ratio among treatments (P > 0.05). Dietary SY, Met-Se, and Nano-Se supplementation increased the activity of glutathione peroxidase in serum and breast muscles and decreased the concentration of malondialdehyde in serum and carbonyl in breast muscles compared with the SS group (P < 0.05). Moreover, SY, Met-Se, and Nano-Se supplementation increased pH_45min, total protein solubility, and myofibrillar protein solubility, as well as decreased the shear force value compared with the SS group (P < 0.05). In addition, birds in the SY and Met-Se groups exhibited lower cooking loss compared with the SS group (P < 0.05). In conclusion, organic Se and Nano-Se supplementation resulted in an improvement of antioxidant capacity and meat quality in local Chinese Subei chickens relative to inorganic Se.

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Effect of the Zinc Oxide Nanoparticles and Thiamine for the Management of Diabetes in Alloxan-Induced Mice: a Stereological and Biochemical Study

Abstract

This research was carried out to evaluate the antidiabetic effects of zinc oxide nanoparticles (ZnO NPs) and thiamine following experimental diabetes. Fifty-six 6-week-old female mice were used and divided into seven groups of eight animals. Diabetes was induced in fasted mice by using intraperitoneal (IP) injection of alloxan (180 mg/kg). Groups included (I) non-diabetic control, (II) thiamine (30 mg/l, IP), (III) alloxan-induced diabetic mice, (IV) diabetes + ZnO NPs (0.1 mg/kg IP), (V) diabetes + ZnO NPs (0.5 mg/kg IP), (VI) diabetes + ZnO NPs (0.1 mg/kg IP) + thiamine (30 mg/l, IP), and (VII) diabetes + ZnO NPs (0.5 mg/kg IP) + thiamine (30 mg/l, IP). Coincident with pancreas recovery, in diabetic treated mice (groups IV to VII), the mean islet volume, islets per square micrometer, and volume density of the pancreas had increased than in alloxan-induced diabetic mice. ZnO NPs and thiamine induced a decreasing blood glucose, lower serum triglyceride (TG), LDL, and total cholesterol (TC) levels in alloxan-induced diabetic mice treated with ZnO NPs and thiamine, simultaneously increasing HDL as well. In conclusion, ZnO NPs and thiamine are potent antidiabetic factors, and that, these compound supplementation possesses hypoglycemic properties and have effect on serum lipid parameters in diabetes mice.

http://ift.tt/2DaQCFq

Effects of Maternal Zinc Glycine on Mortality, Zinc Concentration, and Antioxidant Status in a Developing Embryo and 1-Day-Old Chick

Abstract

This study was conducted to investigate the effects of maternal zinc glycine (Zn-Gly) supplementation as an alternative for zinc sulfate (ZnSO₄) on mortality, zinc (Zn) concentration, and antioxidant status in a developing embryo and 1-day-old chick. Six hundred 39-week-old broiler breeders were randomly assigned to 6 treatments, each treatment including 5 replicates with 20 birds each. Six treatments received a basal diet (control, 24 mg Zn/kg diet) or a basal diet supplemented with ZnSO₄ (80 mg Zn/kg) or Zn-Gly (20, 40, 60, or 80 mg Zn/kg), respectively. The experiment lasted for 8 weeks after a 4-week pre-experiment with a basal diet. At the last week, 100 eggs per replicate were randomly collected for incubation. Compared with the control treatment, Zn supplementation decreased (P < 0.05) embryo mortalities of the late stage and the whole period, increased (P < 0.05) liver Zn concentration in the embryo of d9, d19, and 1-day-old chick, and improved (P < 0.05) antioxidant status in the embryo of d19 and 1-day-old chick. Compared with the ZnSO₄ treatment, 80 mg Zn/kg Zn-Gly treatment significantly decreased (P < 0.05) the late stage embryo mortality and increased (P < 0.05) liver Zn concentration in the embryo of d9, d19, and 1-day-old chick. The 80 mg Zn/kg Zn-Gly treatment significantly increased (P < 0.05) copper-zinc superoxide dismutase activity in d19 embryo and 1-day-old chick, total superoxide dismutase activity in 1-day-old chick, and copper-zinc superoxide dismutase messenger RNA (mRNA) abundance of d9 embryo and 1-day-old chick than that in ZnSO₄ treatment. The liver metallothionein concentration of the developing embryo and 1-day-old chick and its mRNA abundance of d19 embryo were also significantly increased (P < 0.05) in the 80 mg Zn/kg Zn-Gly treatment in comparison with ZnSO₄ treatment. In conclusion, maternal Zn supplementation decreased embryo mortalities of the late stage and the whole period by increasing liver Zn concentration and antioxidant status in d19 embryo and 1-day-old chick, and 80 mg Zn/kg from Zn-Gly treatment was the optimum choice.

http://ift.tt/2mtBo41

Maternal Magnesium Restriction Elevates Glucocorticoid Stress and Inflammation in the Placenta and Fetus of WNIN Rat Dams

Abstract

Magnesium plays a major role in many vital functions in the body. We reported earlier that maternal magnesium restriction altered body composition, fat metabolism, and insulin resistance in WNIN rat offspring and was associated with increased glucocorticoid stress in the offspring in their later life. We hypothesize that increased glucocorticoid stress and inflammation which originate in Mg restricted rat dams is transmitted through placenta to the fetus and underlie the metabolic disturbances in the later life of the offspring. Female weanling WNIN rats received ad libitum, a control diet (MgC) or the same with 62% restriction of Mg (MgR) for 3 months, and their plasma magnesium, inflammatory cytokines, and corticosterone were determined (n = 6 per group) before mating. Following mating with control males, placentae, and fetuses were collected on gestational day 15 (GD 15) from MgC and MgR dams (eight dams from each group and three samples from each dam) and used to determine the levels of inflammatory cytokines, corticosterone, and expression of relevant genes. MgR placentae and fetuses had higher (than MgC) levels of corticosterone and proinflammatory cytokines. Expression of Hsd11b1 was increased (sixfold, p < 0.05), while that of Hsd11b2 was decreased (0.4-fold, p < 0.05) in MgR (than MgC) placenta, whereas expression of Hsd11b1was increased (3.4-fold, p < 0.05) in MgR fetus. Chronic dietary magnesium restriction in WNIN female rats increased their levels of corticosterone, leptin, and proinflammatory cytokines which appeared to be transmitted through placenta to the fetus and could thus be associated with increased stress, altered body composition, fat metabolism, and insulin resistance in the later life of the offspring.

http://ift.tt/2Db4saM

Serum and Hair Zinc Levels in Patients with Endemic Osteochondropathy in China: A Meta-analysis

Abstract

A large number of studies have shown growing interest in the zinc (Zn) levels of serum and hair samples collected from patients with Kashin-Beck disease (KBD), an endemic chronic osteochondral disease. However, inconsistent conclusions regarding the serum and hair Zn levels have been made. The aim of this study is to assess and to explore the change in serum and hair Zn levels among KBD patients. Multiple databases, including PubMed, Web of Science, Chinese National Knowledge Infrastructure (CNKI), Wanfang database and Technology of Chongqing (VIP), were carefully searched for available studies up to January 13, 2017 in this integrated analysis. Standard mean difference (SMD) with a 95% confidence interval (95% CI) was calculated using STATA 11.0. A total of 18 studies, involving 978 KBD cases and 1116 healthy controls, were collected in this analysis. Pooled analysis found the KBD patients had a higher hair Zn level and a lower serum Zn level than the healthy controls (hair Zn (μg/g), SMD = 0.030, 95% CI = −0.315, 0.376; serum Zn (mg/L), SMD = −0.069, 95%CI = −0.924, 0.785). Meta-regression method and sensitivity analysis were utilized to analyze the heterogeneity of data. Positive correlations were separately identified between hair Zn level in KBD patients (r = 0.4639, P = 0.032) and controls (r = 0.4743, P = 0.012) and the survey year. No evidence of publication bias was observed. The available results suggest that increased hair Zn level and decreased serum Zn level are commonly found in KBD patients; however, the role of Zn in the etiology and pathogenesis of KBD could not yet be confirmed.

http://ift.tt/2mr5LIs

Effects of Different Selenium Sources on Growth Performance, Antioxidant Capacity and Meat Quality of Local Chinese Subei Chickens

Abstract

Despite increasing evidence indicating the essential involvement of selenium (Se) on growth performance, antioxidant capacity, and meat quality of commercial broilers, the effects of different Se sources on local Chinese Subei chickens is unclear. A total of 360 50-day-old male chickens were individually weighed and randomly allocated to four treatment groups. Chickens in each of the four groups were fed diets supplemented with 0.3 mg Se/kg as sodium Se (SS), Se-enriched yeast (SY), selenomethionine (Met-Se), or nano red element Se (Nano-Se) for 40 days. At the end of the experiment, one bird of approximately average weight from each cage was selected and slaughtered, and blood and breast muscles samples were collected. The results showed that there was no significant difference in feed intake, body weight gain, or feed to gain ratio among treatments (P > 0.05). Dietary SY, Met-Se, and Nano-Se supplementation increased the activity of glutathione peroxidase in serum and breast muscles and decreased the concentration of malondialdehyde in serum and carbonyl in breast muscles compared with the SS group (P < 0.05). Moreover, SY, Met-Se, and Nano-Se supplementation increased pH_45min, total protein solubility, and myofibrillar protein solubility, as well as decreased the shear force value compared with the SS group (P < 0.05). In addition, birds in the SY and Met-Se groups exhibited lower cooking loss compared with the SS group (P < 0.05). In conclusion, organic Se and Nano-Se supplementation resulted in an improvement of antioxidant capacity and meat quality in local Chinese Subei chickens relative to inorganic Se.

http://ift.tt/2Dbpar7

The Antagonistic Effect of Selenium on Cadmium-Induced Damage and mRNA Levels of Selenoprotein Genes and Inflammatory Factors in Chicken Kidney Tissue

Abstract

Selenium (Se) is a necessary trace mineral in the diet of humans and animals. Cadmium (Cd) is a toxic heavy metal that can damage animal organs, especially the kidneys. Antagonistic interactions between Se and Cd have been reported in previous studies. However, little is known about the effects of Se against Cd toxicity and on the mRNA levels of 25 selenoprotein genes and inflammatory factors in chicken kidneys. In the current study, we fed chickens with a Se-treated, Cd-treated, or Se/Cd treated diet for 90 days. We then analyzed the mRNA expression of inflammatory factors (including prostaglandin E synthase (PTGES), nuclear factor-kappa B (NF-κB), tumor necrosis factor-α (TNF-α), and cyclooxygenase-2 (COX-2)) and 25 selenoprotein genes (Gpx1, Gpx2, Gpx3, Gpx4, Txnrd1, Txnrd2, Txnrd3, Dio1, Dio2, Dio3, SPS2, Sepp1, SelPb, Sep15, Selh, Seli, Selm, Selo, Sels, Sepx1, Selu, Selk, Selw, Seln, Selt). The results demonstrated that Cd exposure increased the Cd content in the chicken kidneys, renal tubular epithelial cells underwent denaturation and necrosis, and the tubules became narrow or disappeared. However, Se supplementation reduced the Cd content in chicken kidneys and induced normal development of renal tubular epithelial cells. In addition, we also observed that Se alleviated the Cd-induced increase in the mRNA levels of inflammatory factors and ameliorated the Cd-induced downtrend in the mRNA levels of 25 selenoprotein genes in chicken kidneys.

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Effects of Selenium Supplementation on Gene Expression Levels of Inflammatory Cytokines and Vascular Endothelial Growth Factor in Patients with Gestational Diabetes

Abstract

Selenium is known to exert multiple beneficial effects including anti-inflammatory actions. The aim of the study was to evaluate the effects of selenium supplementation on gene expression levels of inflammatory cytokines and vascular endothelial growth factor (VEGF) in women with gestational diabetes (GDM). This randomized double-blind, placebo-controlled trial was carried out among 40 subjects diagnosed with GDM aged 18–40 years old. Subjects were randomly allocated into two groups to receive either 200 μg/day selenium supplements (n = 20) or placebo (n = 20) for 6 weeks. Gene expression of inflammatory cytokines and VEGF were assessed in lymphocytes of GDM women with RT-PCR method. Results of RT-PCR indicated that after the 6-week intervention, compared with the placebo, selenium supplementation downregulated gene expression of tumor necrosis factor alpha (TNF-α) (P = 0.02) and transforming growth factor beta (TGF-β) (P = 0.01), and upregulated gene expression of VEGF (P = 0.03) in lymphocytes of patients with GDM. There was no statistically significant change following supplementation with selenium on gene expression of interleukin (IL)-1β and IL-8 in lymphocytes of subjects with GDM. Selenium supplementation for 6 weeks in women with GDM significantly decreased gene expression of TNF-α and TGF-β, and significantly increased gene expression of VEGF, but did not affect gene expression of IL-1β and IL-8. Clinical trial registration number http://www.irct.ir: IRCT201612045623N95.

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The Relationship Between Copper, Iron, and Selenium Levels and Alzheimer Disease

Abstract

This study aimed to evaluate the concentrations of copper, iron, and selenium in elderly people with Alzheimer disease (AD), comparing the same parameters in a paired group of healthy people, in order to verify if the amount of these metals may influence the cognitive impairment progression. Patients' cognitive impairment was evaluated by Clinical Dementia Rating (CDR). The elementary quantification of erythrocytes was performed by inductively coupled plasma mass spectrometry technique. The statistical analyses were carried out by SPSS software 20.0 version, employing Shapiro-Wilk, Wilcoxon, Kruskall-Wallis, and Spearman correlation tests, considering significant results of p < 0.05. The sample was composed of 34% (n = 11) of women and 66% (n = 21) of men in each group. The AD group was characterized by a higher concentration of copper (p < 0.0001) and iron (p < 0.0001); however, there is no significant difference in selenium level. The analyses of the metal levels in different stages of AD were not significant in CDR-1, however in CDR-2 and CDR-3, elevated levels of copper and iron were observed; in CDR-3 patients, the level of selenium was lower (p < 0.008) compared to that of healthy controls. Patients with Alzheimer disease studied present increase in biometal blood levels, especially of copper and iron, and such increase can be different according to the disease stage and can cause more impairment cognitive functions in AD.

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Dose-Dependent Differential Effects of In Vivo Exposure of Cadmium on Myometrial Activity in Rats: Involvement of VDCC and Ca 2+ -Mimicking Pathways

Abstract

Present study was undertaken to study the effect of 28-days exposure of female adult rats to cadmium (Cd) in drinking water @ 3, 10 and 30 parts per million (ppm) on myometrial responsiveness to different spasmogens and unravel the possible mechanism of alterations in myometrial activity. Cadmium and Ca²⁺ levels in blood and uterus were measured by atomic absorption spectroscopy while isometric tension in myometrial strips was measured using data acquisition system-based physiograph. Dose-dependent increase in levels of cadmium was observed in both blood and uterus while calcium was increased only in the uterus as compared to those in control. Significant increase in absolute tension and mean integral tension along with non-significant increase in frequency of myometrial contraction was observed in rats of Cd-treated groups. As compared to the control, cadmium decreased and increased the effects of calcium chloride, 80 mM KCl, histamine (0.1 μM) and oxytocin (10⁻² IU/ml) in lower-dose (3 ppm) and higher-dose groups (10 and 30 ppm), respectively. Cadmium potentiated and inhibited the relaxant response to phenylephrine in myometrium of rats at lower-dose (3 ppm) and highest-dose (30 ppm) Cd-treated groups, respectively. Results of our study revealed that Cd accumulates in the myometrium of rats and alters its responsiveness to oxytocin, histamine, 80 mM KCl, calcium chloride and phenylephrine, and these effects are differentially mediated depending on levels of exposure possibly through voltage-dependent calcium channel (VDCC) and Ca²⁺-mimicking pathways.

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The Identity of “Chromium Malate”

Abstract

Recently, several studies on the effects of a compound named "chromium malate," with the proposed formula "Cr₂malate₃·xH₂O" where x = 3.5 or 5, on the health of healthy and diabetic rats have appeared. However, the compound is poorly characterized, and knowing the identity of this material could be important in the interpretation of the previous and of future studies on the effects of this compound in animals. Consequently, the synthesis, characterization, and identity of this material were explored. A combination of spectroscopic, magnetic, and elemental analyses and mass spectral studies reveal that the compound is probably a polymer, not a discrete molecule, and does not have the composition previously reported. The repeating unit of the polymer possesses an antiferromagnetically coupled trinuclear Cr(III) core. The current study suggests that previous reports on chromium malate and its effects in animals must be viewed with caution.

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Arsenic Induces Thioredoxin 1 and Apoptosis in Human Liver HHL-5 Cells

Abstract

To further characterize the mechanisms underlying liver toxicity induced by arsenic, we examined in this study the effect of arsenic on thioredoxin (Trx) and the apoptotic signaling pathways in human liver HHL-5 cells. The cells were treated with 0, 2, 5, and 10 μM of sodium arsenite for 24 h, and the changes of Trx1 and thioredoxin reductase (TrxR1) as well as intracellular ROS and apoptosis were examined. A concentration-dependent increase in mRNA and protein levels of Trx1 and TrxR1 was observed in arsenic-treated cells. Intracellular ROS levels and apoptosis were also significantly increased in a concentration-dependent manner. In line with this, protein levels of Bax and cytochrome C were increased and Bcl-2 was decreased by arsenic treatments. Increases in caspase 3 activity were observed. These results indicate that Trx is involved in arsenic-induced liver cell injury, probably through the apoptotic signaling pathway. However, further studies are needed to elucidate on these findings.

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Effects of Maternal Zinc Glycine on Mortality, Zinc Concentration, and Antioxidant Status in a Developing Embryo and 1-Day-Old Chick

Abstract

This study was conducted to investigate the effects of maternal zinc glycine (Zn-Gly) supplementation as an alternative for zinc sulfate (ZnSO₄) on mortality, zinc (Zn) concentration, and antioxidant status in a developing embryo and 1-day-old chick. Six hundred 39-week-old broiler breeders were randomly assigned to 6 treatments, each treatment including 5 replicates with 20 birds each. Six treatments received a basal diet (control, 24 mg Zn/kg diet) or a basal diet supplemented with ZnSO₄ (80 mg Zn/kg) or Zn-Gly (20, 40, 60, or 80 mg Zn/kg), respectively. The experiment lasted for 8 weeks after a 4-week pre-experiment with a basal diet. At the last week, 100 eggs per replicate were randomly collected for incubation. Compared with the control treatment, Zn supplementation decreased (P < 0.05) embryo mortalities of the late stage and the whole period, increased (P < 0.05) liver Zn concentration in the embryo of d9, d19, and 1-day-old chick, and improved (P < 0.05) antioxidant status in the embryo of d19 and 1-day-old chick. Compared with the ZnSO₄ treatment, 80 mg Zn/kg Zn-Gly treatment significantly decreased (P < 0.05) the late stage embryo mortality and increased (P < 0.05) liver Zn concentration in the embryo of d9, d19, and 1-day-old chick. The 80 mg Zn/kg Zn-Gly treatment significantly increased (P < 0.05) copper-zinc superoxide dismutase activity in d19 embryo and 1-day-old chick, total superoxide dismutase activity in 1-day-old chick, and copper-zinc superoxide dismutase messenger RNA (mRNA) abundance of d9 embryo and 1-day-old chick than that in ZnSO₄ treatment. The liver metallothionein concentration of the developing embryo and 1-day-old chick and its mRNA abundance of d19 embryo were also significantly increased (P < 0.05) in the 80 mg Zn/kg Zn-Gly treatment in comparison with ZnSO₄ treatment. In conclusion, maternal Zn supplementation decreased embryo mortalities of the late stage and the whole period by increasing liver Zn concentration and antioxidant status in d19 embryo and 1-day-old chick, and 80 mg Zn/kg from Zn-Gly treatment was the optimum choice.

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Effects of Intermittent and Continuous Magnetic Fields on Trace Element Levels in Guinea Pigs

Abstract

Electromagnetic fields (EMFs) can affect living cells due to biochemical changes, followed by changes in levels of trace elements in serum and different organs. This study focuses on the effect of whole body exposure to EMF, presented everywhere in our environment, and on the levels of trace elements in serum, femur, brain, kidney, and liver tissues. The analyses performed on 29 guinea pigs were divided into five groups. Guinea pigs were exposed to a magnetic field of 50 Hz of 1.5 mT. Groups A and B were exposed to the magnetic field for a period of 4 h/day continuously (4 h/day) for 4 and 7 days, respectively. Groups C and D were exposed to the magnetic field for a period of 4 h/day intermittently for 4 and 7 days, respectively. Group E animals were enrolled as control. Copper (Cu), zinc (Zn), calcium (Ca), and magnesium (Mg) levels were determined by atomic absorption spectroscopy in serum, femur, brain, kidney, and liver tissues in all guinea pigs. When compared to the control groups, the changes in the levels of Cu in serum samples, femur, and kidney tissues of the treated groups were statistically significant. The same was also true for the levels of Mg in the brain, kidney, and lung tissues. Our results suggest that in vivo continuous and intermittent exposure to EMF may cause disturbances in homeostasis of bioelements. These effects could be important risk factors for toxic effects of EMF, especially in relation to deterioration of bioelements.

http://ift.tt/2Da6ub5

Serum and Hair Zinc Levels in Patients with Endemic Osteochondropathy in China: A Meta-analysis

Abstract

A large number of studies have shown growing interest in the zinc (Zn) levels of serum and hair samples collected from patients with Kashin-Beck disease (KBD), an endemic chronic osteochondral disease. However, inconsistent conclusions regarding the serum and hair Zn levels have been made. The aim of this study is to assess and to explore the change in serum and hair Zn levels among KBD patients. Multiple databases, including PubMed, Web of Science, Chinese National Knowledge Infrastructure (CNKI), Wanfang database and Technology of Chongqing (VIP), were carefully searched for available studies up to January 13, 2017 in this integrated analysis. Standard mean difference (SMD) with a 95% confidence interval (95% CI) was calculated using STATA 11.0. A total of 18 studies, involving 978 KBD cases and 1116 healthy controls, were collected in this analysis. Pooled analysis found the KBD patients had a higher hair Zn level and a lower serum Zn level than the healthy controls (hair Zn (μg/g), SMD = 0.030, 95% CI = −0.315, 0.376; serum Zn (mg/L), SMD = −0.069, 95%CI = −0.924, 0.785). Meta-regression method and sensitivity analysis were utilized to analyze the heterogeneity of data. Positive correlations were separately identified between hair Zn level in KBD patients (r = 0.4639, P = 0.032) and controls (r = 0.4743, P = 0.012) and the survey year. No evidence of publication bias was observed. The available results suggest that increased hair Zn level and decreased serum Zn level are commonly found in KBD patients; however, the role of Zn in the etiology and pathogenesis of KBD could not yet be confirmed.

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Associations Between Serum Zinc Levels and Mental Health: Findings from the 2010 Korean National Health and Nutrition Examination Survey

Abstract

Mental health problems are a major public health issue worldwide, and zinc may be associated with psychiatric symptoms, but such associations have not been investigated extensively. This study was conducted to evaluate the relationship between serum zinc levels and mental health problems in Korean adults. We used data from the Korean National Health and Nutrition Examination Survey V-1, a cross-sectional survey of Korean civilians. Data from 1748 subjects were analyzed. Serum zinc levels did not differ significantly according to psychiatric symptoms including sleep duration, stress, depressed mood, suicidal ideation, and whether respondents sought psychiatric consultation. The frequencies and odds ratios of psychiatric symptoms according to serum zinc tertiles were not significantly associated after adjusting for age, smoking, alcohol consumption, physical activity, body mass index, total body fat, and renal function and for daily fat, carbohydrate, and protein intake. Serum zinc levels may not be associated with psychiatric symptoms in Korean adults without psychiatric disorders.

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The Antagonistic Effect of Selenium on Cadmium-Induced Damage and mRNA Levels of Selenoprotein Genes and Inflammatory Factors in Chicken Kidney Tissue

Abstract

Selenium (Se) is a necessary trace mineral in the diet of humans and animals. Cadmium (Cd) is a toxic heavy metal that can damage animal organs, especially the kidneys. Antagonistic interactions between Se and Cd have been reported in previous studies. However, little is known about the effects of Se against Cd toxicity and on the mRNA levels of 25 selenoprotein genes and inflammatory factors in chicken kidneys. In the current study, we fed chickens with a Se-treated, Cd-treated, or Se/Cd treated diet for 90 days. We then analyzed the mRNA expression of inflammatory factors (including prostaglandin E synthase (PTGES), nuclear factor-kappa B (NF-κB), tumor necrosis factor-α (TNF-α), and cyclooxygenase-2 (COX-2)) and 25 selenoprotein genes (Gpx1, Gpx2, Gpx3, Gpx4, Txnrd1, Txnrd2, Txnrd3, Dio1, Dio2, Dio3, SPS2, Sepp1, SelPb, Sep15, Selh, Seli, Selm, Selo, Sels, Sepx1, Selu, Selk, Selw, Seln, Selt). The results demonstrated that Cd exposure increased the Cd content in the chicken kidneys, renal tubular epithelial cells underwent denaturation and necrosis, and the tubules became narrow or disappeared. However, Se supplementation reduced the Cd content in chicken kidneys and induced normal development of renal tubular epithelial cells. In addition, we also observed that Se alleviated the Cd-induced increase in the mRNA levels of inflammatory factors and ameliorated the Cd-induced downtrend in the mRNA levels of 25 selenoprotein genes in chicken kidneys.

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Effects of Selenium Supplementation on Gene Expression Levels of Inflammatory Cytokines and Vascular Endothelial Growth Factor in Patients with Gestational Diabetes

Abstract

Selenium is known to exert multiple beneficial effects including anti-inflammatory actions. The aim of the study was to evaluate the effects of selenium supplementation on gene expression levels of inflammatory cytokines and vascular endothelial growth factor (VEGF) in women with gestational diabetes (GDM). This randomized double-blind, placebo-controlled trial was carried out among 40 subjects diagnosed with GDM aged 18–40 years old. Subjects were randomly allocated into two groups to receive either 200 μg/day selenium supplements (n = 20) or placebo (n = 20) for 6 weeks. Gene expression of inflammatory cytokines and VEGF were assessed in lymphocytes of GDM women with RT-PCR method. Results of RT-PCR indicated that after the 6-week intervention, compared with the placebo, selenium supplementation downregulated gene expression of tumor necrosis factor alpha (TNF-α) (P = 0.02) and transforming growth factor beta (TGF-β) (P = 0.01), and upregulated gene expression of VEGF (P = 0.03) in lymphocytes of patients with GDM. There was no statistically significant change following supplementation with selenium on gene expression of interleukin (IL)-1β and IL-8 in lymphocytes of subjects with GDM. Selenium supplementation for 6 weeks in women with GDM significantly decreased gene expression of TNF-α and TGF-β, and significantly increased gene expression of VEGF, but did not affect gene expression of IL-1β and IL-8. Clinical trial registration number http://www.irct.ir: IRCT201612045623N95.

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The Contribution of Superoxide Radical to Cadmium Toxicity in E. coli

Abstract

Numerous reports suggest the involvement of oxidative stress in cadmium toxicity, but the nature of the reactive species and the mechanism of Cd-induced oxidative damage are not clear. In this study, E. coli mutants were used to investigate mechanisms of Cd toxicity. Effects of Cd on metabolic activity, production of superoxide radical by the respiratory chain, and induction of enzymes controlled by the soxRS regulon were investigated. In E. coli, the soxRS regulon controls defense against O₂·⁻and univalent oxidants. Suppression of metabolic activity, inability of E. coli to adapt to new environment, and slow cell division were among the manifestations of Cd toxicity. Cd increased production of O₂·⁻ by the electron transport chain and prevented the induction of soxRS-controlled protective enzymes, even when the regulon was induced by the redox-cycling agent, paraquat. The effect was not limited to soxRS-dependent proteins and can be attributed to previously reported suppression of protein synthesis by Cd. Increased production of superoxide, combined with inability to express protective enzymes and to replace damaged proteins by de novo protein synthesis, seems to be the main reason for growth stasis and cell death in Cd poisoning.

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The Relationship Between Copper, Iron, and Selenium Levels and Alzheimer Disease

Abstract

This study aimed to evaluate the concentrations of copper, iron, and selenium in elderly people with Alzheimer disease (AD), comparing the same parameters in a paired group of healthy people, in order to verify if the amount of these metals may influence the cognitive impairment progression. Patients' cognitive impairment was evaluated by Clinical Dementia Rating (CDR). The elementary quantification of erythrocytes was performed by inductively coupled plasma mass spectrometry technique. The statistical analyses were carried out by SPSS software 20.0 version, employing Shapiro-Wilk, Wilcoxon, Kruskall-Wallis, and Spearman correlation tests, considering significant results of p < 0.05. The sample was composed of 34% (n = 11) of women and 66% (n = 21) of men in each group. The AD group was characterized by a higher concentration of copper (p < 0.0001) and iron (p < 0.0001); however, there is no significant difference in selenium level. The analyses of the metal levels in different stages of AD were not significant in CDR-1, however in CDR-2 and CDR-3, elevated levels of copper and iron were observed; in CDR-3 patients, the level of selenium was lower (p < 0.008) compared to that of healthy controls. Patients with Alzheimer disease studied present increase in biometal blood levels, especially of copper and iron, and such increase can be different according to the disease stage and can cause more impairment cognitive functions in AD.

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Dose-Dependent Differential Effects of In Vivo Exposure of Cadmium on Myometrial Activity in Rats: Involvement of VDCC and Ca 2+ -Mimicking Pathways

Abstract

Present study was undertaken to study the effect of 28-days exposure of female adult rats to cadmium (Cd) in drinking water @ 3, 10 and 30 parts per million (ppm) on myometrial responsiveness to different spasmogens and unravel the possible mechanism of alterations in myometrial activity. Cadmium and Ca²⁺ levels in blood and uterus were measured by atomic absorption spectroscopy while isometric tension in myometrial strips was measured using data acquisition system-based physiograph. Dose-dependent increase in levels of cadmium was observed in both blood and uterus while calcium was increased only in the uterus as compared to those in control. Significant increase in absolute tension and mean integral tension along with non-significant increase in frequency of myometrial contraction was observed in rats of Cd-treated groups. As compared to the control, cadmium decreased and increased the effects of calcium chloride, 80 mM KCl, histamine (0.1 μM) and oxytocin (10⁻² IU/ml) in lower-dose (3 ppm) and higher-dose groups (10 and 30 ppm), respectively. Cadmium potentiated and inhibited the relaxant response to phenylephrine in myometrium of rats at lower-dose (3 ppm) and highest-dose (30 ppm) Cd-treated groups, respectively. Results of our study revealed that Cd accumulates in the myometrium of rats and alters its responsiveness to oxytocin, histamine, 80 mM KCl, calcium chloride and phenylephrine, and these effects are differentially mediated depending on levels of exposure possibly through voltage-dependent calcium channel (VDCC) and Ca²⁺-mimicking pathways.

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Evaluation of Dietary Palygorskite Supplementation on Growth Performance, Mineral Accumulations, Antioxidant Capacities, and Meat Quality of Broilers Fed Lead-Contaminated Diet

Abstract

The objective of this study was to evaluate influence of dietary palygorskite (Pal) supplementation on growth performance, mineral accumulations in the tissues (livers, kidneys, and muscles), antioxidant capacities, and meat quality of broilers fed lead (Pb)-contaminated diet. One-hundred forty-four male broiler chicks were randomly divided into three treatment groups, receiving a corn-soybean meal basal diet (the control group), the basal diet contaminated with 10 mg/kg Pb (the Pb group), and the basal diet with 10-g/kg Pal supplementation and 10-mg/kg Pb contamination (the Pal/Pb group) from 1 to 42 days of age, respectively. Treatments did not affect growth performance of broilers in the 42-day study (P > 0.05). Compared with the control group, Pb contamination increased Pb accumulation in the livers, kidneys, and muscles (P < 0.05); elevated malondialdehyde accumulation in the livers, kidneys, and breast muscles; glutathione peroxidase activity in the livers and superoxide dismutase activity in the kidneys (P < 0.05); exacerbated drip loss in the pectoralis muscles (P < 0.05); and reduced glutathione peroxidase activity in the pectoralis muscles (P < 0.05) of broilers at 42 days of age. The values of these parameters were reversed in the Pal/Pb group to levels comparable with those in the control group (P < 0.05). Additionally, Pal supplementation reduced redness value in the pectoralis muscles (P < 0.05), and decreased Cu concentration in the pectoralis muscles and livers at 42 days of age as well as its accumulation in the kidneys at both 21 and 42 days of age compared with the other two groups (P < 0.05). The results suggested that dietary Pal supplementation would decrease Pb residue in the tissues, alleviate oxidative stress, and affect meat quality of broilers exposed to Pb.

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Arsenic Induces Thioredoxin 1 and Apoptosis in Human Liver HHL-5 Cells

Abstract

To further characterize the mechanisms underlying liver toxicity induced by arsenic, we examined in this study the effect of arsenic on thioredoxin (Trx) and the apoptotic signaling pathways in human liver HHL-5 cells. The cells were treated with 0, 2, 5, and 10 μM of sodium arsenite for 24 h, and the changes of Trx1 and thioredoxin reductase (TrxR1) as well as intracellular ROS and apoptosis were examined. A concentration-dependent increase in mRNA and protein levels of Trx1 and TrxR1 was observed in arsenic-treated cells. Intracellular ROS levels and apoptosis were also significantly increased in a concentration-dependent manner. In line with this, protein levels of Bax and cytochrome C were increased and Bcl-2 was decreased by arsenic treatments. Increases in caspase 3 activity were observed. These results indicate that Trx is involved in arsenic-induced liver cell injury, probably through the apoptotic signaling pathway. However, further studies are needed to elucidate on these findings.

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Effects of Intermittent and Continuous Magnetic Fields on Trace Element Levels in Guinea Pigs

Abstract

Electromagnetic fields (EMFs) can affect living cells due to biochemical changes, followed by changes in levels of trace elements in serum and different organs. This study focuses on the effect of whole body exposure to EMF, presented everywhere in our environment, and on the levels of trace elements in serum, femur, brain, kidney, and liver tissues. The analyses performed on 29 guinea pigs were divided into five groups. Guinea pigs were exposed to a magnetic field of 50 Hz of 1.5 mT. Groups A and B were exposed to the magnetic field for a period of 4 h/day continuously (4 h/day) for 4 and 7 days, respectively. Groups C and D were exposed to the magnetic field for a period of 4 h/day intermittently for 4 and 7 days, respectively. Group E animals were enrolled as control. Copper (Cu), zinc (Zn), calcium (Ca), and magnesium (Mg) levels were determined by atomic absorption spectroscopy in serum, femur, brain, kidney, and liver tissues in all guinea pigs. When compared to the control groups, the changes in the levels of Cu in serum samples, femur, and kidney tissues of the treated groups were statistically significant. The same was also true for the levels of Mg in the brain, kidney, and lung tissues. Our results suggest that in vivo continuous and intermittent exposure to EMF may cause disturbances in homeostasis of bioelements. These effects could be important risk factors for toxic effects of EMF, especially in relation to deterioration of bioelements.

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Associations Between Serum Zinc Levels and Mental Health: Findings from the 2010 Korean National Health and Nutrition Examination Survey

Abstract

Mental health problems are a major public health issue worldwide, and zinc may be associated with psychiatric symptoms, but such associations have not been investigated extensively. This study was conducted to evaluate the relationship between serum zinc levels and mental health problems in Korean adults. We used data from the Korean National Health and Nutrition Examination Survey V-1, a cross-sectional survey of Korean civilians. Data from 1748 subjects were analyzed. Serum zinc levels did not differ significantly according to psychiatric symptoms including sleep duration, stress, depressed mood, suicidal ideation, and whether respondents sought psychiatric consultation. The frequencies and odds ratios of psychiatric symptoms according to serum zinc tertiles were not significantly associated after adjusting for age, smoking, alcohol consumption, physical activity, body mass index, total body fat, and renal function and for daily fat, carbohydrate, and protein intake. Serum zinc levels may not be associated with psychiatric symptoms in Korean adults without psychiatric disorders.

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Microenvironmental Scenario of the Bone Marrow of Inorganic Arsenic-Exposed Experimental Mice

Abstract

Exposure to arsenic on a regular basis, mainly through drinking water, agricultural pesticide, and sometimes therapeutic dose, results in various diseases of different tissues including the bone marrow hematopoietic system. Hematopoiesis is a dynamic process by which bone marrow (BM) hematopoietic stem/progenitor cells (HSPCs) generate a relatively constant pool of functionally mature blood cells by the support of microenvironmental components. The present study has been aimed to understand stem cell microenvironmental status during arsenic toxicity and the consequent reflection of dysregulation involving the hematopoietic machinery in experimental mice. Swiss albino mice were experimentally exposed to 10 μg arsenic trioxide/g body weight through oral gavage and 5 μg arsenic trioxide/g body weight intraperitoneally for a period of 30 days. Altered hemogram values in peripheral blood reflected the impaired hematopoiesis which was further validated by the reduced BM cellularity along with the deviated BM cell morphology as observed by scanning electron microscopy post arsenic exposure. The stromal cells were unable to establish a healthy matrix and the sustainability of hematopoietic progenitors was drastically affected in arsenic-exposed mouse groups, as observed in in vitro explant culture. The inability of stromal cells to establish supportive matrix was also explained by the decreased adherent colony formation in treated animals. Furthermore, the flow cytometric characterization of CXCR4⁺ and Sca-1⁺ CD44⁺ receptor expressions confirmed the dysregulation in the hematopoietic microenvironment. Thus, considering the importance of microenvironment in the maintenance of HSPC, it can be concluded that arsenic toxicity causes microenvironmental damage, leading to niche derangement and impaired hematopoiesis.

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The Contribution of Superoxide Radical to Cadmium Toxicity in E. coli

Abstract

Numerous reports suggest the involvement of oxidative stress in cadmium toxicity, but the nature of the reactive species and the mechanism of Cd-induced oxidative damage are not clear. In this study, E. coli mutants were used to investigate mechanisms of Cd toxicity. Effects of Cd on metabolic activity, production of superoxide radical by the respiratory chain, and induction of enzymes controlled by the soxRS regulon were investigated. In E. coli, the soxRS regulon controls defense against O₂·⁻and univalent oxidants. Suppression of metabolic activity, inability of E. coli to adapt to new environment, and slow cell division were among the manifestations of Cd toxicity. Cd increased production of O₂·⁻ by the electron transport chain and prevented the induction of soxRS-controlled protective enzymes, even when the regulon was induced by the redox-cycling agent, paraquat. The effect was not limited to soxRS-dependent proteins and can be attributed to previously reported suppression of protein synthesis by Cd. Increased production of superoxide, combined with inability to express protective enzymes and to replace damaged proteins by de novo protein synthesis, seems to be the main reason for growth stasis and cell death in Cd poisoning.

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Evaluation of Dietary Palygorskite Supplementation on Growth Performance, Mineral Accumulations, Antioxidant Capacities, and Meat Quality of Broilers Fed Lead-Contaminated Diet

Abstract

The objective of this study was to evaluate influence of dietary palygorskite (Pal) supplementation on growth performance, mineral accumulations in the tissues (livers, kidneys, and muscles), antioxidant capacities, and meat quality of broilers fed lead (Pb)-contaminated diet. One-hundred forty-four male broiler chicks were randomly divided into three treatment groups, receiving a corn-soybean meal basal diet (the control group), the basal diet contaminated with 10 mg/kg Pb (the Pb group), and the basal diet with 10-g/kg Pal supplementation and 10-mg/kg Pb contamination (the Pal/Pb group) from 1 to 42 days of age, respectively. Treatments did not affect growth performance of broilers in the 42-day study (P > 0.05). Compared with the control group, Pb contamination increased Pb accumulation in the livers, kidneys, and muscles (P < 0.05); elevated malondialdehyde accumulation in the livers, kidneys, and breast muscles; glutathione peroxidase activity in the livers and superoxide dismutase activity in the kidneys (P < 0.05); exacerbated drip loss in the pectoralis muscles (P < 0.05); and reduced glutathione peroxidase activity in the pectoralis muscles (P < 0.05) of broilers at 42 days of age. The values of these parameters were reversed in the Pal/Pb group to levels comparable with those in the control group (P < 0.05). Additionally, Pal supplementation reduced redness value in the pectoralis muscles (P < 0.05), and decreased Cu concentration in the pectoralis muscles and livers at 42 days of age as well as its accumulation in the kidneys at both 21 and 42 days of age compared with the other two groups (P < 0.05). The results suggested that dietary Pal supplementation would decrease Pb residue in the tissues, alleviate oxidative stress, and affect meat quality of broilers exposed to Pb.

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High-frequency deregulated expression of Wnt signaling pathway members in breast carcinomas

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The silencing of LncRNA-H19 decreases chemoresistance of human glioma cells to temozolomide by suppressing epithelial-mesenchymal transition via the Wnt/β-Catenin pathway

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A novel tumor suppressor gene NCOA5 is correlated with progression in papillary thyroid carcinoma

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Comparative study of clinical efficacy using three-dimensional and two-dimensional laparoscopies in the treatment of distal gastric cancer

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Prospective trial evaluating the sensitivity and specificity of 3,4-dihydroxy-6-[18F]-fluoro- l -phenylalanine (18F-DOPA) PET and MRI in patients with recurrent gliomas

Abstract

Treatment-related changes can be difficult to differentiate from progressive glioma using MRI with contrast (CE). The purpose of this study is to compare the sensitivity and specificity of 18F-DOPA-PET and MRI in patients with recurrent glioma. Thirteen patients with MRI findings suspicious for recurrent glioma were prospectively enrolled and underwent 18F-DOPA-PET and MRI for neurosurgical planning. Stereotactic biopsies were obtained from regions of concordant and discordant PET and MRI CE, all within regions of T2/FLAIR signal hyperintensity. The sensitivity and specificity of 18F-DOPA-PET and CE were calculated based on histopathologic analysis. Receiver operating characteristic curve analysis revealed optimal tumor to normal (T/N) and SUVmax thresholds. In the 37 specimens obtained, 51% exhibited MRI contrast enhancement (M+) and 78% demonstrated 18F-DOPA-PET avidity (P+). Imaging characteristics included M−P− in 16%, M−P+ in 32%, M+P+ in 46% and M+P− in 5%. Histopathologic review of biopsies revealed grade II components in 16%, grade III in 43%, grade IV in 30% and no tumor in 11%. MRI CE sensitivity for recurrent tumor was 52% and specificity was 50%. PET sensitivity for tumor was 82% and specificity was 50%. A T/N threshold > 2.0 altered sensitivity to 76% and specificity to 100% and SUVmax > 1.36 improved sensitivity and specificity to 94 and 75%, respectively. 18F-DOPA-PET can provide increased sensitivity and specificity compared with MRI CE for visualizing the spatial distribution of recurrent gliomas. Future studies will incorporate 18F-DOPA-PET into re-irradiation target volume delineation for RT planning.

http://ift.tt/2Fz5prE

Prospective trial evaluating the sensitivity and specificity of 3,4-dihydroxy-6-[18F]-fluoro- l -phenylalanine (18F-DOPA) PET and MRI in patients with recurrent gliomas

Abstract

Treatment-related changes can be difficult to differentiate from progressive glioma using MRI with contrast (CE). The purpose of this study is to compare the sensitivity and specificity of 18F-DOPA-PET and MRI in patients with recurrent glioma. Thirteen patients with MRI findings suspicious for recurrent glioma were prospectively enrolled and underwent 18F-DOPA-PET and MRI for neurosurgical planning. Stereotactic biopsies were obtained from regions of concordant and discordant PET and MRI CE, all within regions of T2/FLAIR signal hyperintensity. The sensitivity and specificity of 18F-DOPA-PET and CE were calculated based on histopathologic analysis. Receiver operating characteristic curve analysis revealed optimal tumor to normal (T/N) and SUVmax thresholds. In the 37 specimens obtained, 51% exhibited MRI contrast enhancement (M+) and 78% demonstrated 18F-DOPA-PET avidity (P+). Imaging characteristics included M−P− in 16%, M−P+ in 32%, M+P+ in 46% and M+P− in 5%. Histopathologic review of biopsies revealed grade II components in 16%, grade III in 43%, grade IV in 30% and no tumor in 11%. MRI CE sensitivity for recurrent tumor was 52% and specificity was 50%. PET sensitivity for tumor was 82% and specificity was 50%. A T/N threshold > 2.0 altered sensitivity to 76% and specificity to 100% and SUVmax > 1.36 improved sensitivity and specificity to 94 and 75%, respectively. 18F-DOPA-PET can provide increased sensitivity and specificity compared with MRI CE for visualizing the spatial distribution of recurrent gliomas. Future studies will incorporate 18F-DOPA-PET into re-irradiation target volume delineation for RT planning.

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Metal Concentrations in Tissues of Gadwall and Common Teal from Miankaleh and Gomishan International Wetlands, Iran

Abstract

Miankaleh and Gomishan International Wetlands are important wintering areas for waterbirds in the Caspian Sea region. Previous studies revealed increased exposure to metals in some species of waterbirds using these wetlands. In this study, we examined concentrations of cadmium (Cd), chromium (Cr), iron (Fe), lead (Pb), and zinc (Zn) in kidneys, liver, and pectoral muscle of wintering Gadwall (Anas strepera) and Common Teal (Anas crecca) collected in 2012. In addition, we measured concentrations of these elements in water and sediments from the collection sites. The genders differed in only one element/tissue combination, i.e., concentrations of Fe were greater in the livers of males. Concentrations of elements observed in Gadwall were generally higher than in Common Teal; only renal Cr and muscle Zn did not differ between species. Mean Cd concentrations in Gadwall exceeded background levels, reaching 1.94 μg/g ww in kidneys and 1.09 μg/g ww in liver. Similarly, Pb concentrations in Gadwall were also elevated (4.14 μg/g ww in kidneys, 3.22 μg/g ww in liver). Concentrations of other metals were within ranges commonly found in waterfowl. Concentrations of elements in the environment were elevated above background and comparable with the data obtained for this region by other scientists. However, these levels were deemed to not be great enough to pose an acute health risk to waterfowl. Given increased concentrations of some metals in duck tissues, further inquiry into the source of the exposure is needed for this area.

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Rheumatoid disease: an unusual cause of relapsing meningoencephalitis

A 73-year-old man presented with three episodes of dysphasia and disinhibited behaviour, a single seizure and transient ischaemic attack-like events characterised by right arm and/or leg weakness. These episodes were separated by month-long asymptomatic intervals. Medical history included rheumatoid arthritis, which was clinically quiescent on leflunomide.

Repeated cerebrospinal fluid examination showed a persistent lymphocytosis with mildly reduced glucose and elevated protein; oligoclonal bands and viral PCR were negative. MRI of the brain was initially normal, but 7 months after initial presentation revealed meningeal enhancement with bifrontal cortical hyperintensities on T2/fluid-attenuated inversion recovery. Brain biopsy demonstrated necrotising granulomatous meningitis with mixed T cell and B cell infiltrates and without evidence of vasculitis or infection. Serum anticyclic citrullinated peptide antibodies were strongly positive.

The diagnosis of rheumatoid meningoencephalitis was made on the basis of brain biopsy findings and serological evidence of active rheumatoid disease. Steroids and rituximab therapy were started leading to clinical stabilisation.

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Bancroftian filariasis associated with male sterility

Description

A 33-year-old man presented with recurrent pain and swelling in the inguinal region since the last 8 years, occasional fever and loss of sex drive. The pain and swelling usually lasted for 2–3 weeks with a pain-free interval of 4–5 months. He felt that the size of the left testis is gradually reducing. He had been married for more than 5 years without having any children. Clinical examination revealed swelling and tenderness of the scrotum more on the right (figure 1A).

Fro Figure 1

(A) A 33-year- old man with right-sided testicular swelling. (B) Ultrasonography of the scrotum reveals a hypoechogenic, small right testis with irregularly echogenicity in periphery due to fibrosis. (C) Colour Doppler reveals absence of vascular flow on right-side testis.

Ultrasound examination showed swelling of both epididymis with the outer area appearing irregularly echogenic due to fibrosis (figure 1B)....

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Pelvic and buttock hypoplasia reconstructed with anatomical breast implants

Radiation therapy is used in the management of a number of childhood cancers and can have significant effects on skeletal growth. We present the case of a 35-year-old woman who developed a hypoplastic pelvis and buttocks following radiotherapy for rhabdomyosarcoma of the vagina at the age of 2. At the age of 25, the patient underwent bilateral buttock augmentation with a two-stage reconstruction using tissue expansion followed by definitive augmentation with anatomical breast implant insertion. The patient continues to have a satisfactory outcome 10 years following reconstruction, having undergone a single uplift procedure and exchange of implants through the original incision 9 years postoperatively. This case represents a unique reconstructive challenge to plastic surgeons and was successfully managed with a novel approach.

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Case of chest pain in a young man

A young man with a history of smoking presented with acute-onset chest pain after lifting weights. He also noticed a change in his voice, tightness in his neck and difficulty breathing. A chest radiograph showed soft tissue emphysema in the neck. A CT scan of the chest revealed moderate amount of pneumomediastinum tracking into the neck and down to the diaphragm. He was haemodynamically stable and had no hypoxia or dysphagia. He was monitored for 48 hours and discharged home after resolution of his symptoms. A chest radiograph repeated after 6 weeks was normal.

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Central nervous system graft-versus-host disease (CNS-GvHD) after allogeneic haematopoietic stem cell transplantation

A 60-year-old man presented with impaired consciousness and psychomotor agitation after a second allogeneic haematopoietic stem cell transplantation (HSCT) from a matched unrelated donor for acute myeloid leukaemia. Clinical, biological and radiological evidence suggested a diagnosis of central nervous system graft-versus-host disease (CNS-GvHD). After intrathecal infusion of methylprednisolone, the clinical symptoms as well as the radiological abnormalities disappeared. The present report illustrates the difficulties in the diagnosis and the management of CNS-GvHD, a very rare and still challenging neurological complication that can occur after allogeneic HSCT.

http://ift.tt/2D4aQkS

Spontaneous splenic rupture as a rare complication of G-CSF injection

Splenic rupture is an infrequent and underdiagnosed side effect of granylocyte colony-stimulating factor (G-CSF). We report the case of a 54-year-old woman with brain and bone metastasis in a lung adenocarcinoma who was admitted for faintness 28 days after a G-CSF injection. Abdominal CT scan confirmed the diagnosis of splenic rupture. A conservative treatment was chosen using a peritoneal cleansing during laparoscopic surgery. Clinicians should be aware of this rare toxicity as it could be severe, but easily reversible using appropriate surgical treatment. Even if prognosis remains poor for patients with lung cancer, invasive procedures could be considered in this rapidly evolving setting, especially in case of reversible adverse event.

http://ift.tt/2AVS5u7

Cutis marmorata telangiectatica congenita and major lower limb asymmetry

A 39-week-old male newborn presented at birth with atrophic erythematous and purpuric skin lesions, in a typical right-sided segmental distribution. Lesions were persistent and unaffected by rewarming in the postpartum period. Postnatal echocardiogram showed a predominance of the right cavities and an upper atrial septal defect. Cerebral and abdominal ultrasound were normal along with ophthalmological examination. On follow-up, lower limbs asymmetry was noted. The right lower limb was shorter in length and had a smaller diameter. At 6 months, the right lower limb was 1.5 cm shorter than the left, most likely related to nutritive vessels malformations. The discrepancy was even more pronounced at the age of 9 months. This leg-length asymmetry can lead to severe functional limitations in the future.

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Cerebrofacial arteriovenous metameric syndrome with hypopituitarism: a rare association

Case of cerebrofacial arteriovenous metameric syndrome (CAMS) in a 9-year-old boy is described with arteriovenous malformation simultaneously involving the brain and face, with characteristic CAMS type 1 and 2 involvement. This patient demonstrates the wide spectrum of clinical manifestations of CAMS, and in this particular case, the patient exhibits features of hypopituitarism—an association that was not previously described in the literature to our knowledge. Awareness of the underlying embryological abnormality and recognition of resultant clinical and radiological presentations are paramount for diagnosis and treatment.

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Vitamin B12 deficiency: unusual cause of jaundice in an adolescent

Vitamin B₁₂ deficiency in vegans is a known cause of megaloblastic anaemia. We report an adolescent girl who presented with jaundice and weight loss for 6 months secondary to vitamin B₁₂ deficiency, leading to megaloblastic anaemia. Replacement with vitamin B₁₂ reversed her symptoms, resulting in weight gain, and normalised her haemoglobin, red blood cell morphology, bilirubin levels and serum vitamin B₁₂ levels.

http://ift.tt/2D69ruh

Cutaneous Mycobacterium massiliense infection from tattooing: a common yet under-reported and persistent epidemic hazard for dermatologists

Tattoo popularity continues to rise, with 3 in 10 Americans bearing at least one. Among tattoo complications, non-tuberculous mycobacteria (NTM) has emerged as a global public health concern. NTM infections associated with tattooing of immunocompetent individuals have occurred as sporadic cases and community outbreaks. Water sources are considered the major pathogenic reservoirs. Tattoo-related inoculation has been linked to contamination of ink, either during the manufacturing process or during dilution of black ink using non-sterile water. NTM infections have also been documented in a number of cosmetic and surgical procedures, including cutaneous surgery, Mohs micrographic surgery, mesotherapy, liposuction and laser resurfacing. NTM inoculation through exposure to contaminated water or non-sterile instruments remains a challenge for dermatologists and risk to patients. We reported a case of cutaneous Mycobacterium massiliense infection following tattoo placement. This report underscores the importance of clinicians to consider NTM infections in the differential diagnosis of procedure-related reactions.

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Multiple cranial nerve palsies secondary to a recurrence of Hansens disease

Description

A 31-year-old Indian man presented with drooping of the right eyelid since 1 month, slight deviation of the angle of the mouth to the right since 20 days, difficulty in swallowing (initially with regard to solids, and later on with regard to liquids) since 15 days, nasal regurgitation since 15 days and a nasal twang since 15 days. His past history was not significant, with no history of fever, weight loss, diarrhoea, swollen glands, rash, disfigurement of the hands and feet, loss of eyebrows, or any history suggestive of limb weakness, numbness or tingling. He was not on any medications. None of his parents had any health problems.

He had been previously treated for multibacillary leprosy (Hansen's disease) 3 years back and had taken treatment for 1 year for the same.

On examination, he was found to have bilateral lower motor neuron (LMN)-type glossopharyngeal and vagus nerve palsy; right-sided oculomotor nerve palsy as evidenced...

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Cutaneous larva migrans with pulmonary involvement

Description

After returning from a Carribean cruise, a 52-year-old woman spent an afternoon sitting on a sandy beach in Martinique with her husband. An initial burning sensation over her buttocks was followed the next day by an intensely pruritic eruption with 'red pinprick marks'. This was unsuccessfully treated on the cruise ship with antibiotics, antifungal agents, as well as topical and intramuscular steroids. Examination on day 10 revealed a serpiginous rash over her buttocks with a large number of discrete papular lesions (figure 1). The patient's husband was noted to be itching and examination revealed a rash with equivalent distribution and morphology (figure 2). A clinical diagnosis of cutaneous larva migrans was made.

Figure 1

Florid, serpiginous rash located on the buttock region of the patient.

Figure 2

Rash with identical morphology affecting the same region of patient's...

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Rare cause of isolated severe coagulation failure in cirrhosis: traditional healing with fenugreek

Patients with cirrhosis develop decompensation events during the natural history of the disease that encompass ascites, variceal bleeding, hepatic encephalopathy and jaundice. Coagulation failure, defined using the international normalised ratio, even though not a decompensation event, is important in patients with stratifying cirrhosis into those who require liver transplantation for long-term survival. Isolated coagulation failure in cirrhosis is rare and usually occurs with use of anticoagulants in the setting of vascular diseases. We reported the case of a patient with compensated cirrhosis in whom, isolated severe coagulation failure was found to be due to excessive use of fenugreek milk porridge as part of traditional healing. The coagulation failure was promptly reversed with avoidance of fenugreek and supplementation with vitamin K.

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Hepatic portal venous gas after diving

Description

A 68-year-old man with diabetes and chronic kidney disease presented with severe epigastric pain and nausea 30 min after scuba diving in Ishigaki Island, southern part of Okinawa Prefecture, Japan. He dived to 10 m (32.8 ft) twice, for an hour each diving. The length of bottom time was unknown. The temperature of the water was 29.0°C (84.2°F). His vital signs were stable. On palpation of abdomen, there was no evidence of guarding and tenderness. There was also no rash. Venous blood gas showed a pH of 7.314 and lactate of 3.03 mmol/L. Other laboratory values were unremarkable, including liver function tests and creatine kinase. An abdominal CT without contrast was performed because he had a history of allergic reaction to contrast agent. Abdominal CT demonstrated hepatic portal venous gas (HPVG, figures 1 and 2) and gases in the mesenteric vein (figure 2) and femoral vein (

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Case of acute severe postpartum urinary incontinence: an extravesical subsphincteric prolapsed ureterocoele

A 32-year-old woman presents to outpatients 10 days postpartum, with symptoms of an intermittent vaginal lump and urinary incontinence. Vaginal examination revealed no demonstrable prolapse or stress incontinence. A swelling in the bladder was noted during an antenatal scan suggesting a ureterocoele. She was referred for pelvic floor physiotherapy in the first instance. Forty-eight hours later, she represented to casualty with discomforting vaginal lump symptoms and continuous urinary incontinence. At this stage on vaginal inspection, there was an evident dusky lump emerging from the urethra with continuous incontinence. An extravesical subsphincteric prolapsed ureterocoele was evident, 5 cm beyond the external urethral meatus. The diagnosis was confirmed with an MRI scan which demonstrated the prolapsed obstructing ureterocoele causing significant left-sided hydroureteronephrosis. The ureterocoele was managed with a cystoscopy and transurethral incision of the ureterocoele under anaesthesia, which facilitated drainage and resolution. At 3-month postoperatively, the patient remains continent and satisfied.

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Metal Concentrations in Tissues of Gadwall and Common Teal from Miankaleh and Gomishan International Wetlands, Iran

Abstract

Miankaleh and Gomishan International Wetlands are important wintering areas for waterbirds in the Caspian Sea region. Previous studies revealed increased exposure to metals in some species of waterbirds using these wetlands. In this study, we examined concentrations of cadmium (Cd), chromium (Cr), iron (Fe), lead (Pb), and zinc (Zn) in kidneys, liver, and pectoral muscle of wintering Gadwall (Anas strepera) and Common Teal (Anas crecca) collected in 2012. In addition, we measured concentrations of these elements in water and sediments from the collection sites. The genders differed in only one element/tissue combination, i.e., concentrations of Fe were greater in the livers of males. Concentrations of elements observed in Gadwall were generally higher than in Common Teal; only renal Cr and muscle Zn did not differ between species. Mean Cd concentrations in Gadwall exceeded background levels, reaching 1.94 μg/g ww in kidneys and 1.09 μg/g ww in liver. Similarly, Pb concentrations in Gadwall were also elevated (4.14 μg/g ww in kidneys, 3.22 μg/g ww in liver). Concentrations of other metals were within ranges commonly found in waterfowl. Concentrations of elements in the environment were elevated above background and comparable with the data obtained for this region by other scientists. However, these levels were deemed to not be great enough to pose an acute health risk to waterfowl. Given increased concentrations of some metals in duck tissues, further inquiry into the source of the exposure is needed for this area.

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Microfluidic co-culture of pancreatic tumor spheroids with stellate cells as a novel 3D model for investigation of stroma-mediated cell motility and drug resistance

Pancreatic stellate cells (PSCs), a major component of the tumor microenvironment in pancreatic cancer, play roles in cancer progression as well as drug resistance. Culturing various cells in microfluidic (mic...

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Pazopanib Exposure Relationship with Clinical Efficacy and Safety in the Adjuvant Treatment of Advanced Renal Cell Carcinoma

Purpose: PROTECT, a phase III randomized placebo-controlled study, evaluated pazopanib efficacy and safety in the adjuvant RCC setting. The relationship between pazopanib exposure (C_trough) and efficacy and safety was evaluated. Experimental Design: Evaluable steady-state blood trough concentrations were collected from 311 patients at week 3 or 5 (early C_trough), and 250 patients at week 16 or 20 (late C_trough). Pazopanib pharmacokinetic (PK) data was analyzed via a population model approach. Relationship between C_trough or dose intensity and disease-free survival (DFS) was explored via Kaplan-Meier and multivariate analysis. Adverse events (AEs) and AE-related treatment discontinuation proportions were summarized by C_trough quartiles. Results: Most (>90%) patients with early or late C_trough data started on 600 mg. Mean early and late C_trough overlapped across dose levels. Patients with higher early C_trough quartiles achieved longer DFS (adjusted hazard ratio [HR], 0.58; 95% CI, 0.42-0.82; P = 0.002). Patients achieving early or late C_trough >20.5 µg/mL had significantly longer DFS, not estimable (NE) vs 29.5 months, P = 0.006, and NE vs 29.9 months, P = 0.008, respectively. Dose intensity up to week 8 did not correlate with DFS, consistent with population PK model-based simulations showing overlapping pazopanib exposure with 600 mg and 800 mg doses. The proportion of AE-related treatment discontinuation and grade 3/4 AEs, with the exception of hypertension, was not correlated to C_trough. Conclusions: In the adjuvant setting, higher pazopanib C_trough was associated with improved DFS, and did not increase treatment discontinuations or grade 3/4 AEs with the exception of hypertension.

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Evolution of cytogenetically normal acute myeloid leukemia during therapy and relapse: An exome sequencing study of 50 patients

Purpose: To study mechanisms of therapy-resistance and disease progression, we analyzed the evolution of cytogenetically normal acute myeloid leukemia (CN-AML) based on somatic alterations. Experimental Design: We performed exome-sequencing of matched diagnosis, remission and relapse samples from 50 CN-AML patients treated with intensive chemotherapy. Mutation patterns were correlated with clinical parameters. Results: Evolutionary patterns correlated with clinical outcome. Gain of mutations was associated with late relapse. Alterations of epigenetic regulators were frequently gained at relapse with recurring alterations of KDM6A constituting a mechanism of cytarabine resistance. Low KDM6A expression correlated with adverse clinical outcome, particularly in male patients. At complete remission, persistent mutations representing pre-leukemic lesions were observed in 48% of patients. The persistence of DNMT3A mutations correlated with shorter time to relapse. Conclusion: Chemotherapy resistance might be acquired through gain of mutations. Insights into the evolution during therapy and disease progression lay the foundation for tailored approaches to treat or prevent relapse of CN-AML.

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High-risk TP53 mutations are associated with extra nodal extension (ENE) in oral cavity squamous cell carcinoma (OSCC).

Purpose:  Development of extra-nodal extension (ENE) has been associated with poor survival in patients with oral cavity squamous cell carcinoma (OSCC). Here we sought to confirm the role of ENE as a poor prognostic factor, and identify genomic and epigenetic markers of ENE in order to develop a predictive model and improve treatment selection. Experimental design: An institutional cohort (University of Texas MD Anderson Cancer Center) was utilized to confirm the impact of ENE on clinical outcomes and evaluate the genomic signature of primary and ENE containing tissue. OSCC data from The Cancer Genome Atlas (TCGA) were analyzed for the presence of molecular events associated with nodal and ENE status. Results: ENE was associated with decreased overall and disease free survival. Mutation of the TP53 gene was the most common event in ENE+ OSCC. The frequency of TP53 mutation in ENE+ tumors was higher compared to ENE- tumors and wild-type (wt) TP53 was highly-represented in pN0 tumors. pN+ENE+ patients had the highest proportion of high-risk TP53 mutations. Both primary tumors (PT) and lymph nodes with ENE (LN) exhibited a high rate of TP53 mutations (58.8%, 58.8% respectively) with no significant change in allele frequency between the two tissue sites. Conclusions: ENE is one of the most significant markers of OSCC OS and DFS. There is a shift toward a more aggressive biological phenotype associated with high-risk mutations of the TP53 gene. Prospective clinical trials are required to determine whether TP53 mutational status can be used for personalized treatment decisions.

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High-risk TP53 mutations are associated with extra nodal extension (ENE) in oral cavity squamous cell carcinoma (OSCC).

Purpose:  Development of extra-nodal extension (ENE) has been associated with poor survival in patients with oral cavity squamous cell carcinoma (OSCC). Here we sought to confirm the role of ENE as a poor prognostic factor, and identify genomic and epigenetic markers of ENE in order to develop a predictive model and improve treatment selection. Experimental design: An institutional cohort (University of Texas MD Anderson Cancer Center) was utilized to confirm the impact of ENE on clinical outcomes and evaluate the genomic signature of primary and ENE containing tissue. OSCC data from The Cancer Genome Atlas (TCGA) were analyzed for the presence of molecular events associated with nodal and ENE status. Results: ENE was associated with decreased overall and disease free survival. Mutation of the TP53 gene was the most common event in ENE+ OSCC. The frequency of TP53 mutation in ENE+ tumors was higher compared to ENE- tumors and wild-type (wt) TP53 was highly-represented in pN0 tumors. pN+ENE+ patients had the highest proportion of high-risk TP53 mutations. Both primary tumors (PT) and lymph nodes with ENE (LN) exhibited a high rate of TP53 mutations (58.8%, 58.8% respectively) with no significant change in allele frequency between the two tissue sites. Conclusions: ENE is one of the most significant markers of OSCC OS and DFS. There is a shift toward a more aggressive biological phenotype associated with high-risk mutations of the TP53 gene. Prospective clinical trials are required to determine whether TP53 mutational status can be used for personalized treatment decisions.

http://ift.tt/2FxeTDP

Personalized RNA-medicine for pancreatic cancer

Purpose: Since drug responses vary between patients, it is crucial to develop pre-clinical or co-clinical strategies that forecast patient response. In this study, we tested whether RNA-based therapeutics were suitable for personalized medicine by using patient-derived-organoid (PDO) and patient-derived-xenograft (PDX) models.  Experimental Design: We performed microRNA (miRNA) profiling of PDX samples to determine the status of miRNA deregulation in individual pancreatic ductal adenocarcinoma (PDAC) patients. To deliver personalized RNA-based-therapy targeting oncogenic miRNAs that form part of this common PDAC miRNA over-expression signature, we packaged antimiR oligonucleotides against one of these miRNAs in tumor-penetrating nanocomplexes (TPN) targeting cell surface proteins on PDAC tumors. Results: As a validation for our pre-clinical strategy, the therapeutic potential of one of our nano-drugs, TPN-21 was first shown to decrease tumor cell growth and survival in PDO avatars for individual patients, then in their PDX avatars. Conclusions: This general approach appears suitable for co-clinical validation of personalized RNA medicine and paves the way to prospectively identify patients with eligible miRNA profiles for personalized RNA-based therapy.

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Clinical utility of a STAT3-regulated microRNA-200 family signature with prognostic potential in early gastric cancer

Purpose: The majority of gastric cancer (GC) patients are diagnosed with late stage disease, for which distinct molecular subtypes have been identified that are potentially amenable to targeted therapies. However, there exists no molecular classification system with prognostic power for early stage GC (EGC) because the molecular events promoting GC initiation remain ill-defined. Experimental Design: miRNA microarrays were performed on gastric tissue from the gp130^F/F preclinical EGC mouse model, prior to tumor initiation. Computation prediction algorithms were performed on multiple datasets and independent GC patient cohorts. Quantitative real-time PCR expression profiling was undertaken in gp130^F/F-based mouse strains and human GC cells genetically-engineered for suppressed activation of the oncogenic latent transcription factor, STAT3. Human GC cells with modulated expression of the miR-200 family member, miR-429, were also assessed for their proliferative response. Results: Increased expression of miR-200 family members is associated with both tumor initiation in a STAT3-dependent manner in gp130^F/F mice, and EGC (i.e. Stage IA) in patient cohorts. Over-expression of miR-429 also elicited contrasting pro- and anti-proliferative responses in human GC cells dependent upon their cellular histological subtype. We also identified a miR-200 family-regulated 15-gene signature which integrates multiple key current indicators of EGC, namely tumor invasion depth, differentiation, histology and stage, and provides superior predictive power for overall survival compared to each EGC indicator alone.  Conclusions: Collectively, our discovery of a STAT3-regulated, miR-200 family-associated gene signature specific for EGC, with predictive power, provides a molecular rationale to classify and stratify EGC patients for endoscopic treatment.

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Early Assessment of Lung Cancer Immunotherapy Response via Circulating Tumor DNA

Purpose: Decisions to continue or suspend therapy with immune checkpoint inhibitors are commonly guided by tumor dynamics seen on serial imaging.  However, immunotherapy responses are uniquely challenging to interpret because tumors often shrink slowly or can appear transiently enlarged due to inflammation.  We hypothesized that monitoring tumor cell death in real-time by quantifying changes in circulating tumor DNA (ctDNA) levels could enable early assessment of immunotherapy efficacy.  Experimental Design: We compared longitudinal changes in ctDNA levels with changes in radiographic tumor size and with survival outcomes in 28 metastatic non-small cell lung cancer patients receiving immune checkpoint inhibitor therapy.  CtDNA was quantified by determining the allele fraction of cancer-associated somatic mutations in plasma using a multi-gene next-generation sequencing assay.  We defined a ctDNA response as a >50% decrease in mutant allele fraction from baseline, with a second confirmatory measurement. Results: Strong agreement was observed between ctDNA response and radiographic response (Cohen's kappa, 0.753).  Median time to initial response among patients who achieved responses in both categories was 24.5 days by ctDNA vs. 72.5 days by imaging.  Time on treatment was significantly longer for ctDNA responders vs. non-responders (median 205.5 vs. 69 days; P<0.001).  A ctDNA response was associated with superior progression-free survival (hazard ratio [HR], 0.29; 95% CI, 0.09-0.89; P=0.03), and superior overall survival (HR, 0.17; 95% CI, 0.05-0.62; P=0.007). Conclusions: A drop in ctDNA level is an early marker of therapeutic efficacy and predicts prolonged survival in patients treated with immune checkpoint inhibitors for non-small cell lung cancer.

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Pazopanib Exposure Relationship with Clinical Efficacy and Safety in the Adjuvant Treatment of Advanced Renal Cell Carcinoma

Purpose: PROTECT, a phase III randomized placebo-controlled study, evaluated pazopanib efficacy and safety in the adjuvant RCC setting. The relationship between pazopanib exposure (C_trough) and efficacy and safety was evaluated. Experimental Design: Evaluable steady-state blood trough concentrations were collected from 311 patients at week 3 or 5 (early C_trough), and 250 patients at week 16 or 20 (late C_trough). Pazopanib pharmacokinetic (PK) data was analyzed via a population model approach. Relationship between C_trough or dose intensity and disease-free survival (DFS) was explored via Kaplan-Meier and multivariate analysis. Adverse events (AEs) and AE-related treatment discontinuation proportions were summarized by C_trough quartiles. Results: Most (>90%) patients with early or late C_trough data started on 600 mg. Mean early and late C_trough overlapped across dose levels. Patients with higher early C_trough quartiles achieved longer DFS (adjusted hazard ratio [HR], 0.58; 95% CI, 0.42-0.82; P = 0.002). Patients achieving early or late C_trough >20.5 µg/mL had significantly longer DFS, not estimable (NE) vs 29.5 months, P = 0.006, and NE vs 29.9 months, P = 0.008, respectively. Dose intensity up to week 8 did not correlate with DFS, consistent with population PK model-based simulations showing overlapping pazopanib exposure with 600 mg and 800 mg doses. The proportion of AE-related treatment discontinuation and grade 3/4 AEs, with the exception of hypertension, was not correlated to C_trough. Conclusions: In the adjuvant setting, higher pazopanib C_trough was associated with improved DFS, and did not increase treatment discontinuations or grade 3/4 AEs with the exception of hypertension.

http://ift.tt/2EC4Z2x

Personalized RNA-medicine for pancreatic cancer

Purpose: Since drug responses vary between patients, it is crucial to develop pre-clinical or co-clinical strategies that forecast patient response. In this study, we tested whether RNA-based therapeutics were suitable for personalized medicine by using patient-derived-organoid (PDO) and patient-derived-xenograft (PDX) models.  Experimental Design: We performed microRNA (miRNA) profiling of PDX samples to determine the status of miRNA deregulation in individual pancreatic ductal adenocarcinoma (PDAC) patients. To deliver personalized RNA-based-therapy targeting oncogenic miRNAs that form part of this common PDAC miRNA over-expression signature, we packaged antimiR oligonucleotides against one of these miRNAs in tumor-penetrating nanocomplexes (TPN) targeting cell surface proteins on PDAC tumors. Results: As a validation for our pre-clinical strategy, the therapeutic potential of one of our nano-drugs, TPN-21 was first shown to decrease tumor cell growth and survival in PDO avatars for individual patients, then in their PDX avatars. Conclusions: This general approach appears suitable for co-clinical validation of personalized RNA medicine and paves the way to prospectively identify patients with eligible miRNA profiles for personalized RNA-based therapy.

http://ift.tt/2FvW97R

Clinical utility of a STAT3-regulated microRNA-200 family signature with prognostic potential in early gastric cancer

Purpose: The majority of gastric cancer (GC) patients are diagnosed with late stage disease, for which distinct molecular subtypes have been identified that are potentially amenable to targeted therapies. However, there exists no molecular classification system with prognostic power for early stage GC (EGC) because the molecular events promoting GC initiation remain ill-defined. Experimental Design: miRNA microarrays were performed on gastric tissue from the gp130^F/F preclinical EGC mouse model, prior to tumor initiation. Computation prediction algorithms were performed on multiple datasets and independent GC patient cohorts. Quantitative real-time PCR expression profiling was undertaken in gp130^F/F-based mouse strains and human GC cells genetically-engineered for suppressed activation of the oncogenic latent transcription factor, STAT3. Human GC cells with modulated expression of the miR-200 family member, miR-429, were also assessed for their proliferative response. Results: Increased expression of miR-200 family members is associated with both tumor initiation in a STAT3-dependent manner in gp130^F/F mice, and EGC (i.e. Stage IA) in patient cohorts. Over-expression of miR-429 also elicited contrasting pro- and anti-proliferative responses in human GC cells dependent upon their cellular histological subtype. We also identified a miR-200 family-regulated 15-gene signature which integrates multiple key current indicators of EGC, namely tumor invasion depth, differentiation, histology and stage, and provides superior predictive power for overall survival compared to each EGC indicator alone.  Conclusions: Collectively, our discovery of a STAT3-regulated, miR-200 family-associated gene signature specific for EGC, with predictive power, provides a molecular rationale to classify and stratify EGC patients for endoscopic treatment.

http://ift.tt/2EDRijV

Early Assessment of Lung Cancer Immunotherapy Response via Circulating Tumor DNA

Purpose: Decisions to continue or suspend therapy with immune checkpoint inhibitors are commonly guided by tumor dynamics seen on serial imaging.  However, immunotherapy responses are uniquely challenging to interpret because tumors often shrink slowly or can appear transiently enlarged due to inflammation.  We hypothesized that monitoring tumor cell death in real-time by quantifying changes in circulating tumor DNA (ctDNA) levels could enable early assessment of immunotherapy efficacy.  Experimental Design: We compared longitudinal changes in ctDNA levels with changes in radiographic tumor size and with survival outcomes in 28 metastatic non-small cell lung cancer patients receiving immune checkpoint inhibitor therapy.  CtDNA was quantified by determining the allele fraction of cancer-associated somatic mutations in plasma using a multi-gene next-generation sequencing assay.  We defined a ctDNA response as a >50% decrease in mutant allele fraction from baseline, with a second confirmatory measurement. Results: Strong agreement was observed between ctDNA response and radiographic response (Cohen's kappa, 0.753).  Median time to initial response among patients who achieved responses in both categories was 24.5 days by ctDNA vs. 72.5 days by imaging.  Time on treatment was significantly longer for ctDNA responders vs. non-responders (median 205.5 vs. 69 days; P<0.001).  A ctDNA response was associated with superior progression-free survival (hazard ratio [HR], 0.29; 95% CI, 0.09-0.89; P=0.03), and superior overall survival (HR, 0.17; 95% CI, 0.05-0.62; P=0.007). Conclusions: A drop in ctDNA level is an early marker of therapeutic efficacy and predicts prolonged survival in patients treated with immune checkpoint inhibitors for non-small cell lung cancer.

http://ift.tt/2FvW7Nh

Evolution of cytogenetically normal acute myeloid leukemia during therapy and relapse: An exome sequencing study of 50 patients

Purpose: To study mechanisms of therapy-resistance and disease progression, we analyzed the evolution of cytogenetically normal acute myeloid leukemia (CN-AML) based on somatic alterations. Experimental Design: We performed exome-sequencing of matched diagnosis, remission and relapse samples from 50 CN-AML patients treated with intensive chemotherapy. Mutation patterns were correlated with clinical parameters. Results: Evolutionary patterns correlated with clinical outcome. Gain of mutations was associated with late relapse. Alterations of epigenetic regulators were frequently gained at relapse with recurring alterations of KDM6A constituting a mechanism of cytarabine resistance. Low KDM6A expression correlated with adverse clinical outcome, particularly in male patients. At complete remission, persistent mutations representing pre-leukemic lesions were observed in 48% of patients. The persistence of DNMT3A mutations correlated with shorter time to relapse. Conclusion: Chemotherapy resistance might be acquired through gain of mutations. Insights into the evolution during therapy and disease progression lay the foundation for tailored approaches to treat or prevent relapse of CN-AML.

http://ift.tt/2EAsfOz

Breast cancer targeting through inhibition of the endoplasmic reticulum-based apoptosis regulator Nrh/BCL2L10

Drug resistance and metastatic relapse remain a top challenge in breast cancer treatment. In this study, we present preclinical evidence for a strategy to eradicate advanced breast cancers by targeting the BCL2 homolog Nrh/BCL2L10, which we discovered to be overexpressed in >45% of a large cohort of breast invasive carcinomas. Nrh expression in these tumors correlated with reduced metastasis-free survival and we determined it to be an independent marker of poor prognosis. Nrh protein localized to the endoplasmic reticulum (ER). Mechanistic investigations showed that Nrh made BH4 domain-dependent interactions with the ligand-binding domain of the inositol-1,4,5-triphosphate receptor (IP3R), a type I/III Ca2+ channel, allowing Nrh to negatively regulate ER-Ca2+ release and mediate anti-apoptosis. Notably, disrupting Nrh/IP3R complexes by BH4 mimetic peptides was sufficient to inhibit the growth of breast cancer cells in vitro and in vivo. Taken together, our results highlighted Nrh as a novel prognostic marker and a candidate therapeutic target for late stage breast cancers that may be addicted to Nrh.

http://ift.tt/2mvxZTe

Genetic ablation of Rbm38 promotes lymphomagenesis in the context of mutant p53 by downregulating PTEN

Mutant p53 exerts gain-of-function effects that drive metastatic progression and therapeutic resistance, but the basis for these effects remain obscure. The RNA binding protein RBM38 limits translation of mutant p53 and is often ablated in tumors harboring it. Here we show how loss of Rbm38 significantly alters cancer susceptibility in mutant p53 knock-in mice, by shortening lifespan, altering tumor incidence and promoting T cell lymphomagenesis. Loss of Rbm38 enhanced mutant p53 expression and decreased expression of the tumor suppressor Pten, a key regulator of T cell development. Furthermore, Rbm38 was required for Pten expression via stabilization of Pten mRNA through an AU-rich element in its 3'UTR. Our results suggest that Rbm38 controls T cell lymphomagenesis by jointly modulating mutant p53 and Pten, with possible therapeutic implications for treating T cell malignancies.

http://ift.tt/2mvBaKz

Demethylation-induced overexpression of Shc3 drives c-Raf-independent activation of MEK/ERK in HCC

Invasion and intrahepatic metastasis are major factors of poor prognosis in patients with hepatocellular carcinoma (HCC). In this study, we show that increased Src homolog and collagen homolog 3 (Shc3) expression in malignant HCC cell lines associate with HCC invasion and metastasis. Shc3 was significantly upregulated in tumors of 33 HCC patient samples as compared to adjacent normal tissues. Further analysis of 52 HCC patient samples showed that Shc3 expression correlated with microvascular invasion, cancer staging, and poor prognosis. Shc3 interacted with major vault protein (MVP), resulting in activation of MEK1/2 and ERK1/2 independently of Shc1 and c-Raf; this interaction consequently induced epithelial-mesenchymal transition (EMT) and promoted HCC cell proliferation and metastasis. The observed increase in Shc3 levels was due to demethylation of its upstream promoter, which allowed c-Jun binding. In turn, Shc3 expression promoted c-Jun phosphorylation in a positive feedback loop. Analysis of metastasis using a tumor xenograft mouse model further confirmed the role of Shc3 in vivo. Taken together, our results indicate the importance of Shc3 in HCC progression and identify Shc3 as a novel biomarker and potential therapeutic target in HCC.

http://ift.tt/2r0zOMw

MBD2 ablation impairs lymphopoiesis and impedes progression and maintenance of T-ALL

Aberrant DNA methylation patterns in leukemia might be exploited for therapeutic targeting. In this study, we employed a genetically deficient mouse model to explore the role of the methylated DNA binding protein MBD2 in normal and malignant hematopoiesis. MBD2 ablation led to diminished lymphocytes. Functional defects of the lymphoid compartment were also observed after in vivo reconstitution of MBD2-deficient hematopoietic stem cells (HSC). In an established model of Notch1-driven T cell acute lymphoblastic leukemia (T-ALL), MBD2 ablation impeded malignant progression and maintenance by attenuating the Wnt signaling pathway. In clinical specimens of human T-ALL, Wnt signaling pathway signatures were significantly enhanced and positively correlated with the expression and function of MBD2. Further, a number of typical Wnt signaling inhibitory genes were abnormally hypermethylated in primary human T-ALL. Abnormal activation of Wnt signaling in T-ALL was switched off by MBD2 deletion, partially by reactivating epigenetically silenced Wnt signaling inhibitors. Taken together, our results define essential roles for MBD2 in lymphopoiesis and T-ALL and suggest MBD2 as a candidate therapeutic target in T-ALL.

http://ift.tt/2my3oUR