The impact of [ 68 Ga]PSMA I&T PET/CT on radiotherapy planning in patients with prostate cancer

Abstract

Purpose

To determine the impact of Gallium-68-labled prostate-specific membrane antigen positron-emission tomography/computed tomography ([⁶⁸Ga]PSMA PET/CT) on radiotherapy planning for primary disease, biochemical cancer relapse, and advanced disease of prostate cancer.

Methods

A total of 106 patients with prostate cancer scheduled for radiation therapy underwent 120 [⁶⁸Ga]PSMA PET/CT scans prior to radiotherapy treatment. In 20 cases, patients underwent [⁶⁸Ga]PSMA PET/CT for primary therapy (PT), 75 cases were referred for biochemical relapse after surgery (RL), and 25 cases were intended for palliative treatment of localized metastases (MD). We retrospectively compared the impact of [⁶⁸Ga]PSMA PET/CT on lesion detection and treatment decision to CT alone.

Results

[⁶⁸Ga]PSMA PET/CT revealed a total of 271 positive lesions, whereas CT detected 86 lesions (32%). Overall, the radiotherapy regime was changed in 55 of 120 cases (46%) based on the higher detection rate of [⁶⁸Ga]PSMA PET/CT: in 15% of cases with PT, in 43% of cases with RL, and in 44% of cases with MD.

Conclusion

[⁶⁸Ga]PSMA PET/CT is superior to CT alone for lesion detection in prostate cancer, thereby significantly impacting on radiotherapy planning for primary disease, biochemical cancer relapse, and advanced disease of prostate cancer.

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Immunogenicity and safety of a Trivalent Influenza HA vaccine in Indonesian infants and children

Publication date: 12 April 2018
Source:Vaccine, Volume 36, Issue 16
Author(s): Soedjatmiko Soedjatmiko, Bernie Endyarni Medise, Hartono Gunardi, Rini Sekartini, Hindra Irawan Satari, Sri Rezeki Hadinegoro, Novilia Sjafri Bachtiar, Rini Mulia Sari
IntroductionHigh rate of influenza infection in children made influenza vaccination strongly recommended for all person aged >6 months in Indonesia. Bio Farma Trivalent Influenza HA (Flubio®) vaccine has been used in adolescents and adults, resulted in increased seroconversion, seroprotection rates and geometric mean titer (GMT). However, no data is available regarding its efficacy and safety in children. This study aimed to assess the immunogenicity and safety of Flubio® vaccine in infants and children.Materials and methodsThis was a phase II, open-labeled, clinical trial conducted on healthy children aged 6 month-11 years, vaccinated with 1 or 2 doses of Influenza HA vaccine, with a 28-day interval. Flubio® vaccine composed of A/California/7/2009 (H1N1) pandemic 09, A/Texas/50/2012 (H3N2), and B/Massachusetts/2/2012 strain. This study was held at East Jakarta, Indonesia from May until July 2014. A Total of 405 subjects were included and divided into three groups: A(6–35 months), B(3–8 years), and C(9–11 years). Antibody titer was measured at visit V1 (Day 0), V2 (28 days/+7days after the first dose) and V3 (28 days/+7days after second dose). The seroprotection and seroconversion rates were assessed. Safety was assessed up to 28 days following each dose.ResultsA total of 404 subjects completed the study. After vaccination, all subjects achieved seroprotection and increased seroconversion rates, with post-vaccination antibody titer of ≥1:40 HI for all strains. The GMT also increased significantly. Within 30 min after vaccination, 14.6% and 2% had local and systemic reactions; meanwhile, between 30 min to 72 h after vaccination, 35.1% and 13.6% subjects had local and systemic reactions, respectively. Most reactions were mild. No serious adverse event (SAE) was reported related to vaccine.ConclusionFlubio® (Influenza HA Trivalent) vaccine is immunogenic and safe for children aged 6 months-11 years.Trial Registration: The trial is registered at the US National Institutes of Health (ClinicalTrials.gov) #NCT02093260.



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Post-licensure safety surveillance study of routine use of quadrivalent meningococcal diphtheria toxoid conjugate vaccine (MenACWY-D) in infants and children

Publication date: 12 April 2018
Source:Vaccine, Volume 36, Issue 16
Author(s): J. Hansen, L. Zhang, A. Eaton, R. Baxter, C.A. Robertson, M.D. Decker, D.P. Greenberg, E. Bassily, N.P. Klein
BackgroundMenactra® vaccine (MenACWY-D) was licensed in the United States in 2005 for persons 11–55 years of age, in 2007 for children 2–10 years of age, and in 2011 for infants/toddlers 9–23 months of age. We conducted two studies at Kaiser Permanente Northern California (KPNC), an integrated health care organization, to assess the safety of MenACWY-D in 2–10-year-olds and 9–23-month-olds receiving the vaccine during routine clinical care.MethodsWe conducted observational, retrospective studies of MenACWY-D in 2–10-year-olds (October 2007–October 2010) and in 9–23-month-olds (June 2011–June 2014). We monitored all subjects for non-elective hospitalizations, emergency department visits, and selected outpatient outcomes (specified neurological conditions, hypersensitivity reactions and new-onset autoimmune diseases) up to 6 months after vaccination, depending on the study. Using a self-control risk-interval design, we calculated incidence rate ratios (IRRs) comparing outcomes during the post-vaccination risk interval (0–30 days) with those during more remote post-vaccination comparison intervals (31–60 and 31–180 days [children] or 31–75 days [infants/toddlers]).ResultsThere were 1421 children aged 2–10 years and 116 infants/toddlers aged 9–23 months who received MenACWY-D. Approximately 30% of the 2–10-year-olds and 67% of the 9–23-month-olds were considered at increased risk of meningococcal disease. Among 2–10-year-olds, there was 1 hospitalization on post-vaccination day 5 for fever, which was considered possibly related to vaccination. The only significantly elevated outcome among 2–10-year-olds was cellulitis/abscess (2 cases occurred during the risk interval versus 0 during comparison interval; IRR not evaluable [NE], 95% CI: 1.42, NE). After medical record review, the 2 cases were considered unrelated to vaccination. Among 9–23-month-olds, no outcomes were significantly elevated after vaccination and there were no hospitalizations. There were no deaths observed during the three-year accrual and subsequent six-month surveillance period for either study.ConclusionsImmunization of infants and young children with MenACWY-D vaccine was not associated with any new safety concerns; however, these small studies had limited power to detect rare or uncommon safety events.ClinicalTrials.gov Identifiers are NCT00728260 and NCT01689155.



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Morphological characterization of a plant-made virus-like particle vaccine bearing influenza virus hemagglutinins by electron microscopy

Publication date: 12 April 2018
Source:Vaccine, Volume 36, Issue 16
Author(s): Brianne J. Lindsay, Michal M. Bonar, Ian N. Costas-Cancelas, Kristin Hunt, Alexander I. Makarkov, Sabrina Chierzi, Connie M. Krawczyk, Nathalie Landry, Brian J. Ward, Isabelle Rouiller
Plant-made virus-like particle (VLP) vaccines that display wild-type influenza hemagglutinin (HA) are rapidly advancing through clinical trials. Produced by transient transfection of Nicotiana benthamiana, these novel vaccines are unusually immunogenic, eliciting both humoral and cellular responses. Here, we directly visualized VLPs bearing either HA trimers derived from strains A/California/7/2009 or A/Indonesia/5/05 using cryo-electron microscopy and determined the 3D organization of the VLPs using cryo-electron tomography. More than 99.9% of the HA trimers in the vaccine preparations were found on discoid and ovoid-shaped particles. The discoid-shaped VLPs presented HA trimers on their outer diameter. The ovoid-shaped VLPs contained HA trimers evenly distributed at their surface. The VLPs were stable for 12 months at 4 °C. Early interactions of the VLPs with mouse dendritic and human monocytoid (U-937) cells were visualized by electron microscopy after resin-embedding and sectioning. The VLP particles were observed bound to plasma membranes as well as inside vesicles. Mouse dendritic cells exposed to VLPs displayed classic morphological changes associated with activation including the extensive formation of dendrites. Our findings demonstrate that plant-made VLPs bearing influenza HA trimers are morphologically stable over time and raise the possibility that these VLPs may interact with and activate antigen-presenting cells in a manner similar to the intact virus.



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Nanoconjugation of bicistronic DNA vaccine against Edwardsiella tarda using chitosan nanoparticles: Evaluation of its protective efficacy and immune modulatory effects in Labeo rohita vaccinated by different delivery routes

Publication date: 12 April 2018
Source:Vaccine, Volume 36, Issue 16
Author(s): Sajal Kole, Ranjeeta Kumari, Deepika Anand, Saurav Kumar, Rupam Sharma, Gayatri Tripathi, M. Makesh, K.V. Rajendran, Megha Kadam Bedekar
DNA-based immunization has proven to be an effective prophylactic measure to control aquatic animal diseases. In order to improve the efficiency of vaccine against fish pathogen, novel delivery mechanism needs to be adopted. In the present study we nanoconjugated the previously constructed DNA vaccine (pGPD + IFN) with chitosan nanoparticles (CNPs) by complex coacervation process. After construction of the vaccine, an in vivo vaccination trial was conducted in which 2 groups of rohu (L. rohita) fingerlings were vaccinated with CNPs-pGPD + IFN, one group by oral route (incorporated in feed for 14 days) and the other by immersion route (primary and booster immunised), whereas, a third group was intramuscularly (I/M) injected (initial and booster immunised) with naked pGPD + IFN and subsequently challenged with E. tarda (8.7 × 10⁴ CFU/fish) at 35-day post initial vaccination. The protective immune responses were determined in terms of relative percentage survival (RPS), specific antibody production, non-specific immune response, expression kinetics of immune-related genes and pathological manifestation. Evaluation of RPS analysis revealed that CNPs-pGPD + IFN groups recorded highest RPS (81.82% and 72.73% in oral and immersion vaccinated fish group respectively) while the naked pGPD + IFN injected group showed 63.62% RPS when compared with 55% cumulative mortality of control group. In addition, NBT, myeloperoxidase activity, serum lysozyme activity and specific antibody titre in case of CNPs-pGPD + IFN groups showed higher activities during all the time points. Furthermore, CNPs-pGPD + IFN groups showed significant (p < 0.05) upregulation of different immune gene transcripts (IgHC, iNOS, TLR22, NOD1 and IL-1β) in three immunologically important tissues post immunization (both primary and booster dose) as well as after challenge. Thus, from this study, we can conclude that oral or immersion vaccination with CNPs-pGPD + IFN can orchestrate an effective immunisation strategy in organizing a coordinative immune response against E. tarda in L. rohita exhibiting minimum stress to the host with maximum efficacy.



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Influenza vaccine effectiveness to prevent influenza-related hospitalizations and serious outcomes in Canadian adults over the 2011/12 through 2013/14 influenza seasons: A pooled analysis from the Canadian Immunization Research Network (CIRN) Serious Outcomes Surveillance (SOS Network)

Publication date: 12 April 2018
Source:Vaccine, Volume 36, Issue 16
Author(s): Michaela K. Nichols, Melissa K. Andrew, Todd F. Hatchette, Ardith Ambrose, Guy Boivin, William Bowie, Ayman Chit, Gael Dos Santos, May ElSherif, Karen Green, Francois Haguinet, Scott A. Halperin, Barbara Ibarguchi, Jennie Johnstone, Kevin Katz, Phillipe Lagacé-Wiens, Joanne M. Langley, Jason LeBlanc, Mark Loeb, Donna MacKinnon-Cameron, Anne McCarthy, Janet E. McElhaney, Allison McGeer, Andre Poirier, Jeff Powis, David Richardson, Anne Schuind, Makeda Semret, Vivek Shinde, Stephanie Smith, Daniel Smyth, Grant Stiver, Geoffrey Taylor, Sylvie Trottier, Louis Valiquette, Duncan Webster, Lingyun Ye, Shelly A. McNeil
BackgroundOngoing assessment of influenza vaccine effectiveness (VE) is critical to inform public health policy. This study aimed to determine the VE of trivalent influenza vaccine (TIV) for preventing influenza-related hospitalizations and other serious outcomes over three consecutive influenza seasons.MethodsThe Serious Outcomes Surveillance (SOS) Network of the Canadian Immunization Research Network (CIRN) conducted active surveillance for influenza in adults ≥16 years (y) of age during the 2011/2012, 2012/2013 and 2013/2014 seasons in hospitals across Canada. A test-negative design was employed: cases were polymerase chain reaction (PCR)-positive for influenza; controls were PCR-negative for influenza and were matched to cases by date, admission site, and age (≥65 y or <65 y). All cases and controls had demographic and clinical characteristics (including influenza immunization status) obtained from the medical record. VE was estimated as 1-OR (odds ratio) in vaccinated vs. unvaccinated patients × 100%. The primary outcome was VE of TIV for preventing laboratory-confirmed influenza-related hospitalization; secondary outcomes included VE of TIV for preventing influenza-related intensive care unit (ICU) admission/mechanical ventilation, and influenza-related death.ResultsOverall, 3394 cases and 4560 controls were enrolled; 2078 (61.2%) cases and 2939 (64.5%) controls were ≥65 y. Overall matched, adjusted VE was 41.7% (95% Confidence Interval (CI): 34.4–48.3%); corresponding VE in adults ≥65 y was 39.3% (95% CI: 29.4–47.8%) and 48.0% (95% CI: 37.5–56.7%) in adults <65 y, respectively. VE for preventing influenza-related ICU admission/mechanical ventilation in all ages was 54.1% (95% CI: 39.8–65.0%); in adults ≥65 y, VE for preventing influenza-related death was 74.5% (95% CI: 44.0–88.4%).ConclusionsWhile effectiveness of TIV to prevent serious outcomes varies year to year, we demonstrate a statistically significant and clinically important TIV VE for preventing hospitalization and other serious outcomes over three seasons. Public health messaging should highlight the overall benefit of influenza vaccines over time while acknowledging year to year variability.ClinicalTrials.gov Identifier: NCT01517191.



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Preclinical development of peptide vaccination combined with oncolytic MG1-E6E7 for HPV-associated cancer

Publication date: 12 April 2018
Source:Vaccine, Volume 36, Issue 16
Author(s): Matthew J. Atherton, Kyle B. Stephenson, Jake K. Nikota, Qian N. Hu, Andrew Nguyen, Yonghong Wan, Brian D. Lichty
Human papilloma virus (HPV)-associated cancer is a significant global health burden and despite the presence of viral transforming antigens within neoplastic cells, therapeutic vaccinations are ineffective for advanced disease. HPV positive TC1 cells are susceptible to viral oncolysis by MG1-E6E7, a custom designed oncolytic Maraba virus. Epitope mapping of mice vaccinated with MG1-E6E7 enabled the rational design of synthetic long peptide (SLP) vaccines against HPV16 and HPV18 antigens. SLPs were able to induce specific CD8+ immune responses and the magnitude of these responses significantly increased when boosted by MG1-E6E7. Logically designed vaccination induced multi-functional CD8+ T cells and provided complete sterilising immunity of mice challenged with TC1 cells. In mice bearing large HPV-positive tumours, SLP vaccination combined with MG1-E6E7 was able to clear tumours in 60% of mice and these mice were completely protected against a long term aggressive re-challenge with the TC1 tumour model. Combining conventional SLPs with the multi-functional oncolytic MG1-E6E7 represents a promising approach against advanced HPV positive neoplasia.



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A canine adenovirus type 2 vaccine vector confers protection against foot-and-mouth disease in guinea pigs

Publication date: 12 April 2018
Source:Vaccine, Volume 36, Issue 16
Author(s): Annebel R. De Vleeschauwer, Xiaocui Zhou, David J. Lefebvre, Annabelle Garnier, Fleur Watier, Charly Pignon, Sandrine A. Lacour, Stephan Zientara, Labib Bakkali-Kassimi, Kris De Clercq, Bernard Klonjkowski
Vaccination is a key element in the control of foot-and-mouth disease (FMD). The majority of the antigenic sites that induce protective immune responses are localized on the FMD virus (FMDV) capsid that is formed by four virus-encoded structural proteins, VP1 to VP4. In the present study, recombinant canine adenovirus type 2 (CAV2)-based FMD vaccines, Cav-P1/3C R° and Cav-VP1 R°, respectively expressing the structural P1 precursor protein along with the non-structural 3C protein or expressing the structural VP1 protein of the FMDV strain O/FRA/1/2001, were evaluated as novel vaccines against FMD. A strong humoral immune response was elicited in guinea pigs (GP) following immunization with Cav-P1/3C R°, while administration of Cav-VP1 R° did not induce a satisfying antibody response in GP or mice. GP were then used as an experimental model for the determination of the protection afforded by the Cav-P1/3C R° vaccine against challenge with the FMDV strain O1 Manisa/Turkey/1969. The Cav-P1/3C R° vaccine protected GP from generalized FMD to a similar extent as a high potency double-oil emulsion O1 Manisa vaccine. The results of the present study show that CAV2-based vector vaccines can express immunogenic FMDV antigens and offer protection against generalized FMD in GP. This suggest that Cav-P1/3C R° FMDV vaccine may protect natural host species from FMD. In combination with an appropriate diagnostic test, the Cav-P1/3C R° FMDV vaccine may also serve as a marker vaccine to differentiate vaccinated from infected animals.



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A recombinant trivalent vaccine candidate against human adenovirus types 3, 7, and 55

Publication date: 12 April 2018
Source:Vaccine, Volume 36, Issue 16
Author(s): Tiantian Liu, Zhichao Zhou, Xingui Tian, Wenkuan Liu, Duo Xu, Ye Fan, Jiayi Liao, Shujun Gu, Xiao Li, Rong Zhou
Human adenoviruses types 3 (HAdV-3), 7 (HAdV-7) and 55 (HAdV-55) are major pathogens of acute respiratory infections (ARI) in children and adults. More than one type of HAdV can infect patients simultaneously, and the infections are sometimes fatal. However, there is currently no vaccine approved for general use in children and adults. Thus, development of a multivalent HAdV vaccine to combat HAdV infection becomes imperative. In this study, we constructed a new recombinant trivalent human adenovirus vaccine (rAdMHE3-h55), which expresses the hexon protein of HAdV-55 in the E3 region of rAdMHE3, a previously prepared bivalent vaccine candidate against HAdV-3 and HAdV-7. The results of in vitro neutralization assays indicate that rAdMHE3-h55 can induce the production of neutralizing antibodies against HAdV-3, HAdV-7, and HAdV-55 in mice. Furthermore, immunization with the recombinant trivalent vaccine candidate completely protected the mice challenged with HAdV-3, HAdV-7, orHAdV-55, respectively, showing lower lung viral loads and less lung Pathological changes was compared with those in unvaccinated mice. The current findings contribute to the development of a new adenovirus vaccine candidate and also advance this construction method for the generation of recombinant adenovirus vaccines. In conclusion, our recombinant trivalent vaccine rAdMHE3-h55 can provides protection against challenge with HAdV-3, HAdV-7, or HAdV-55 in mice. Future work of optimizing this vaccine candidate may lead to a more effective way of preventing respiratory diseases caused by common human adenoviruses.



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Antibody response to hepatitis B vaccine is independently associated with hepatitis B breakthrough infection among adults: Results from a three-year follow-up study in China

Publication date: 12 April 2018
Source:Vaccine, Volume 36, Issue 16
Author(s): Li Zhang, Bingyu Yan, Jingjing Lv, Jiaye Liu, Wenlong Wu, Yi Feng, Aiqiang Xu
Hepatitis B breakthrough infection (HBBI) and its risk factors are rarely reported among adults in China. In 2009–2010 in three townships of China, hepatitis B vaccine (HepB) administration and anti-HBs detection after HepB were conducted among the residents aged 18–59 years. HBsAg, anti-HBs and anti-HBc were detected for these vaccinees in 2013. A total of 252 out of 4701 vaccinees turned to be positive for anti-HBc in 2013, but nobody was positive for HBsAg. The HBBI rate was 5.36% (95% CI 4.73, 6.04). The highest rate was found in age-group of 18–29 years (7.33%, 95% CI: 5.31, 9.82). The rate was significantly different by the residential townships (P < 0.001) and by the antibody response to HepB (P = 0.003). Multivariate analysis showed that anti-HBs response to HepB was the independent risk factor of HBBI. The study documents the association between hyporesponse to HepB and HBBI among adults. It also suggests more attention should be given to new HBV infection among young adults.



https://ift.tt/2DPCn55

Impact of pre-existing immunity on the induction of functional cross-reactive anti-hemagglutinin stalk antibodies following vaccination with an AS03 adjuvanted pandemic H1N1 vaccine

Publication date: 12 April 2018
Source:Vaccine, Volume 36, Issue 16
Author(s): Sarah M. Tete, Åsne Jul-Larsen, Sina Rostami, Turid Helen Felli Lunde, Hanne Søland, Florian Krammer, Rebecca J. Cox
The 2009 pandemic H1N1 (A(H1N1)pdm09) virus had a highly divergent hemagglutinin (HA) compared to pre-2009 seasonal H1N1 strains. Most peoples were immunologically naïve to the A(H1N1)pdm09, although hospital workers were exposed early in the pandemic before pandemic vaccines became available. Here, we evaluated how pre-existing antibodies influence the induction of cross-functional HA stalk antibodies following A(H1N1)pdm09 vaccination.Fifty-six healthcare workers vaccinated with AS03 adjuvanted A(H1N1)pdm09 vaccine were chosen by their pre-vaccination priming status (primed HI titers ≥ 40 or unprimed < 40). We analyzed the HA head- and stalk-specific serum IgG subclasses at pre- and 21 days post-vaccination. We also assessed the functionality of the HA stalk-specific antibodies to neutralize virus and mediate antibody dependent cellular cytotoxicity (ADCC).Primed individuals had higher pre-existing HA head- and stalk-specific IgG1, as well as higher ADCC functionality of stalk antibodies. However, following vaccination with the adjuvanted pandemic vaccine, only the quantity of HA head specific IgG1 antibodies were significantly higher than in unprimed individuals. The priming status did not impact upon the cross-reactive HA stalk specific IgG antibodies or their ability to neutralize virus or induce ADCC post-vaccination. In conclusion, a single dose of AS03 adjuvanted pandemic vaccine elicited similar levels of functional antibodies in naïve and primed individuals. These findings are important for understanding the immunological factors that impact or modulate pandemic vaccine responses in humans.



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Effect of influenza vaccine on tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in older adults

Publication date: 12 April 2018
Source:Vaccine, Volume 36, Issue 16
Author(s): Maryam Keshtkar-Jahromi, Min Ouyang, Marzieh Keshtkarjahromi, Samah Almed, Huifen Li, Jeremy D. Walston, Rebeca Rios, Sean X. Leng
Influenza immunization is recommended for older adults annually, and has been reported to have cardiovascular protective effects. TNF-related weak inducer of apoptosis (TWEAK), an inflammatory mediator implicated in the development of cardiovascular diseases, could be a mechanism for such effect. The objective of this study was to evaluate the effect of influenza vaccine on TWEAK levels. Older persons over 70 years of age were recruited during 2007–2008 influenza season and immunized with the standard dose trivalent inactivated influenza vaccine. Frailty was evaluated using a validated set of criteria. Sera were collected immediately before and during the 4th week after vaccination. Pre- and post-vaccination levels of TWEAK, soluble CD163 (sCD163) and strain-specific influenza antibody titers were measured in 69 participants. Multiple regression analyses were employed to examine the effect of influenza vaccine on TWEAK and sCD163, adjusting for age, sex, and hypertension. Post-vaccination TWEAK [mean ± standard deviation (SD) = 591.7 ± 290.1 pg/ml] was significantly lower than pre-vaccination level (690.6 ± 330.0 pg/ml) (p = .003). No significant difference was observed between pre and post-vaccination sCD163 levels (p = .71). Post-vaccination TWEAK levels were significantly higher in men (p = .01) and in participants with college or higher level of education (p = .044). There was no significant difference in post-vaccination TWEAK according to other demographics or pre-existing medical conditions. A 2-fold or greater antibody titer against H1N1 vaccine strain was associated with a more pronounced reduction in TWEAK at the p < .10 level (p = .091). A time by frailty interaction term (p = .091) indicated that the vaccination-induced reduction of TWEAK was greatest among frail individuals. These results of this observational study indicate that the impact of Influenza vaccine on TWEAK, including the role of specific antibody responses of specific vaccine strains and frailty status, warrants further investigation. Such investigation may elucidate whether this effect plays a role in mediating cardiovascular protection of influenza vaccination.



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Detection of the natural origin hydrocarbon contamination in carbonate aquifers (central Apennine, Italy)

Abstract

The water–rock interaction is discussed in this study for some Central Apennine aquifers and their relative springs, where the geological and hydrogeological setting is potentially responsible for hydrocarbon contamination. The contamination is related to the presence of limestone formations with high organic content that are connected to the genesis of hydrocarbons in the Central-Southern Apennines. Thanks to a multidisciplinary approach based on a seasonal monitoring of hydrogeological, hydrogeochemical, organic chemical, and isotopic variables, and to a detailed geological analysis, it was possible to demonstrate that the bituminous schists within the bituminous dolomite formation (a Triassic Formation presents in the Gran Sasso acquifer), the bituminous intercalations within the Bolognano Formation (an Olocenic calcareous Formation in the Majella acquifer), and the petroleum-saturated rocks of the Bolognano Formation (in the Morrone acquifer) are all able to leach hydrocarbons into groundwater. The results suggest that more detailed studies are required for areas where lithologies with fossil organic components are present. Insights should further investigate the interaction between groundwater and rocks in terms of organic compounds as well as inorganic compounds. In particular, the study also suggests that the supplementary quantification of hydrocarbon compounds in bituminous rock and the leaching tests are analyses that provide reliable results. From the normative point of view, the results of the study can be useful when dealing with hydrocarbon contamination resulting from anthropogenic activities within catchments where formations with high concentration of organic matter are present. In these cases, it will possible to assess the natural background concentrations and review the threshold values upwards.

http://ift.tt/2I0qCLw

The Homeostatic Force of Ghrelin

Publication date: Available online 22 March 2018
Source:Cell Metabolism
Author(s): Shigehisa Yanagi, Takahiro Sato, Kenji Kangawa, Masamitsu Nakazato
Ghrelin, a gastric-derived acylated peptide, regulates energy homeostasis by transmitting information about peripheral nutritional status to the brain, and is essential for protecting organisms against famine. Ghrelin operates brain circuits to regulate homeostatic and hedonic feeding. Recent research advances have shed new light on ghrelin's multifaceted roles in cellular homeostasis, which could maintain the internal environment and overcome metaflammation in metabolic organs. Here, we highlight our current understanding of the regulatory mechanisms of the ghrelin system in energy metabolism and cellular homeostasis and its clinical trials. Future studies of ghrelin will further elucidate how the stomach regulates systemic homeostasis.

Teaser

Yanagi, Nakazato et al. provide a comprehensive overview of the ghrelin system and highlight the regulatory mechanisms of ghrelin signaling in energy metabolism and feeding behavior. The authors describe ghrelin's recently uncovered multifaceted roles in cellular homeostasis, which could maintain the internal environment and overcome metaflammation and metabolic organ dysfunctions.


https://ift.tt/2IL6eiY

Metabolic Slowing and Reduced Oxidative Damage with Sustained Caloric Restriction Support the Rate of Living and Oxidative Damage Theories of Aging

Publication date: Available online 22 March 2018
Source:Cell Metabolism
Author(s): Leanne M. Redman, Steven R. Smith, Jeffrey H. Burton, Corby K. Martin, Dora Il'yasova, Eric Ravussin
Calorie restriction (CR) is a dietary intervention with potential benefits for healthspan improvement and lifespan extension. In 53 (34 CR and 19 control) non-obese adults, we tested the hypothesis that energy expenditure (EE) and its endocrine mediators are reduced with a CR diet over 2 years. Approximately 15% CR was achieved over 2 years, resulting in an average 8.7 kg weight loss, whereas controls gained 1.8 kg. In the CR group, EE measured over 24 hr or during sleep was approximately 80–120 kcal/day lower than expected on the basis of weight loss, indicating sustained metabolic adaptation over 2 years. This metabolic adaptation was accompanied by significantly reduced thyroid axis activity and reactive oxygen species (F2-isoprostane) production. Findings from this 2-year CR trial in healthy, non-obese humans provide new evidence of persistent metabolic slowing accompanied by reduced oxidative stress, which supports the rate of living and oxidative damage theories of mammalian aging.

Graphical abstract

Teaser

Calorie restriction (CR) has been shown to have health benefits and to extend lifespan in diverse species. Redman et al. conducted a 2-year CR trial in healthy, non-obese humans and found evidence that prolonged CR enhances resting energy efficiency, resulting in decreased systemic oxidative damage.


https://ift.tt/2DQ5pS6

γ-Secretase Inhibition Lowers Plasma Triglyceride-Rich Lipoproteins by Stabilizing the LDL Receptor

Publication date: Available online 22 March 2018
Source:Cell Metabolism
Author(s): KyeongJin Kim, Ira J. Goldberg, Mark J. Graham, Meenakshi Sundaram, Enrico Bertaggia, Samuel X. Lee, Li Qiang, Rebecca A. Haeusler, Daniel Metzger, Pierre Chambon, Zemin Yao, Henry N. Ginsberg, Utpal B. Pajvani
Excess plasma triglycerides (TGs) are a key component of obesity-induced metabolic syndrome. We have shown that γ-secretase inhibitor (GSI) treatment improves glucose tolerance due to inhibition of hepatic Notch signaling but found additional Notch-independent reduction of plasma TG-rich lipoproteins (TRLs) in GSI-treated, as well as hepatocyte-specific, γ-secretase knockout (L-Ncst) mice, which suggested a primary effect on hepatocyte TRL uptake. Indeed, we found increased VLDL and LDL particle uptake in L-Ncst hepatocytes and Ncst-deficient hepatoma cells, in part through reduced γ-secretase-mediated low-density lipoprotein receptor (LDLR) cleavage and degradation. To exploit this novel finding, we generated a liver-selective Nicastrin ASO, which recapitulated glucose and lipid improvements of L-Ncst mice, with increased levels of hepatocyte LDLR. Collectively, these results identify the role of hepatic γ-secretase to regulate LDLR and suggest that liver-specific GSIs may simultaneously improve multiple aspects of the metabolic syndrome.

Graphical abstract

Teaser

Kim et al. discover that hepatic γ-secretase inhibition improves glucose homeostasis and simultaneously reduces plasma triglycerides and non-HDL cholesterol, in part through blocking LDLR cleavage and degradation


https://ift.tt/2IOnwvl

Hsp83 regulates the fate of germline stem cells in Drosophila ovary

Publication date: Available online 22 March 2018
Source:Journal of Genetics and Genomics
Author(s): Dongsheng Chen, Shuang Wang, Xiaoqian Tao, Lijuan Zhou, Jian Wang, Fuling Sun, Mingzhong Sun, Xiaoli Gao




http://ift.tt/2pAvcc1

Zhen-wu-tang ameliorates adenine-induced chronic renal failure in rats: regulation of the canonical Wnt4/beta-catenin signaling in the kidneys

Publication date: 12 June 2018
Source:Journal of Ethnopharmacology, Volume 219
Author(s): Lei La, Lili Wang, Fei Qin, Jian Jiang, Songqi He, Chunxia Wang, Yuhao Li
Ethnopharmacological relevanceZhen-wu-tang (ZWT), composed of Radix Aconiti lateralis, Rhizoma Atractylodis macrocephalae, Poria, Radix Paeoniae alba and ginger, is a classic Chinese herbal formula for the treatment of chronic kidney diseases that may cause chronic renal failure (CRF).Aim of the studyTo better understand its clinical use, this study investigated the effects and underlying mechanisms of action of ZWT on CRF.Materials and methodsCRF was induced by adenine. ZWT was given via an oral gavage method. The serum biochemical parameters were measured enzymatically or by ELISA. The kidneys were examined pathohistologically. The gene expression was analyzed by real time PCR and Western blot.ResultsSimilar to the positive control losartan, ZWT extract inhibited adenine-induced increase in serum concentrations of creatinine, BUN and advanced oxidation protein products in rats. These effects were accompanied by attenuation of proteinuria and renal pathological changes and suppression of renal mRNA and protein overexpression of Collagen IV and fibronectin, two of the key components of fibrosis. Mechanistically, renal mRNA and protein expression of Wnt4, a Wnt signaling ligand, was increased in the adenine-treated group, compared to the vehicle-treated control. Consistently, Wnt4 downstream genes beta-catenin and Axin were also overexpressed. Treatment with ZWT extract and losartan suppressed adenine-stimulated overexpression of these mRNAs and proteins.ConclusionsThe present results demonstrate that ZWT extract ameliorates adenine-induced CRF in rats by regulation of the canonical Wnt4/beta-catenin signaling in the kidneys. Our findings provide new insight into the underlying renoprotective mechanisms of the ancient formula.

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Viscum articulatum Burm. f. aqueous extract exerts antiproliferative effect and induces cell cycle arrest and apoptosis in leukemia cells

Publication date: 12 June 2018
Source:Journal of Ethnopharmacology, Volume 219
Author(s): Ruchi Mishra, Saurabh Sharma, Radhey Shyam Sharma, Savita Singh, Milind Madhav Sardesai, Sadhna Sharma, Vandana Mishra
Ethnopharmacological relevanceViscum articulatum Burm. f. (leafless mistletoe) has been used in traditional system of medicines in India, China, Taiwan, Cambodia, Laos, and Vietnam, to treat blood-related diseases and various inflammatory and degenerative diseases including cancer. Anticancer activities of some phytomolecules purified from Viscum articulatum Burm. f. have been tested. However scientific evidence for the anticancerous potential of aqueous extract of V. articularum (VAQE) used in traditional medicine is lacking.Aim of the studyTo study the antiproliferative and apoptotic effect of VAQE on Jurkat E6.1 and THP1 leukemia cells.Materials and methodsThe aqueous extract of the whole plant of Viscum articulatum Burm. f. was prepared in phosphate buffer saline. In VAQE, total soluble protein was estimated using Bradford's dye-binding assay; flavonoid content was determined using aluminum chloride colorimetric assay; and phenolic content was estimated following Folin-Ciocalteu colorimetric assay. XTT cell viability assay was used to test VAQE induced cytotoxicity in Jurkat E6.1 and THP1 leukemia cells and peripheral blood mononuclear cells (PBMC). The effect of VAQE on cell cycle progression was analyzed by PI staining using flow cytometry. Annexin-V-FITC/PI differential staining method was used for detecting the onset of apoptosis in leukemia cells. Rhodamine 123 dye was used to detect the change in mitochondrial membrane potential (MMP) using flow cytometry. DCF-DA fluorescence dye was used to estimate the level of reactive oxygen species (ROS). The ROS inhibitors were used to evaluate the role of ROS in mediating DNA degradation in VAQE-treated leukemia cells. The molecular mechanisms underlying VAQE induced apoptosis induction was studied by analyzing the expression of anti-apoptotic (Bcl-2) and pro-apoptotic (Bax) proteins, caspase-8 and caspase-3 enzymes using western blot. Diphenylamine (DPA) assay was used to determine the DNA fragmentation and conclusion of apoptosis.ResultsVAQE triggered cytotoxic effect on Jurkat E6.1 (IC50-2.4 µg/ml; 24 h) and THP1 (IC50-1.0 µg/ml; 24 h) cells in a dose- and time-dependent manner. The apoptosis induction and G2/M arrest of the cell cycle are the cause of VAQE-induced cytotoxicity in leukemia cells. The apoptosis in VAQE-treated Jurkat E6.1 and THP1 cells was mediated via a reduction in MMP, elevation of intracellular ROS, decreased expression of the anti-apoptotic (Bcl-2) and increased expression of the pro-apoptotic (Bax) protein, activation of caspase-8 and caspase-3 and DNA fragmentation.ConclusionVAQE has a high efficacy to exert a cytotoxic effect in Jurkat E6.1 and THP1 cells and to induce apoptosis and G2/M cell cycle arrest. VAQE induces extrinsic pathway of apoptosis in both the leukemia cell lines via disruption of MMP, intracellular ROS imbalance, increased ratio of Bax/Bcl-2, activation of caspase-8, caspase-3 and ROS-mediated DNA fragmentation. The knowledge gained from the outcomes of the study may encourage the identification of novel chemotherapeutic agent from Viscum articulatum Burm. f. to treat leukemia.

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Calycophyllum spruceanum BENTH ameliorates acute inflammation in mice

Publication date: 12 June 2018
Source:Journal of Ethnopharmacology, Volume 219
Author(s): Ana Paula Azevedo Barros da Silva, Renata Morais Ferreira Amorim, Roberta de Freitas Lopes, Mário Rogério Lima Mota, Felipe Moura Araújo da Silva, Hector Henrique Ferreira Koolen, Emerson Silva Lima, Ana Maria S. Assreuy, Renildo Moura da Cunha
Ethnopharmacological relevanceCalycophyllum spruceanum (Benth.) Hook. F. ex K. Schum. is widely distributed in the Amazonian region of Brazil, where it is popularly known as "mulateiro", "pau-mulato", "pau-mulato-de-várzea", "escorrega-macaco" or "pau-marfim". Preparations of C. spruceanum barks are used in the form of tea, poultice or skin patches to treat stomach diseases, skin inflammation and uterus tumors.Purpose of the studyTo investigate in vivo the antinociceptive and anti-inflammatory activities of the hydroalcoholic extract of Calycophyllum spruceanum barks (HECSb) in order to validate its popular usage in inflammatory conditions.Materials and methodsChemical analysis of HECSb was performed using the UHPLC-MS system. Mice were treated per oral with HECSb (5–5000 mg/kg) and evaluated for acute toxicity (during 15 days); motor activity (Rota rod test); body weight (up to 72 h); antinociceptive activity: writhes induced by 0.8% acetic acid; paw licking induced by 2.5% formalin; paw withdrawal (von Frey test) induced by carrageenan (300 μg) or PGE2 (100 ng); anti-inflammatory (paw edema model). For histopathological analysis subplantar tissue fragments were collected 1 h after paw edema induction.ResultsHECSb chemical analysis revealed the presence of caffeoylquinic derivatives, small organic acids, and phenolic compounds. HECSb showed antinociceptive effect, reducing the number of acetic acid-induced writhes by 72% at 120 mg/kg, paw licking (phase 2- Formalin test) by 33% at 60 mg/kg and 49% at 120 mg/kg; and paw withdrawal elicited by carrageenan (53% at 120 mg/kg) and PGE2 (120 mg/kg) at 0.5 h (48%) and 1 h (45%). HECSb (120 mg/kg) also inhibited the paw edema elicited both by carrageenan (48%) and PGE2 (92%). Histopathological analysis (leukocyte infiltration, edema, focal areas of hemorrhage, vascular congestion) of HECSb treatment at 120 mg/kg demonstrated normal morphology [median 0 (0,1)] compared to PGE2, showing severe alterations [median 3 (2,3); p = 0,0035]. HECSb did not induce acute toxicity nor altered body mass or motor coordination.ConclusionsHECSb shows antinociceptive and anti-inflammatory effect in mice without inducing apparent acute toxicity.

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