There is an increased interest in secondary plant metabolites, such as polyphenols and carotenoids, due to their proposed health benefits. Much attention has focused on their bioavailability, a ...prerequisite for further physiological functions. As human studies are time consuming, costly, and restricted by ethical concerns, in vitro models for investigating the effects of digestion on these compounds have been developed and employed to predict their release from the food matrix, bioaccessibility, and assess changes in their profiles prior to absorption. Most typically, models simulate digestion in the oral cavity, the stomach, the small intestine, and, occasionally, the large intestine. A plethora of models have been reported, the choice mostly driven by the type of phytochemical studied, whether the purpose is screening or studying under close physiological conditions, and the availability of the model systems. Unfortunately, the diversity of model conditions has hampered the ability to compare results across different studies. For example, there is substantial variability in the time of digestion, concentrations of salts, enzymes, and bile acids used, pH, the inclusion of various digestion stages; and whether chosen conditions are static (with fixed concentrations of enzymes, bile salts, digesta, and so on) or dynamic (varying concentrations of these constituents). This review presents an overview of models that have been employed to study the digestion of both lipophilic and hydrophilic phytochemicals, comparing digestive conditions in vitro and in vivo and, finally, suggests a set of parameters for static models that resemble physiological conditions.
Summary Background Laparoscopic surgery as an alternative to open surgery in patients with rectal cancer has not yet been shown to be oncologically safe. The aim in the COlorectal cancer Laparoscopic ...or Open Resection (COLOR II) trial was to compare laparoscopic and open surgery in patients with rectal cancer. Methods A non-inferiority phase 3 trial was undertaken at 30 centres and hospitals in eight countries. Patients (aged ≥18 years) with rectal cancer within 15 cm from the anal verge without evidence of distant metastases were randomly assigned to either laparoscopic or open surgery in a 2:1 ratio, stratified by centre, location of tumour, and preoperative radiotherapy. The study was not masked. Secondary (short-term) outcomes—including operative findings, complications, mortality, and results at pathological examination—are reported here. Analysis was by modified intention to treat, excluding those patients with post-randomisation exclusion criteria and for whom data were not available. This study is registered with ClinicalTrials.gov , number NCT00297791. Findings The study was undertaken between Jan 20, 2004, and May 4, 2010. 1103 patients were randomly assigned to the laparoscopic (n=739) and open surgery groups (n=364), and 1044 were eligible for analyses (699 and 345, respectively). Patients in the laparoscopic surgery group lost less blood than did those in the open surgery group (median 200 mL IQR 100–400 vs 400 mL 200–700, p<0·0001); however, laparoscopic procedures took longer (240 min 184–300 vs 188 min 150–240; p<0·0001). In the laparoscopic surgery group, bowel function returned sooner (2·0 days 1·0–3·0 vs 3·0 days 2·0–4·0; p<0·0001) and hospital stay was shorter (8·0 days 6·0–13·0 vs 9·0 days 7·0–14·0; p=0·036). Macroscopically, completeness of the resection was not different between groups (589 88% of 666 vs 303 92% of 331; p=0·250). Positive circumferential resection margin (<2 mm) was noted in 56 (10%) of 588 patients in the laparoscopic surgery group and 30 (10%) of 300 in the open surgery group (p=0·850). Median tumour distance to distal resection margin did not differ significantly between the groups (3·0 cm IQR 2·0–4·8 vs 3·0 cm 1·8–5·0, respectively; p=0·676). In the laparoscopic and open surgery groups, morbidity (278 40% of 697 vs 128 37% of 345, respectively; p=0·424) and mortality (eight 1% of 699 vs six 2% of 345, respectively; p=0·409) within 28 days after surgery were similar. Interpretation In selected patients with rectal cancer treated by skilled surgeons, laparoscopic surgery resulted in similar safety, resection margins, and completeness of resection to that of open surgery, and recovery was improved after laparoscopic surgery. Results for the primary endpoint—locoregional recurrence—are expected by the end of 2013. Funding Ethicon Endo-Surgery Europe, Swedish Cancer Foundation, West Gothia Region, Sahlgrenska University Hospital.
The ANAIS (Annual modulation with NaI(Tl) Scintillators) experiment aims at the confirmation or refutation of the DAMA/LIBRA positive annual modulation signal in the low energy detection rate, using ...the same target and technique, at the Canfranc Underground Laboratory (LSC) in Spain. ANAIS-112, consisting of nine 12.5 kg NaI(Tl) modules produced by Alpha Spectra Inc. in a
3
×
3
matrix configuration, is taking data smoothly in “dark matter search” mode since August, 2017, after a commissioning phase and operation of the first detectors during the last years in various set-ups. A large effort has been carried out within ANAIS to characterize the background of sodium iodide detectors, before unblinding the data and performing the first annual modulation analysis. Here, the background models developed for all the nine ANAIS-112 detectors are presented. Measured spectra from threshold to high energy in different conditions are well described by the models based on quantified activities independently estimated following several approaches. In the region from 1 to
6
keV
ee
the measured, efficiency corrected background level is
3.58
±
0.02
keV
-
1
kg
-
1
day
-
1
; NaI crystal bulk contamination is the dominant background source being
210
Pb
,
40
K
,
22
Na
and
3
H
contributions the most relevant ones. This background level, added to the achieved
1
keV
ee
analysis threshold (thanks to the outstanding light collection and robust filtering procedures developed), allow ANAIS-112 to be sensitive to the modulation amplitude measured by DAMA/LIBRA, and able to explore at three sigma level in 5 years the WIMP parameter region singled out by this experiment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tonically active cholinergic interneurons (TANs) from the nucleus accumbens (NAc) are centrally involved in reward behavior. TANs express a vesicular glutamate transporter referred to as VGLUT3 and ...thus use both acetylcholine and glutamate as neurotransmitters. The respective roles of each transmitter in the regulation of reward and addiction are still unknown. In this study, we showed that disruption of the gene that encodes VGLUT3 (Slc17a8) markedly increased cocaine self-administration in mice. Concomitantly, the amount of dopamine (DA) release was strongly augmented in the NAc of VGLUT3(-/-) mice because of a lack of signaling by metabotropic glutamate receptors. Furthermore, dendritic spines and glutamatergic synaptic transmission on medium spiny neurons were increased in the NAc of VGLUT3(-/-) mice. Increased DA and glutamate signaling in the NAc are hallmarks of addiction. Our study shows that TANs use glutamate to reduce DA release and decrease reinforcing properties of cocaine in mice. Interestingly, we also observed an increased frequency of rare variations in SLC17A8 in a cohort of severe drug abusers compared with controls. Our findings identify VGLUT3 as an unexpected regulator of drug abuse.
ABSTRACT
Motivated by the many associations of gamma-ray bursts (GRBs) with energetic supernova (SN) explosions, we study the propagation of relativistic jets within the progenitor star in which an ...SN shock wave may be launched briefly before the jets start to propagate. Based on analytic considerations and verified with an extensive set of 2D axisymmetric relativistic hydrodynamic simulations, we have estimated a threshold intrinsic jet luminosity, $L_{\rm j}^{\rm thr}$, for successfully launching a jet. This threshold depends on the structure of the progenitor and, thus, it is sensitive to its mass and to its metallicity. For a prototype host of cosmological long GRBs, a low-metallicity star of 35 M⊙, it is $L_{\rm j}^{\rm thr}\simeq 1.35\times 10^{49}$ erg s−1. The observed equivalent isotropic gamma-ray luminosity, $L_{\rm \gamma ,iso,BO} \simeq 4 \epsilon _\gamma L_{\rm j} \theta _{\rm BO}^{-2}$, crucially depends on the jet opening angle after breakout, θBO, and on the efficiency for converting the intrinsic jet luminosity into γ-radiation, εγ. Highly energetic jets can produce low-luminosity events if either their opening angle after the breakout is large, which is found in our models, or if the conversion efficiency of kinetic and internal energy into radiation is low enough. Beyond this theoretical analysis, we show how the presence of an SN shock wave may reduce this luminosity threshold by means of numerical simulations. We foresee that the high-energy transients released by jets produced near the luminosity threshold will be more similar to llGRBs or X-ray flashes than to GRBs.
ANAIS is a direct detection dark matter experiment aiming at the study of the annual modulation expected in the interaction rate. It uses same target and technique as the DAMA/LIBRA experiment, which ...reported a highly significant positive modulation compatible with that expected for dark matter particles distributed in the galactic halo. However, other very sensitive experiments do not find any hint of particles with the required properties, although comparison is model dependent. In 2017, ANAIS-112 experiment was installed at the Canfranc Underground Laboratory (LSC), in Spain, and after the commissioning run for calibration and general assessment, ANAIS-112 started data taking in dark matter mode on August 3rd, 2017. It consists of nine NaI(Tl) modules, amounting 112.5 kg of mass in total. Here we report on the experimental apparatus and detector performance after the first year of data taking. Total live time available amounts to 341.72 days, being the corresponding exposure 105.32 kg
×
year. ANAIS-112 has achieved an analysis energy threshold of 1 keVee and an average background in the region of interest, from 1 to 6 keVee, of 3.6 counts/keVee/kg/day after correcting by the event selection efficiencies. In these conditions, ANAIS-112 will be able to test the DAMA/LIBRA result at three sigma level in five years of data taking.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Secondary resection of initially unresectable colorectal cancer liver metastases (CRLM) can prolong survival. The added value of selective internal radiotherapy (SIRT) to downsize lesions ...for resection is not known. This study evaluated the change in technical resectability of CRLM with the addition of SIRT to FOLFOX‐based chemotherapy.
Methods
Baseline and follow‐up hepatic imaging of patients who received modified FOLFOX (mFOLFOX6: fluorouracil, leucovorin, oxaliplatin) chemotherapy with or without bevacizumab (control arm) versus mFOLFOX6 (with or without bevacizumab) plus SIRT using yttrium‐90 resin microspheres (SIRT arm) in the phase III SIRFLOX trial were reviewed by three or five (of 14) expert hepatopancreatobiliary surgeons for resectability. Reviewers were blinded to one another, treatment assignment, extrahepatic disease status, and information on clinical and scanning time points. Technical resectability was defined as at least 60 per cent of reviewers (3 of 5, or 2 of 3) assessing a patient's liver metastases as surgically removable.
Results
Some 472 patients were evaluable (SIRT, 244; control, 228). There was no significant baseline difference in the proportion of technically resectable liver metastases between SIRT (29, 11·9 per cent) and control (25, 11·0 per cent) arms (P = 0·775). At follow‐up, significantly more patients in both arms were deemed technically resectable compared with baseline: 159 of 472 (33·7 per cent) versus 54 of 472 (11·4 per cent) respectively (P = 0·001). More patients were resectable in the SIRT than in the control arm: 93 of 244 (38·1 per cent) versus 66 of 228 (28·9 per cent) respectively (P < 0·001).
Conclusion
Adding SIRT to chemotherapy may improve the resectability of unresectable CRLM.
Antecedentes
La resección secundaria de metástasis hepáticas de cáncer colorrectal (colorectal cancer liver metastases, CRLM) inicialmente irresecables puede prolongar la supervivencia. Se desconoce el valor añadido de la radioterapia interna selectiva (selective internal radiation therapy, SIRT). Este estudio evaluó el cambio en la resecabilidad técnica de las CRLM secundario a la adición de SIRT a una quimioterapia tipo FOLFOX.
Métodos
Las pruebas de radioimagen basales y durante el seguimiento de pacientes tratados con un régimen FOLFOX modificado (mFOLFOX6: fluorouracilo, leucovorina, oxaliplatino) ± bevacizumab (grupo control) versus mFOLFOX6 (± bevacizumab) más SIRT usando microesferas de resina de yttrium‐90, en el ensayo de fase III SIRFLOX, fueron revisadas por 3‐5 (de 14) cirujanos expertos hepatobiliares para determinar la resecabilidad. Los expertos efectuaron la revisión de forma ciega unos respecto a otros en relación con la asignación al tratamiento, estado de la enfermedad extra‐hepática y situación clínica en el momento del estudio radiológico. La resecabilidad técnica se definió como ≥ 60% de revisores evaluando las metástasis del paciente como quirúrgicamente resecables.
Resultados
Fueron evaluables un total de 472 pacientes (control, n = 228; SIRT, n = 244). No hubo diferencias significativas basales en la proporción de metástasis hepáticas técnicamente resecables entre SIRT (29/244; 11,9%) y el grupo control (25/228; 11,0%: P = 0,775). Durante el seguimiento y en ambos brazos de tratamiento, un número significativamente mayor de pacientes se consideraron técnicamente resecables en comparación con la situación basal (54/472 (11,4%) basal y 159/472 (33,7%) al seguimiento). Hubo más pacientes resecables en el grupo SIRT que en el control (93/244 (38,1%) y 66/228 (28,9%); P < 0,001, respectivamente).
Conclusión
La adición de SIRT a la quimioterapia puede mejorar la resecabilidad de las CRLM irresecables.
Secondary resection of initially unresectable colorectal cancer liver metastases (CRLM) can prolong survival. This study of 472 patients suggests that chemotherapy with FOLFOX with or without bevacizumab may improve the technical resectability rate of CRLM, especially in patients with an initial hepatic tumour burden of 25 per cent or less, and that this effect is enhanced substantially by adding selective internal radiotherapy to systemic chemotherapy.
Might improve resectability
This study aimed to identify the oncogenes at 20q involved in colorectal adenoma to carcinoma progression by measuring the effect of 20q gain on mRNA expression of genes in this amplicon.
...Segmentation of DNA copy number changes on 20q was performed by array CGH (comparative genomic hybridisation) in 34 non-progressed colorectal adenomas, 41 progressed adenomas (ie, adenomas that present a focus of cancer) and 33 adenocarcinomas. Moreover, a robust analysis of altered expression of genes in these segments was performed by microarray analysis in 37 adenomas and 31 adenocarcinomas. Protein expression was evaluated by immunohistochemistry on tissue microarrays.
The genes C20orf24, AURKA, RNPC1, TH1L, ADRM1, C20orf20 and TCFL5, mapping at 20q, were significantly overexpressed in carcinomas compared with adenomas as a consequence of copy number gain of 20q.
This approach revealed C20orf24, AURKA, RNPC1, TH1L, ADRM1, C20orf20 and TCFL5 genes to be important in chromosomal instability-related adenoma to carcinoma progression. These genes therefore may serve as highly specific biomarkers for colorectal cancer with potential clinical applications.
Neoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard of care for patients with esophageal or junctional cancer, but the long-term impact of nCRT on health-related quality of life (HRQOL) ...is unknown. The purpose of this study is to compare very long-term HRQOL in long-term survivors of esophageal cancer who received nCRT plus surgery or surgery alone.
Patients were randomly assigned to receive nCRT (carboplatin/paclitaxel with 41.4-Gy radiotherapy) plus surgery or surgery alone. HRQOL was measured using EORTC-QLQ-C30, EORTC-QLQ-OES24 and K-BILD questionnaires after a minimum follow-up of 6 years. To allow for examination over time, EORTC-QLQ-C30 and QLQ-OES24 questionnaire scores were compared with pretreatment and 12 months postoperative questionnaire scores. Physical functioning (QLQ-C30), eating problems (QLQ-OES24) and respiratory problems (K-BILD) were predefined primary end points. Predefined secondary end points were global quality of life and fatigue (both QLQ-C30).
After a median follow-up of 105 months, 123/368 included patients (33%) were still alive (70 nCRT plus surgery, 53 surgery alone). No statistically significant or clinically relevant differential effects in HRQOL end points were found between both groups. Compared with 1-year postoperative levels, eating problems, physical functioning, global quality of life and fatigue remained at the same level in both groups. Compared with pretreatment levels, eating problems had improved (Cohen’s d −0.37, P = 0.011) during long-term follow-up, whereas physical functioning and fatigue were not restored to pretreatment levels in both groups (Cohen’s d −0.56 and 0.51, respectively, both P < 0.001).
Although physical functioning and fatigue remain reduced after long-term follow-up, no adverse impact of nCRT is apparent on long-term HRQOL compared with patients who were treated with surgery alone. In addition to the earlier reported improvement in survival and the absence of impact on short-term HRQOL, these results support the view that nCRT according to CROSS can be considered as a standard of care.
Netherlands Trial Register NTR487.
The annual modulation measured by the DAMA/LIBRA experiment can be explained by the interaction of dark matter WIMPs in NaI(Tl) scintillator detectors. Other experiments, with different targets or ...techniques, exclude the region of parameters singled out by DAMA/LIBRA, but the comparison of their results relies on several hypotheses regarding the dark matter model. ANAIS-112 is a dark matter search with 112.5 kg of NaI(Tl) scintillators at the Canfranc Underground Laboratory (LSC) to test the DAMA/LIBRA result in a model independent way. We analyze its prospects in terms of the
a priori
critical and detection limits of the experiment. A simple figure of merit has been obtained to compare the different experiments looking for the annual modulation observed by DAMA/LIBRA. We conclude that after 5 years of measurement, ANAIS-112 can detect the annual modulation in the
3
σ
region compatible with the DAMA/LIBRA result.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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