Programmed cell death 1 (PD-1) inhibitors have limited effect in pancreatic ductal adenocarcinoma (PDAC), underscoring the need to co-target alternative pathways. CXC chemokine receptor 4 (CXCR4) ...blockade promotes T cell tumor infiltration and is synergistic with anti-PD-1 therapy in PDAC mouse models. We conducted a phase IIa, open-label, two-cohort study to assess the safety, efficacy and immunobiological effects of the CXCR4 antagonist BL-8040 (motixafortide) with pembrolizumab and chemotherapy in metastatic PDAC (NCT02826486). The primary outcome was objective response rate (ORR). Secondary outcomes were overall survival (OS), disease control rate (DCR) and safety. In cohort 1, 37 patients with chemotherapy-resistant disease received BL-8040 and pembrolizumab. The DCR was 34.5% in the evaluable population (modified intention to treat, mITT; N = 29), including nine patients (31%) with stable disease and one patient (3.4%) with partial response. Median OS (mOS) was 3.3 months in the ITT population. Notably, in patients receiving study drugs as second-line therapy, the mOS was 7.5 months. BL-8040 increased CD8
effector T cell tumor infiltration, decreased myeloid-derived suppressor cells (MDSCs) and further decreased circulating regulatory T cells. In cohort 2, 22 patients received BL-8040 and pembrolizumab with chemotherapy, with an ORR, DCR and median duration of response of 32%, 77% and 7.8 months, respectively. These data suggest that combined CXCR4 and PD-1 blockade may expand the benefit of chemotherapy in PDAC and warrants confirmation in subsequent randomized trials.
A new, simple, economical and validated high-performance liquid chromatography linked with electrochemical detector (HPLC–ECD) method has been developed and optimized for different experimental ...parameters to analyze the most common monothiols and disulfide (cystine, cysteine, homocysteine, methionine, reduced (GSH) and oxidized glutathione (GSSG)) and ascorbic acid present in human plasma and erythrocytes using dopamine as internal standard (IS). Complete separation of all the targets analytes and IS at 35
°C on Discovery HS C18 RP column (250
mm
×
4.6
mm, 5
μm) was achieved using 0.05% TFA:methanol (97:3, v/v) as a mobile phase pumped at the rate of 0.6
ml
min
−1 using electrochemical detector in DC mode at the detector potential of 900
mV. The limits of detection (3 S/N) and limits of quantification (10 S/N) of the studied compounds were evaluated using dilution method. The proposed method was validated according to standard guidelines and optimization of various experimental parameters and chromatographic conditions was carried out. The optimized and validated HPLC–ECD method was successfully applied for the determination of the abovementioned compounds in human plasma and erythrocytes. The method will be quite suitable for the determination of plasma and erythrocyte profile of ascorbic acid and aminothiols in oxidative stress and other basic research studies.
A novel, simple and fast reversed-phase HPLC/UV method was developed, optimized for various chromatographic conditions, and validated according to international guidelines for simultaneous ...determination of all-trans-retinol and α-tocopherol in human serum using retinyl acetate as internal standard in the concentration of 0.5
μg/ml. A liquid-phase extraction was applied to the 250
μl of serum with n-hexane–dichloromethane mixture (70:30, v/v), in two steps, using ethanol–methanol mixture (95:5, v/v) for protein precipitation and BHT (butylated hydroxy toluene) as stabilizer for sample preparation. Both analytes were analyzed on Kromasil 100 C
18 column (150
mm
×
4.6
mm, 5
μm), Brownlee analytical (Perkin Elmer) C
18 column (150
mm
×
4.6
mm, 5
μm), and Supelco (Supelcosil) LC-18 column (150
mm
×
3
mm, 3
μm), protected by a Perkin Elmer C
18 (30
mm
×
4.6
mm, 10
μm; Norwalk, USA) pre-column guard cartridge, at 292
nm wavelength, using methanol–water (99:1, v/v), in isocratic mode as mobile phase applied at flow rate of 1.5
ml/min and 1
ml/min for both 5
μm and 3
μm columns, respectively. Complete separation of all the analytes was achieved in 3 and 6
min on 3
μm and 5
μm columns, respectively by injecting 20
μl of sample into the HPLC system by autosampler, keeping column oven temperature at 25
°C. Different particulate reversed-phase chromatographic columns were evaluated in order to select the best column in terms of sensitivity, selectivity, resolution and short run time of both the analytes and it was concluded that 3
μm columns are better to be used in clinical set up as well as in laboratories for the separation of these analytes in a shorter time as compared with 5
μm columns. The method was validated and applied for the analysis of all-trans-retinol and α-tocopherol in the serum of human volunteers.
This overview paper highlights the successes of the Ozone Monitoring Instrument (OMI) on board the Aura satellite spanning a period of nearly 14 years. Data from OMI has been used in a wide range of ...applications and research resulting in many new findings. Due to its unprecedented spatial resolution, in combination with daily global coverage, OMI plays a unique role in measuring trace gases important for the ozone layer, air quality, and climate change. With the operational very fast delivery (VFD; direct readout) and near real-time (NRT) availability of the data, OMI also plays an important role in the development of operational services in the atmospheric chemistry domain.
A rapid, inexpensive, sensitive and specific HPLC-ECD method for the determination of lipoic acid in human plasma was developed and validated over the linearity range of 0.001–10
μg/ml using naproxen ...sodium as an internal standard (IS). Extraction of lipoic acid and IS from plasma (250
μl) was carried out with a simple one step liquid–liquid extraction using dichloromethane. Similarly solid-phase extraction was carried out using dichloromethane as extraction solvent. The separated organic layer was dried under the stream of nitrogen at 40
°C and the residue was reconstituted with the mobile phase. Complete separation of both lipoic acid and IS at 30
°C on Discovery HS C18 RP column (250
mm
×
4.6
mm, 5
μm) was achieved in 6
min using 0.05
M phosphate buffer (pH 2.5 adjusted with phosphoric acid):acetonitrile (50:50, v/v) as a mobile phase pumped at the rate of 1.5
ml/min using electrochemical detector in DC mode at the detector potential of 1.0
V. The limit of detection and limit of quantification of lipoic acid were 200
pg/ml and 1
ng/ml, respectively. While on column limit of detection and limit of quantification of lipoic acid were 10 and 50
pg/ml, respectively. The absolute recoveries of lipoic acid with liquid–liquid and solid-phase extraction were 98.43, 95.65, 101.45, and 97.36, 102.73, 100.17% at 0.5, 1 and 5
μg/ml levels, respectively. Coefficient of variations for both intra-day and inter-day were between 0.28 and 4.97%. The method is validated and will be quite suitable for the analysis of lipoic acid in the plasma of human volunteers as well as patients with diabetes and cardiovascular diseases.
A fast, simple, and a reliable high-performance liquid chromatography linked with electrochemical detector (HPLC–ECD) method for the assessment of lipoic acid (LA) and dihydrolipoic acid (DHLA) in ...plasma was developed using naproxen sodium as an internal standard (IS) and validated according to standard guidelines. Extraction of both analytes and IS from plasma (250
μl) was carried out with a single step liquid–liquid extraction applying dichloromethane. The separated organic layer was dried under stream of nitrogen at 40
°C and the residue was reconstituted with the mobile phase. Complete separation of both compounds and IS at 30
°C on Discovery HS C18 RP column (250
mm
×
4.6
mm, 5
μm) was achieved in 9
min using acetonitrile: 0.05
M phosphate buffer (pH 2.4 adjusted with phosphoric acid) (52:48, v/v) as a mobile phase pumped at flow rate of 1.5
ml
min
−1 using electrochemical detector in DC mode at the detector potential of 1.0
V. The limit of detection and limit of quantification for lipoic acid were 500
pg/ml and 3
ng/ml, and for dihydrolipoic acid were 3
ng/ml and 10
ng/ml, respectively. The absolute recoveries of lipoic acid and dihydrolipoic acid determined on three nominal concentrations were in the range of 93.40–97.06, and 93.00–97.10, respectively. Similarly coefficient of variations (% CV) for both intra-day and inter-day were between 0.829 and 3.097% for lipoic acid and between 1.620 and 5.681% for dihydrolipoic acid, respectively. This validated method was applied for the analysis of lipoic acid/dihydrolipoic acid in the plasma of human volunteers and will be used for the quantification of these compounds in patients with oxidative stress induced pathologies.
Novel species of fungi described in this study include those from various countries as follows: Antarctica, Cladosporium arenosum from marine sediment sand. Argentina, Kosmimatamyces alatophylus ...(incl. Kosmimatamyces gen. nov.) from soil. Australia,
Aspergillus banksianus, Aspergillus kumbius, Aspergillus luteorubrus, Aspergillus malvicolor and Aspergillus nanangensis from soil, Erysiphe medicaginis from leaves of Medicago polymorpha, Hymenotorrendiella communis on leaf litter of Eucalyptus
bicostata, Lactifluus albopicri and Lactifluus austropiperatus on soil, Macalpinomyces collinsiae on Eriachne benthamii, Marasmius vagus on soil, Microdochium dawsoniorum from leaves of Sporobolus natalensis, Neopestalotiopsis nebuloides
from leaves of Sporobolus elongatus, Pestalotiopsis etonensis from leaves of Sporobolus jacquemontii, Phytophthora personensis from soil associated with dying Grevillea mccutcheonii. Brazil, Aspergillus oxumiae from soil, Calvatia
baixaverdensis on soil, Geastrum calycicoriaceum on leaf litter, Greeneria kielmeyerae on leaf spots of Kielmeyera coriacea. Chile, Phytophthora aysenensis on collar rot and stem of Aristotelia chilensis. Croatia, Mollisia gibbospora
on fallen branch of Fagus sylvatica. Czech Republic, Neosetophoma hnaniceana from Buxus sempervirens. Ecuador, Exophiala frigidotolerans from soil. Estonia, Elaphomyces bucholtzii in soil. France, Venturia paralias
from leaves of Euphorbia paralias. India, Cortinarius balteatoindicus and Cortinarius ulkhagarhiensis on leaf litter. Indonesia, Hymenotorrendiella indonesiana on Eucalyptus urophylla leaf litter. Italy, Penicillium taurinense
from indoor chestnut mill. Malaysia, Hemileucoglossum kelabitense on soil, Satchmopsis pini on dead needles of Pinus tecunumanii. Poland, Lecanicillium praecognitum on insects' frass. Portugal, Neodevriesia aestuarina from saline
water. Republic of Korea, Gongronella namwonensis from freshwater. Russia, Candida pellucida from Exomias pellucidus, Heterocephalacria septentrionalis as endophyte from Cladonia rangiferina, Vishniacozyma phoenicis from dates fruit,
Volvariella paludosa from swamp. Slovenia, Mallocybe crassivelata on soil. South Africa, Beltraniella podocarpi, Hamatocanthoscypha podocarpi, Coleophoma podocarpi and Nothoseiridium podocarpi (incl. Nothoseiridium gen. nov.)from
leaves of Podocarpus latifolius, Gyrothrix encephalarti from leaves of Encephalartos sp., Paraphyton cutaneum from skin of human patient, Phacidiella alsophilae from leaves of Alsophila capensis, and Satchmopsis metrosideri on leaf litter of
Metrosideros excelsa. Spain, Cladophialophora cabanerensis from soil, Cortinarius paezii on soil, Cylindrium magnoliae from leaves of Magnolia grandiflora, Trichophoma cylindrospora (incl. Trichophoma gen. nov.) from plant debris, Tuber
alcaracense in calcareus soil, Tuber buendiae in calcareus soil. Thailand, Annulohypoxylon spougei on corticated wood, Poaceascoma filiforme from leaves of unknown Poaceae. UK, Dendrostoma luteum on branch lesions of Castanea
sativa, Ypsilina buttingtonensis from heartwood of Quercus sp. Ukraine, Myrmecridium phragmiticola from leaves of Phragmites australis. USA, Absidia pararepens from air, Juncomyces californiensis (incl. Juncomyces
gen. nov.) from leaves of Juncus effusus, Montagnula cylindrospora from a human skin sample, Muriphila oklahomaensis (incl. Muriphila gen. nov.)on outside wall of alcohol distillery, Neofabraea eucalyptorum from leaves of Eucalyptus macrandra,
Diabolocovidia claustri (incl. Diabolocovidia gen. nov.)from leaves of Serenoa repens, Paecilomyces penicilliformis from air, Pseudopezicula betulae from leaves of leaf spots of Populus tremuloides. Vietnam, Diaporthe durionigena on branches
of Durio zibethinus and Roridomyces pseudoirritans on rotten wood. Morphological and culture characteristics are supported by DNA barcodes.
Most patients with pancreatic ductal adenocarcinoma (PDAC) die within 6 months of diagnosis. However, 20% to 25% patients undergoing total tumor resection remain alive and disease-free 5 years after ...diagnostic surgery. Few studies on tumor markers have predicted patient prognosis and/or survival. We evaluated the effect of tumor cytogenetic copy number changes detected by interphase fluorescence in situ hybridization on overall survival (OS) of 55 PDAC patients. The prognostic value of copy number changes showing an effect on OS was validated in an external cohort of 44 surgically resected PDAC patients by comparative genomic hybridization arrays, and the genes coded in altered chromosomes with prognostic value were identified by high-density single-nucleotide polymorphism arrays in 20 cases. Copy number changes of chromosomes 4 and 9q34 with gains of 8q24 were independently associated with shorter OS. On the basis of these three chromosomal alterations, a score is proposed that identifies patients with significantly different ( P < 0.001) 5-year OS rates: 60% ± 20%, 16% ± 8%, and 0% ± 0%, respectively. Our results show an association between tumor cytogenetics and OS of PDAC patients and provide the basis for further prognostic stratification of patients undergoing complete tumor resection. Further studies to identify specific genes coded in these chromosomes and their functional consequences are necessary to understand the clinical effect of these changes.
A novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the determination of rosuvastatin (rosuva) and its metabolite N-desmethyl rosuvastatin (NDM-rosuva) in human ...plasma using atorvastatin as internal standard. The method was validated according to international guidelines. The analytical column used was HiChrom
®
C18 (150 × 3.0 mm, 3 µm; Reading, UK) and the mobile phase comprised of 0.1% formic acid in acetonitrile and 0.1% formic acid in water (70:30 v/v), pumped at 300 µL/min. The precipitation of plasma proteins and extraction of analytes were carried out by a simple one-step procedure using acetonitrile. The calibration curves were linear (r
2
= 0.999) over the concentration range of 0.2-20 ng/mL for rosuva and 0.1-10 ng/mL for NDM-rosuva. The lower limits of detection and quantification for rosuva were 0.1 and 0.2 ng/mL, whereas for NDM-rosuva, these were 0.03 and 0.1 ng/mL, respectively. The intra- and inter-day precisions expressed as relative standard deviations (RSDs) were less than 2.5%. The average absolute recoveries of both rosuva and NDM-rosuva were greater than 95%. The method was successfully applied for the determination of rosuva and NDM-rosuva pharmacokinetics and drug-drug interaction studies.
Although suicide is a leading cause of death worldwide, clinicians and researchers lack a data-driven method to assess the risk of suicide attempts. This study reports the results of an analysis of a ...large cross-national epidemiologic survey database that estimates the 12-month prevalence of suicidal behaviors, identifies risk factors for suicide attempts, and combines these factors to create a risk index for 12-month suicide attempts separately for developed and developing countries.
Data come from the World Health Organization (WHO) World Mental Health (WMH) Surveys (conducted 2001-2007), in which 108,705 adults from 21 countries were interviewed using the WHO Composite International Diagnostic Interview. The survey assessed suicidal behaviors and potential risk factors across multiple domains, including sociodemographic characteristics, parent psychopathology, childhood adversities, DSM-IV disorders, and history of suicidal behavior.
Twelve-month prevalence estimates of suicide ideation, plans, and attempts are 2.0%, 0.6%, and 0.3%, respectively, for developed countries and 2.1%, 0.7%, and 0.4%, respectively, for developing countries. Risk factors for suicidal behaviors in both developed and developing countries include female sex, younger age, lower education and income, unmarried status, unemployment, parent psychopathology, childhood adversities, and presence of diverse 12-month DSM-IV mental disorders. Combining risk factors from multiple domains produced risk indices that accurately predicted 12-month suicide attempts in both developed and developing countries (area under the receiver operating characteristic curve = 0.74-0.80).
Suicidal behaviors occur at similar rates in both developed and developing countries. Risk indices assessing multiple domains can predict suicide attempts with fairly good accuracy and may be useful in aiding clinicians in the prediction of these behaviors.
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