Conjugated linoleic acid (CLA) modulates bovine peripheral blood mononuclear cells (PBMC) proteome in vitro.

Conjugated linoleic acid (CLA) is a group of natural isomers of the n-6 polyunsaturated fatty acid (PUFA) linoleic acid, exerting biological effects on cow physiology. This study assessed the impact of the mixture 50:50 (vol:vol) of CLA isomers (cis-9, trans-11 and trans-10, cis-12) on bovine peripheral blood mononuclear cells (PBMC) proteome, identifying 1608 quantifiable proteins. A supervised multivariate statistical analysis, sparse variant partial least squares - discriminant analysis (sPLS-DA) for paired data identified 407 discriminant proteins (DP), allowing the clustering between the CLA and controls. The ProteINSIDE workflow found that DP with higher abundance in the CLA group included proteins related to innate immune defenses (PLIN2, CD36, C3, C4, and AGP), with antiapoptotic (SERPINF2 and ITIH4) and antioxidant effects (HMOX1). These results demonstrated that CLA modulates the bovine PBMC proteome, supports the antiapoptotic and immunomodulatory effects observed in previous in vitro studies on bovine PBMC, and suggests a cytoprotective role against oxidative stress. SIGNIFICANCE: In this study, we report for the first time that the mixture 50:50 (vol:vol) of cis-9, trans-11, and trans-10, cis-12-CLA isomers modulates the bovine PBMC proteome. Our results support the immunomodulatory and antiapoptotic effects observed in bovine PBMC in vitro. In addition, the present study proposes a cytoprotective role of CLA mixture against oxidative stress. We suggest a molecular signature of CLA treatment based on combining a multivariate sparse discriminant analysis and a clustering method. This demonstrates the great value of sPLS-DA as an alternative option to identify discriminant proteins with relevant biological significance.

Implementation of a laser-neutron pump-probe capability for inelastic neutron scattering.

Knowledge about nonequilibrium dynamics in spin systems is of great importance to both fundamental science and technological applications. Inelastic neutron scattering (INS) is an indispensable tool to study spin excitations in complex magnetic materials. However, conventional INS spectrometers currently only perform steady-state measurements and probe averaged properties over many collision events between spin excitations in thermodynamic equilibrium, while the exact picture of re-equilibration of these excitations remains unknown. In this paper, we report on the design and implementation of a time-resolved laser-neutron pump-probe capability at hybrid spectrometer (beamline 14-B) at the Spallation Neutron Source (SNS) at Oak Ridge National Laboratory. This capability allows us to excite out-of-equilibrium magnons with a nanosecond pulsed laser source and probe the resulting dynamics using INS. Here, we discussed technical aspects to implement such a capability in a neutron beamline, including choices of suitable neutron instrumentation and material systems, laser excitation scheme, experimental configurations, and relevant firmware and software development to allow for time-synchronized pump-probe measurements. We demonstrated that the laser-induced nonequilibrium structure factor is able to be resolved by INS in a quantum magnet. The method developed in this work will provide SNS with advanced capabilities for performing out-of-equilibrium measurements, opening up an entirely new research direction to study out-of-equilibrium phenomena using neutrons.

Structure and magnetism of the triangular lattice material YbBO3.

YbBO3is a member of the orthoborate family of materials which contains a triangular arrangement of Yb3+ions. Here we study the physical properties of YbBO3with neutron diffraction, inelastic neutron scattering, specific heat, and ac susceptibility measurements. The neutron diffraction measurements confirm that our samples of YbBO3crystallize in the monoclinic space groupC2/c(#15) which contains two crystallographically distinct Yb3+sites decorating a slightly distorted triangular lattice. Heat capacity and ac susceptibility measurements indicate a potential transition to magnetic order at 0.4 K. In agreement with these observations, neutron diffraction measurements at 0.044 K observe magnetic Bragg peaks which can be indexed by a propagation vector of (0 0 1). Although determining a unique spin configuration corresponding to the observed magnetic Bragg peaks is not possible, model refinements indicate that the ordered moments are likely in the range of 0.4-0.9 µBand, notably, require moments on both Yb sites. In addition to the magnetic Bragg peaks, diffuse scattering at lowQis observed indicating that the transition does not correspond to complete long range magnetic order. The two-site picture for YbBO3is further evidenced by the number of crystal field excitations observed by inelastic neutron scattering measurements. Together these results show that YbBO3is a two-site triangular lattice material with signatures of long-range order as well as shorter ranged spin correlations.

Dynamical Scaling as a Signature of Multiple Phase Competition in Yb_{2}Ti_{2}O_{7}.

Yb_{2}Ti_{2}O_{7} is a celebrated example of a pyrochlore magnet with highly frustrated, anisotropic exchange interactions. To date, attention has largely focused on its unusual, static properties, many of which can be understood as coming from the competition between different types of magnetic order. Here we use inelastic neutron scattering with exceptionally high energy resolution to explore the dynamical properties of Yb_{2}Ti_{2}O_{7}. We find that spin correlations exhibit dynamical scaling, analogous to behavior found near to a quantum critical point. We show that the observed scaling collapse can be explained within a phenomenological theory of multiple-phase competition, and confirm that a scaling collapse is also seen in semiclassical simulations of a microscopic model of Yb_{2}Ti_{2}O_{7}. These results suggest that dynamical scaling may be general to systems with competing ground states.

CHESS: The future direct geometry spectrometer at the second target station.

CHESS, chopper spectrometer examining small samples, is a planned direct geometry neutron chopper spectrometer designed to detect and analyze weak signals intrinsic to small cross sections (e.g., small mass, small magnetic moments, or neutron absorbing materials) in powders, liquids, and crystals. CHESS is optimized to enable transformative investigations of quantum materials, spin liquids, thermoelectrics, battery materials, and liquids. The broad dynamic range of the instrument is also well suited to study relaxation processes and excitations in soft and biological matter. The 15 Hz repetition rate of the Second Target Station at the Spallation Neutron Source enables the use of multiple incident energies within a single source pulse, greatly expanding the information gained in a single measurement. Furthermore, the high flux grants an enhanced capability for polarization analysis. This enables the separation of nuclear from magnetic scattering or coherent from incoherent scattering in hydrogenous materials over a large range of energy and momentum transfer. This paper presents optimizations and technical solutions to address the key requirements envisioned in the science case and the anticipated uses of this instrument.

Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans.

Over the past decade, immunotherapy delivered novel treatments for many cancer types. However, lung cancer still leads cancer mortality, and non-small-cell lung carcinoma patients with mutant EGFR cannot benefit from checkpoint inhibitors due to toxicity, relying only on palliative chemotherapy and the third-generation tyrosine kinase inhibitor (TKI) osimertinib. This new drug extends lifespan by 9-months vs. second-generation TKIs, but unfortunately, cancers relapse due to resistance mechanisms and the lack of antitumor immune responses. Here we explored the combination of osimertinib with anti-HER3 monoclonal antibodies and observed that the immune system contributed to eliminate tumor cells in mice and co-culture experiments using bone marrow-derived macrophages and human PBMCs. Osimertinib led to apoptosis of tumors but simultaneously, it triggered inositol-requiring-enzyme (IRE1α)-dependent HER3 upregulation, increased macrophage infiltration, and activated cGAS in cancer cells to produce cGAMP (detected by a lentivirally transduced STING activity biosensor), transactivating STING in macrophages. We sought to target osimertinib-induced HER3 upregulation with monoclonal antibodies, which engaged Fc receptor-dependent tumor elimination by macrophages, and STING agonists enhanced macrophage-mediated tumor elimination further. Thus, by engaging a tumor non-autonomous mechanism involving cGAS-STING and innate immunity, the combination of osimertinib and anti-HER3 antibodies could improve the limited therapeutic and stratification options for advanced stage lung cancer patients with mutant EGFR.

Study of energetic properties of different tree organs in six Olea europaea L. cultivars.

Pruning is an important horticultural practice for the management of olive orchards (Olea europaea L.) that generates a considerable amount of residues every year. Olive orchards are increasingly expanding beyond the Mediterranean Basin to new growing Countries (Australia, California, Argentina, Chile and Uruguay) and this will certainly lead to larger availability of pruning material. Currently, the interest in use of olive tree pruning residues for energy purposes is increasing but unfortunately, the information on the differences among organs of the tree, in terms of calorific value and ash content, is scarce. Another unknown aspect is the effect of cultivar vigour on dry matter partition among different tree organs, these are important traits to establish the energetic quality of pruning residues. The aim of this research was to study energetic aspects of six olive cultivars, largely grown in the Sicilian olive industry and characterized by different vigour. The trees taken into consideration in the study were selected in an experimental orchard to avoid any effect due to differences in environmental conditions and management. The energetic characteristics, calorific value and ash content, were evaluated for the various tree organs particularly shoots, leaves and branches; also root system was evaluated, although the roots can only be used once the trees are uprooted. Significant differences were observed in the calorific values among the different tree organs and the cultivars. Regarding the ash, shoots and leaves showed the highest content with respect to the other organs, thus causing a possible tendency in slagging with fouling and corrosion of boiler components.

Short communication: Diagnostic accuracy of focused lung ultrasonography as a rapid method for the diagnosis of respiratory disease in dairy calves.

This study estimates the accuracy of the focused lung ultrasound (FLUS) compared with systematic thoracic ultrasonography (TUS) as the reference test for diagnosing pneumonia in pre- and postweaned dairy calves. One hundred thirty-five Holstein Friesian calves, aged between 1 to 6 mo were enrolled and were kept in the same pen with one or more animals showing signs of bovine respiratory disease complex (BRDC). One operator performed FLUS on each calf, and then a second, blinded operator performed TUS on the same calf. For the FLUS, we only scanned the lung lobes that are most frequently affected during BRDC and are thus easier to detect, such as the caudal aspect of the cranial lobe of the left lung (fifth and fourth left intercostal spaces; ICS), the middle lobe of the right lung (fifth right ICS), and the caudal aspect of the cranial lobe of the right lung (fourth right ICS). Pneumonia was diagnosed when a calf had a minimum of one small lobular lung lesion that was at least 1 cm deep within a normally aerated lobe (TUS score of ≥2). Diagnostic accuracy indexes of the FLUS were calculated using TUS as the gold standard. The McNemar test was performed to evaluate the differences between the 2 techniques. In addition, an intertest agreement was assessed using the weighted kappa test. A total of 76 out of 135 calves had a TUS score of ≥2 and were therefore considered to be affected by BRDC. The FLUS had a sensitivity of 81.6% (95% CI = 71.0-89.5%), specificity = 100% (95% CI = 93.9-100%), positive predictive value was 100%, negative predictive value was 96.6% (95% CI = 94.7---97.9%), and accuracy was 97% (95% CI = 92.6-99.2%). The McNemar test highlighted a difference of 10.3% between the FLUS and TUS. The agreement between the TUS and FLUS was substantial (weighted kappa test 0.78). Although FLUS shows some limitations in diagnosing lung lesions associated with BRDC compared with the systematic approach, this study shows that the focused method could be used as an additional tool for evaluating consolidation, especially when examining a large number of postweaned dairy calves.

Van Hove singularity in the magnon spectrum of the antiferromagnetic quantum honeycomb lattice.

In quantum magnets, magnetic moments fluctuate heavily and are strongly entangled with each other, a fundamental distinction from classical magnetism. Here, with inelastic neutron scattering measurements, we probe the spin correlations of the honeycomb lattice quantum magnet YbCl3. A linear spin wave theory with a single Heisenberg interaction on the honeycomb lattice, including both transverse and longitudinal channels of the neutron response, reproduces all of the key features in the spectrum. In particular, we identify a Van Hove singularity, a clearly observable sharp feature within a continuum response. The demonstration of such a Van Hove singularity in a two-magnon continuum is important as a confirmation of broadly held notions of continua in quantum magnetism and additionally because analogous features in two-spinon continua could be used to distinguish quantum spin liquids from merely disordered systems. These results establish YbCl3 as a benchmark material for quantum magnetism on the honeycomb lattice.

Real-time Hall-effect detection of current-induced magnetization dynamics in ferrimagnets.

Measurements of the transverse Hall resistance are widely used to investigate electron transport, magnetization phenomena, and topological quantum states. Owing to the difficulty of probing transient changes of the transverse resistance, the vast majority of Hall effect experiments are carried out in stationary conditions using either dc or ac. Here we present an approach to perform time-resolved measurements of the transient Hall resistance during current-pulse injection with sub-nanosecond temporal resolution. We apply this technique to investigate in real-time the magnetization reversal caused by spin-orbit torques in ferrimagnetic GdFeCo dots. Single-shot Hall effect measurements show that the current-induced switching of GdFeCo is widely distributed in time and characterized by significant activation delays, which limit the total switching speed despite the high domain-wall velocity typical of ferrimagnets. Our method applies to a broad range of current-induced phenomena and can be combined with non-electrical excitations to perform pump-probe Hall effect measurements.

Spin-orbit torque switching of an antiferromagnetic metallic heterostructure.

The ability to represent information using an antiferromagnetic material is attractive for future antiferromagnetic spintronic devices. Previous studies have focussed on the utilization of antiferromagnetic materials with biaxial magnetic anisotropy for electrical manipulation. A practical realization of these antiferromagnetic devices is limited by the requirement of material-specific constraints. Here, we demonstrate current-induced switching in a polycrystalline PtMn/Pt metallic heterostructure. A comparison of electrical transport measurements in PtMn with and without the Pt layer, corroborated by x-ray imaging, reveals reversible switching of the thermally-stable antiferromagnetic Néel vector by spin-orbit torques. The presented results demonstrate the potential of polycrystalline metals for antiferromagnetic spintronics.

In vitro effects of conjugated linoleic acid (CLA) on inflammatory functions of bovine monocytes.

The conjugated linoleic acid (CLA) isomers, a group of naturally occurring isomers of the essential fatty acid (FA) linoleic acid, have received special attention in animal and human nutrition. Although they have long been used as dietary integrators in dairy cows, the effects of CLA isomers on bovine immune cells remain mostly undisclosed. The present study aimed to cover this gap and investigate the in vitro effects of CLA on inflammatory functions, including chemotaxis, phagocytosis, killing capability, and extracellular respiratory burst of purified bovine monocytes (CD14+). The apoptosis rate of monocytes was addressed as well. Once assessed, the effects of different concentrations (10, 50, 100, and 500 µM) of the 2 main CLA isomers, namely cis-9,trans-11 and trans-10,cis-12, the experiments were carried out using a concentration of 50 µM of the CLA isomers, both individually and in a mixture (50:50). The immunomodulatory activities of linoleic acid, an essential FA, and stearic acid, a saturated FA, were also investigated. Only the 50:50 CLA mixture was able to reduce monocyte apoptosis and to increase the extracellular respiratory burst during experimental proinflammatory conditions, as assessed by measuring production of reactive oxygen species. Linoleic acid and CLA had no effects on chemotaxis, phagocytosis, or killing capability. Remarkably, treatment of monocytes with stearic acid significantly reduced their chemotactic capability. The present results demonstrated that CLA isomers do have immunomodulatory effects on some functions of bovine monocytes, and that the mixture of the 2 CLA isomers is more effective than the CLA isomers individually.

Permanence of de novo segmental aneuploidy in sequential embryo biopsies.

STUDY QUESTION: Is de novo segmental aneuploidy (SA) a biological event or an artifact that is erroneously interpreted as partial chromosome imbalance? SUMMARY ANSWER: The detection of de novo SA in sequential biopsies of preimplantation embryos supports the biological nature of SA. WHAT IS KNOWN ALREADY: Although some SAs are detected in oocytes and in blastocysts, the highest incidence is observed in cleavage-stage embryos. Based on these findings, we can postulate that the majority of cells affected by SAs are eliminated by apoptosis or that affected embryos mainly undergo developmental arrest. STUDY DESIGN, SIZE, DURATION: This retrospective study includes 342 preimplantation genetic testing for aneuploidy (PGT-A) cycles performed between January 2014 and December 2018. Chromosome analysis was performed on 331 oocytes, 886 cleavage-stage embryos and 570 blastocysts (n = 1787). From 268 expanded blastocysts, the blastocoelic fluid (BF) was also analyzed (resulting in 2025 samples in total). In cases of SAs involving loss or gain in excess of 15 Mb, embryos were not considered for transfer and sequential biopsies were performed at following stages. This resulted in 66 sets where the initial diagnosis of SAs (4 made in polar bodies, 25 in blastomeres and 37 in trophectoderm (TE) cells) was followed up. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 2082 samples (2025 + 27 whole embryos) were processed by whole genome amplification followed by array comparative genomic hybridization. MAIN RESULTS AND THE ROLE OF CHANCE: The incidence of SAs was 6.3% in oocytes, increased to 16.6% in cleavage-stage embryos (P < 0.001) and decreased to 11.2% in blastocysts (P < 0.025 versus oocytes; P < 0.01 versus cleavage-stage embryos). The highest incidence of SAs was found in BFs (26.1%, P < 0.001). The analysis of 66 sets of sequential biopsies revealed that the initial finding was confirmed in all following samples from 39 sets (59.1% full concordance). In 12 additional sets, SAs were detected in some samples while in others the interested chromosome had full aneuploidy (18.2%). In three more sets, there was a partial concordance with the initial diagnosis in some samples, but in all TE samples the interested chromosome was clearly euploid (4.5%). In the remaining 12 sets, the initial SA was not confirmed at any stage and the corresponding chromosomes were euploid (18.2% no concordance). The pattern of concordance was not affected by the number of SAs in the original biopsy (single, double or complex) or by the absence or presence of concomitant aneuploidies for full chromosomes. LIMITATIONS, REASONS FOR CAUTION: Chromosome analyses were performed on biopsies that might not be representative of the true constitution of the embryo itself due to the occurrence of mosaicism. WIDER IMPLICATIONS OF THE FINDINGS: The permanence of SAs throughout the following stages of embryo development in more than half of the analyzed sets suggests for this dataset a very early origin of this type of chromosome imbalance, either at meiosis or at the first mitotic divisions. Since SAs remained in full concordance with the initial diagnosis until the blastocyst stage, a corrective mechanism seems not to be in place. In the remaining cases, it is likely that, as for full chromosome aneuploidy, mosaicism derived from mitotic errors could have occurred. In following cell divisions, euploid cell lines could prevail preserving the embryo chances of implantation. Due to the scarcity of data available, the transfer of embryos with SAs should be strictly followed up to establish possible clinical consequences related to this condition. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was obtained. There are no conflicts of interest.

Octupolar versus Néel Order in Cubic 5d

We report time-of-flight neutron spectroscopy and neutron and x-ray diffraction studies of the 5d^{2} double perovskite magnets, Ba_{2}MOsO_{6} (M=Zn,Mg,Ca). These materials host antiferromagnetically coupled 5d^{2} Os^{6+} ions decorating a face-centered cubic (fcc) lattice and are found to remain cubic down to the lowest temperatures. They all exhibit thermodynamic anomalies consistent with a single phase transition at a temperature T^{*}, and a gapped magnetic excitation spectrum with spectral weight concentrated at wave vectors typical of type-I antiferromagnetic orders. However, while muon spin resonance experiments show clear evidence for time-reversal symmetry breaking below T^{*}, we observe no corresponding magnetic Bragg scattering signal. These results are shown to be consistent with ferro-octupolar symmetry breaking below T^{*}, and are discussed in the context of other 5d double perovskite magnets and theories of exotic orders driven by multipolar interactions.

Correction to: Contribution of cryopreservation to the cumulative live birth rate: a large multicentric cycle-based data analysis from the Italian National Registry.

The original article unfortunately contained a mistake. The names of the collaborators were captured as authors of the article.

Contribution of cryopreservation to the cumulative live birth rate: a large multicentric cycle-based data analysis from the Italian National Registry.

PURPOSE: To estimate the contribution of cryopreservation to the cumulative live birth rate (CLBR) after law modification in Italy in the era of vitrification and freeze-all. METHODS: The Italian National Registry performed a cycle-based data collection. Nine Italian IVF clinics were involved incorporating a total of 10,260 fresh cycles performed between January 2015 and April 2016 resulting in 9273 oocyte retrievals and 3266 subsequent warming cycles from the same oocyte retrievals performed up to December 2016. Mean female age was 37 ± 4.3 years. Primary outcome measure was CLBR per oocyte retrieval. Confounding factors were tested in multivariate regression analysis, and the relative impact of cryopreservation to the CLBR in different patient categories was calculated. RESULTS: CLBR per oocyte retrieval was 32.6%, 26.5%, 18.7%, 13.0%, and 5.5% for women younger than 36, aged 36-39, 40-41, and older than 41 years, respectively. The total relative contribution of oocyte/embryo cryopreservation was 40.6% (95% CI 38.41-42.75). An association between maternal age, number of oocytes retrieved, fertilization rate, cryopreservation, and cumulative live birth was shown. When adjusted for confounders, a 2.3-fold increase was observed in the chance of live birth when cryopreservation was performed (OR 2.3; 95% CI 1.99-2.56). In high responder patients (> 15 oocytes retrieved) where freeze-all was applied in 67.6% of cycles to avoid the risk of hyper stimulation syndrome, the relative contribution of vitrification to the CLBR was 80.6%. CONCLUSIONS: Cryopreservation is essential in IVF and should always be available to patients to optimize success rates. Multicentric, cycle-based data analyses are crucial to provide infertile couples, clinicians, and regulatory bodies with accurate information on IVF effectiveness including fresh and cryopreserved cycles.

Novel Strongly Spin-Orbit Coupled Quantum Dimer Magnet: Yb_{2}Si_{2}O_{7}.

The quantum dimer magnet (QDM) is the canonical example of quantum magnetism. The QDM state consists of entangled nearest-neighbor spin dimers and often exhibits a field-induced triplon Bose-Einstein condensate (BEC) phase. We report on a new QDM in the strongly spin-orbit coupled, distorted honeycomb-lattice material Yb_{2}Si_{2}O_{7}. Our single crystal neutron scattering, specific heat, and ultrasound velocity measurements reveal a gapped singlet ground state at zero field with sharp, dispersive excitations. We find a field-induced magnetically ordered phase reminiscent of a BEC phase, with exceptionally low critical fields of H_{c1}∼0.4 and H_{c2}∼1.4 T. Using inelastic neutron scattering in an applied magnetic field we observe a Goldstone mode (gapless to within δE=0.037 meV) that persists throughout the entire field-induced magnetically ordered phase, suggestive of the spontaneous breaking of U(1) symmetry expected for a triplon BEC. However, in contrast to other well-known cases of this phase, the high-field (µ_{0}H≥1.2 T) part of the phase diagram in Yb_{2}Si_{2}O_{7} is interrupted by an unusual regime signaled by a change in the field dependence of the ultrasound velocity and magnetization, as well as the disappearance of a sharp anomaly in the specific heat. These measurements raise the question of how anisotropy in strongly spin-orbit coupled materials modifies the field induced phases of QDMs.

Tomonaga-Luttinger liquid behavior and spinon confinement in YbAlO3.

Low dimensional quantum magnets are interesting because of the emerging collective behavior arising from strong quantum fluctuations. The one-dimensional (1D) S = 1/2 Heisenberg antiferromagnet is a paradigmatic example, whose low-energy excitations, known as spinons, carry fractional spin S = 1/2. These fractional modes can be reconfined by the application of a staggered magnetic field. Even though considerable progress has been made in the theoretical understanding of such magnets, experimental realizations of this low-dimensional physics are relatively rare. This is particularly true for rare-earth-based magnets because of the large effective spin anisotropy induced by the combination of strong spin-orbit coupling and crystal field splitting. Here, we demonstrate that the rare-earth perovskite YbAlO3 provides a realization of a quantum spin S = 1/2 chain material exhibiting both quantum critical Tomonaga-Luttinger liquid behavior and spinon confinement-deconfinement transitions in different regions of magnetic field-temperature phase diagram.

Tuning the biomimetic performances of 4-hydroxyproline-containing cyclic peptoids.

Five new cyclic peptoids containing (2S,4R)-4-hydroxyproline (Hyp) residues have been designed and synthesized using a mixed "submonomer/monomer" approach. Alkali metal cation affinities and ion transport activities were assessed by experimental (NMR and HPTS assay in liposomes) and computational methods. Easy functionalization of hydroxyproline residues afforded a bouquet of cyclic oligomers showing correlation between ion transport abilities and cytotoxic activities on selected human cancer cell lines.

GPR55 signalling promotes proliferation of pancreatic cancer cells and tumour growth in mice, and its inhibition increases effects of gemcitabine.

The life expectancy for pancreatic cancer patients has seen no substantial changes in the last 40 years as very few and mostly just palliative treatments are available. As the five years survival rate remains around 5%, the identification of novel pharmacological targets and development of new therapeutic strategies are urgently needed. Here we demonstrate that inhibition of the G protein-coupled receptor GPR55, using genetic and pharmacological approaches, reduces pancreatic cancer cell growth in vitro and in vivo and we propose that this may represent a novel strategy to inhibit pancreatic ductal adenocarcinoma (PDAC) progression. Specifically, we show that genetic ablation of Gpr55 in the KRASWT/G12D/TP53WT/R172H/Pdx1-Cre+/+ (KPC) mouse model of PDAC significantly prolonged survival. Importantly, KPC mice treated with a combination of the GPR55 antagonist Cannabidiol (CBD) and gemcitabine (GEM, one of the most used drugs to treat PDAC), survived nearly three times longer compared to mice treated with vehicle or GEM alone. Mechanistically, knockdown or pharmacologic inhibition of GPR55 reduced anchorage-dependent and independent growth, cell cycle progression, activation of mitogen-activated protein kinase (MAPK) signalling and protein levels of ribonucleotide reductases in PDAC cells. Consistent with this, genetic ablation of Gpr55 reduced proliferation of tumour cells, MAPK signalling and ribonucleotide reductase M1 levels in KPC mice. Combination of CBD and GEM inhibited tumour cell proliferation in KPC mice and it opposed mechanisms involved in development of resistance to GEM in vitro and in vivo. Finally, we demonstrate that the tumour suppressor p53 regulates GPR55 protein expression through modulation of the microRNA miR34b-3p. Our results demonstrate the important role played by GPR55 downstream of p53 in PDAC progression. Moreover our data indicate that combination of CBD and GEM, both currently approved for medical use, might be tested in clinical trials as a novel promising treatment to improve PDAC patients' outcome.