Multivalent γ-PGA-Exendin-4 Conjugates to Target Pancreatic ß-Cells.

Targeting of glucagon-like peptide 1 receptor (GLP-1R), expressed on the surface of pancreatic ß-cells, is of great interest for the development of advanced therapies for diabetes and diagnostics for insulinoma. We report the conjugation of exendin-4 (Ex-4), an approved drug to treat type 2 diabetes, to poly-γ-glutamic acid (γ-PGA) to obtain more stable and effective GLP-1R ligands. Exendin-4 modified at Lysine-27 with PEG4-maleimide was conjugated to γ-PGA functionalized with furan, in different molar ratios, exploiting a chemoselective Diels-Alder cycloaddition. The γ-PGA presenting the highest number of conjugated Ex-4 molecules (average 120 per polymeric chain) showed a double affinity towards GLP-1R with respect to exendin per se, paving the way to improved therapeutic and diagnostic applications.

Predicting post-discharge cancer surgery complications via telemonitoring of patient-reported outcomes and patient-generated health data.

BACKGROUND AND OBJECTIVES: Post-discharge oncologic surgical complications are costly for patients, families, and healthcare systems. The capacity to predict complications and early intervention can improve postoperative outcomes. In this proof-of-concept study, we used a machine learning approach to explore the potential added value of patient-reported outcomes (PROs) and patient-generated health data (PGHD) in predicting post-discharge complications for gastrointestinal (GI) and lung cancer surgery patients. METHODS: We formulated post-discharge complication prediction as a binary classification task. Features were extracted from clinical variables, PROs (MD Anderson Symptom Inventory [MDASI]), and PGHD (VivoFit) from a cohort of 52 patients with 134 temporal observation points pre- and post-discharge that were collected from two pilot studies. We trained and evaluated supervised learning classifiers via nested cross-validation. RESULTS: A logistic regression model with L2 regularization trained with clinical data, PROs and PGHD from wearable pedometers achieved an area under the receiver operating characteristic of 0.74. CONCLUSIONS: PROs and PGHDs captured through remote patient telemonitoring approaches have the potential to improve prediction performance for postoperative complications.

Patient generated health data and electronic health record integration in oncologic surgery: A call for artificial intelligence and machine learning.

In this review, we aim to assess the current state of science in relation to the integration of patient-generated health data (PGHD) and patient-reported outcomes (PROs) into routine clinical care with a focus on surgical oncology populations. We will also describe the critical role of artificial intelligence and machine-learning methodology in the efficient translation of PGHD, PROs, and traditional outcome measures into meaningful patient care models.

Signature of Generalized Gibbs Ensemble Deviation from Equilibrium: Negative Absorption Induced by a Local Quench.

When a parameter quench is performed in an isolated quantum system with a complete set of constants of motion, its out of equilibrium dynamics is considered to be well captured by the Generalized Gibbs Ensemble (GGE), characterized by a set {λα} of coefficients related to the constants of motion. We determine the most elementary GGE deviation from the equilibrium distribution that leads to detectable effects. By quenching a suitable local attractive potential in a one-dimensional electron system, the resulting GGE differs from equilibrium by only one single λα, corresponding to the emergence of an only partially occupied bound state lying below a fully occupied continuum of states. The effect is shown to induce optical gain, i.e., a negative peak in the absorption spectrum, indicating the stimulated emission of radiation, enabling one to identify GGE signatures in fermionic systems through optical measurements. We discuss the implementation in realistic setups.

Naïve validity.

Beall and Murzi (J Philos 110(3):143-165, 2013) introduce an object-linguistic predicate for naïve validity, governed by intuitive principles that are inconsistent with the classical structural rules (over sufficiently expressive base theories). As a consequence, they suggest that revisionary approaches to semantic paradox must be substructural. In response to Beall and Murzi, Field (Notre Dame J Form Log 58(1):1-19, 2017) has argued that naïve validity principles do not admit of a coherent reading and that, for this reason, a non-classical solution to the semantic paradoxes need not be substructural. The aim of this paper is to respond to Field's objections and to point to a coherent notion of validity which underwrites a coherent reading of Beall and Murzi's principles: grounded validity. The notion, first introduced by Nicolai and Rossi (J Philos Log. doi:10.1007/s10992-017-9438-x, 2017), is a generalisation of Kripke's notion of grounded truth (J Philos 72:690-716, 1975), and yields an irreflexive logic. While we do not advocate the adoption of a substructural logic (nor, more generally, of a revisionary approach to semantic paradox), we take the notion of naïve validity to be a legitimate semantic notion that points to genuine expressive limitations of fully structural revisionary approaches.

Conservative deflationism?

Deflationists argue that 'true' is merely a logico-linguistic device for expressing blind ascriptions and infinite generalisations. For this reason, some authors have argued that deflationary truth must be conservative, i.e. that a deflationary theory of truth for a theory S (that interprets a sufficient amount of mathematics, or syntax) must not entail sentences in S's language that are not already entailed by S. However, it has been forcefully argued that any adequate theory of truth for S must be non-conservative and that, for this reason, truth cannot be deflationary (Shapiro in J Philos XCVI(10):493-521, 1998; Ketland in Mind 108(429):69-94, 1999). We consider two defences of conservative deflationism, respectively proposed by Waxman (Mind 126(502):429-463, 2017) and Tennant (Mind 111(443):551-582, 2002), and argue that they are both unsuccessful. In Waxman's hands, deflationists are committed either to a non-purely expressive notion of truth, or to a conception of mathematics that does not allow them to justifiably exclude non-conservative theories of truth. Tennant's conservative deflationism fares no better: if deflationist truth must be conservative over arithmetic, it can be shown to collapse into a non-conservative variety of deflationism.

Non-contractability and Revenge.

It is often argued that fully structural theories of truth and related notions are incapable of expressing a nonstratified notion of defectiveness. We argue that recently much-discussed non-contractive theories suffer from the same expressive limitation, provided they identify the defective sentences with the sentences that yield triviality if they are assumed to satisfy structural contraction.

Clinical outcomes after palbociclib with or without endocrine therapy in postmenopausal women with hormone receptor positive and HER2-negative metastatic breast cancer enrolled in the TREnd trial.

Currently, there is limited data regarding the effectiveness of standard subsequent line therapies such as endocrine therapy, chemotherapy, or targeted agents after progression on CDK4/6 inhibitor-based regimens. This paper describes time-to-treatment failure beyond progression on palbociclib or palbociclib+endocrine therapy in patients enrolled in the phase II, multicenter TREnd trial. Our results indicate that there is limited benefit from post-palbociclib treatment, regardless of the type of therapy received. A small population of long responders were identified who demonstrated ongoing benefit from a subsequent line of endocrine therapy after progression to palbociclib-based regimens. A translational research program is ongoing on this population of outliers.

Diagnosis and Treatment of Breast Cancer in Young Women.

OPINION STATEMENT: Despite the increase of breast cancer incidence with age, approximately 7 to 10% ofwomen diagnosed with breast cancer are younger than the age 40. This subgroup ofpatients has different risk factors, tumour biology, clinical outcomes, and specific psy- chosocial issues, such as fertility preservation, family planning, and job reintegration. However, age alone should not be the main consideration when choosing the aggressive- ness of the treatment, as other factors must be considered, including the biologic aggressiveness of the tumour, potential long-term toxicities, and the preferences of the patient. Fertility preservation techniques should be discussed with the patient before starting any cancer treatment. Despite the significant percentage of breast cancer patients younger than age 40, fewclinical studies have specifically investigated disease characteristics and outcomes of this population, and most therapies routinely administered to these younger women were tested in older patients. Moreover, young women who have breast cancer are at a greater risk of sexual and psychological distress, and clinicians should address these issues in order to properly support patients during the long diagnostic and therapeutic journey. Consequently, it is essential to follow diagnostic and treatment guidelines specificallyaddressed to young women. Additional specific procedures should be followed to treat pregnant patients with breast cancer.

The Sicilian Wolf: Genetic Identity of a Recently Extinct Insular Population.

Historically, many local grey wolf (Canis lupus) populations have undergone substantial reductions in size or become extinct. Among these, the wolf population once living in Sicily, the largest island in the Mediterranean Sea, was completely eradicated by human activity in the early decades of the 20th century. To gain a better understanding of the genetic identity of the Sicilian wolf, we used techniques for the study of ancient DNA to analyze the mitochondrial (mt) variability of six specimens stored in Italian museums. We were able to amplify a diagnostic mtDNA fragment of the control region (CR) in four of the samples. Two of the samples shared the same haplotype, differing by two substitutions from the currently most diffused Italian wolf haplotype (W14) and one substitution from the only other Italian haplotype (W16). The third sample showed a previously unreported wolf-like haplotype, and the fourth a haplotype commonly found in dogs. All of the wolf haplotypes analyzed in this study belonged to the mitochondrial haplogroup that includes haplotypes detected in all the known European Pleistocene wolves and in several modern southern European populations. Unfortunately, this endemic island population, which exhibited unique mtDNA variability, was definitively lost before it was possible to understand its taxonomic uniqueness and conservational value.

Early triple negative breast cancer: Are we getting better outcomes? A retrospective analysis from a single institution.

Overall survival (OS), disease-free survival (DFS), and distant recurrence-free interval (DRFI) were evaluated from 169 patients diagnosed with early triple negative breast cancer. Overall, 5 and 10 years OS, DFS, and DRFI were 77% and 65%; 60% and 46%; and 74% and 73%, respectively. Forty-seven patients did not receive chemotherapy. A separate analysis was performed excluding those patients. In this subgroup, 5- and 10-year OS, DFS, and DRFI were 86% and 77%; 68% and 54%, 77% both at 5 and 10 years. Prognosis is better than previously described; adjuvant chemotherapy should be offered to fit elderly patients if clinically warranted.

Model-theoretic semantics and revenge paradoxes.

Revenge arguments purport to show that any proposed solution to the semantic paradoxes generates new paradoxes that prove that solution to be inadequate. In this paper, I focus on revenge arguments that employ the model-theoretic semantics of a target theory and I argue, contra the current revenge-theoretic wisdom, that they can constitute genuine expressive limitations. I consider the anti-revenge strategy elaborated by Field (J Philos Log 32:139-177, 2003; Revenge of the Liar, Oxford University Press, Oxford, pp 53-144, 2007; Saving truth from paradox, Oxford University Press, Oxford, 2008, §§21-23) and argue that it does not offer a way out of the revenge problem. More generally, I argue that the difference between 'standard' and 'revenge' paradoxes is ill-conceived and should be abandoned. This will contribute to show that the theories that provide a uniform account of truth and other semantic notions are the ones best equipped to avoid the paradoxes altogether-'standard' and 'revenge' alike.

Principles for Object-Linguistic Consequence: from Logical to Irreflexive.

We discuss the principles for a primitive, object-linguistic notion of consequence proposed by (Beall and Murzi, Journal of Philosophy, 3 pp. 143-65 (2013)) that yield a version of Curry's paradox. We propose and study several strategies to weaken these principles and overcome paradox: all these strategies are based on the intuition that the object-linguistic consequence predicate internalizes whichever meta-linguistic notion of consequence we accept in the first place. To these solutions will correspond different conceptions of consequence. In one possible reading of these principles, they give rise to a notion of logical consequence: we study the corresponding theory of validity (and some of its variants) by showing that it is conservative over a wide range of base theories: this result is achieved via a well-behaved form of local reduction. The theory of logical consequence is based on a restriction of the introduction rule for the consequence predicate. To unrestrictedly maintain this principle, we develop a conception of object-linguistic consequence, which we call grounded consequence, that displays a restriction of the structural rule of reflexivity. This construction is obtained by generalizing Saul Kripke's inductive theory of truth (strong Kleene version). Grounded validity will be shown to satisfy several desirable principles for a naïve, self-applicable notion of consequence.

Uptake, Accumulation, and in Planta Distribution of Coexisting Cerium Oxide Nanoparticles and Cadmium in Glycine max (L.) Merr. .

Agricultural soils are likely to be polluted by both conventional and emerging contaminants at the same time. Understanding the interactions of coexisting engineered nanoparticles (ENPs) and trace elements (a common source of abiotic stress) is critical to gaining insights into the accumulation of these two groups of chemicals by plants. The objectives of this study were to determine the uptake and accumulation of coexisting ENPs and trace elements by soybeans and to gain insights into the physiological mechanisms resulting in different plant accumulation of these materials. The combinations of three cadmium levels (0 [control] and 0.25 and 1 milligrams per kilogram of dry soil) and two CeO2 NPs concentrations (0 [control] and 500 milligrams per kilogram of dry soil) were investigated. Measurements of the plant biomass and physiological parameters indicated that CeO2 NPs led to higher variable fluorescence to maximum fluorescence ratio, suggesting that CeO2 NPs enhanced the plant light energy use efficiency by photosystem II. In addition, the presence of CeO2 NPs did not affect Cd accumulation in soybean, but Cd significantly increased the accumulation of Ce in plant tissues, especially in roots and older leaves. The altered Ce in planta distribution was partially associated with the formation of root apoplastic barriers in the co-presence of Cd and CeO2 NPs.

Adjuvant Endocrine Therapy in Breast Cancer: Evolving Paradigms in Premenopausal Women.

OPINION STATEMENT: In the last few years, new adjuvant endocrine treatment options have become available in young women with early breast cancer, such as the addition of ovarian function suppression to tamoxifen or aromatase inhibitors. Treatment duration has been also adapted in the latest guidelines based on the individual risk of recurrence. The oncologist is therefore challenged to precisely assess the risk of recurrence according to currently available predictive and prognostic factors in order to offer the most appropriate therapeutic option to the individual patient, considering also potential side effects, quality of life, pregnancy planning and patients' preferences. The adjuvant treatment planning should always be discussed and agreed in a multidisciplinary context. Tamoxifen remains the standard of care in low-risk patients or in case of intolerance to combined treatment with pharmacological ovarian function suppression or aromatase inhibitors. Combination treatment is indicated in intermediate high-risk disease. The patient should always be considered an active partner in the treatment decision process, to improve treatment motivation and adherence. Finally, the therapeutic choice should take into account drug availability and pharmacoeconomic issues, which unfortunately may prevent, in many low-income countries, the provision of such effective treatments.

Accuracy of Flight Altitude Measured with Low-Cost GNSS, Radar and Barometer Sensors: Implications for Airborne Radiometric Surveys.

Flight height is a fundamental parameter for correcting the gamma signal produced by terrestrial radionuclides measured during airborne surveys. The frontiers of radiometric measurements with UAV require light and accurate altimeters flying at some 10 m from the ground. We equipped an aircraft with seven altimetric sensors (three low-cost GNSS receivers, one inertial measurement unit, one radar altimeter and two barometers) and analyzed ~3 h of data collected over the sea in the (35-2194) m altitude range. At low altitudes (H < 70 m) radar and barometric altimeters provide the best performances, while GNSS data are used only for barometer calibration as they are affected by a large noise due to the multipath from the sea. The ~1 m median standard deviation at 50 m altitude affects the estimation of the ground radioisotope abundances with an uncertainty less than 1.3%. The GNSS double-difference post-processing enhanced significantly the data quality for H > 80 m in terms of both altitude median standard deviation and agreement between the reconstructed and measured GPS antennas distances. Flying at 100 m the estimated uncertainty on the ground total activity due to the uncertainty on the flight height is of the order of 2%.

Overexpression of a synthetic insect-plant geranyl pyrophosphate synthase gene in Camelina sativa alters plant growth and terpene biosynthesis.

MAIN CONCLUSION: A novel plastidial homodimeric insect-plant geranyl pyrophosphate synthase gene is synthesized from three different cDNA origins. Its overexpression in Camelina sativa effectively alters plant development and terpenoid metabolism. Geranyl pyrophosphate synthase (GPPS) converts one isopentenyl pyrophosphate and dimethylallyl pyrophosphate to GPP. Here, we report a synthetic insect-plant GPPS gene and effects of its overexpression on plant growth and terpenoid metabolism of Camelina sativa. We synthesized a 1353-bp cDNA, namely PTP-MpGPPS. This synthetic cDNA was composed of a 1086-bp cDNA fragment encoding a small GPPS isomer of the aphid Myzus persicae (Mp), 240-bp Arabidopsis thaliana cDNA fragment encoding a plastidial transit peptide (PTP), and a 27-bp short cDNA fragment encoding a human influenza hemagglutinin tag peptide. Structural modeling showed that the deduced protein was a homodimeric prenyltransferase. Confocal microscopy analysis demonstrated that the PTP-MpGPPS fused with green florescent protein was localized in the plastids. The synthetic PTP-MpGPPS cDNA driven by 2 × 35S promoters was introduced into Camelina (Camelina sativa) by Agrobacterium-mediated transformation and its overexpression in transgenic plants were demonstrated by western blot. T2 and T3 progeny of transgenic plants developed larger leaves, grew more and longer internodes, and flowered earlier than wild-type plants. Metabolic analysis showed that the levels of beta-amyrin and campesterol were higher in tissues of transgenic plants than in those of wild-type plants. Fast isoprene sensor analysis demonstrated that transgenic Camelina plants emitted significantly less isoprene than wild-type plants. In addition, transcriptional analyses revealed that the expression levels of gibberellic acid and brassinosteroids-responsive genes were higher in transgenic plants than in wild-type plants. Taken together, these data demonstrated that this novel synthetic insect-plant GPPS cDNA was effective to improve growth traits and alter terpenoid metabolism of Camelina.

Cerium Oxide Nanoparticles and Bulk Cerium Oxide Leading to Different Physiological and Biochemical Responses in Brassica rapa.

Cerium oxide nanoparticles (CeO2NPs) have been incorporated into many commercial products, and their potential release into the environment through the use and disposal of these products has caused serious concerns. Despite the previous efforts and rapid progress on elucidating the environmental impact of CeO2NPs, the long-term impact of CeO2NPs to plants, a key component of the ecosystem, is still not well understood. The potentially different impact of CeO2NPs and their bulk counterparts to plants is also unclear. The main objectives of this study were (1) to investigate whether continued irrigation with solutions containing different concentrations of CeO2NPs (0, 10, and 100 mg/L) would induce physiological and biochemical adjustments in Brassica rapa in soil growing conditions and (2) to determine whether CeO2NPs and bulk CeO2 particles exert different impacts on plants. The results indicated that bulk CeO2 at 10 and 100 mg/L enhanced plant biomass by 28% and 35%, respectively, while CeO2NPs at equivalent concentrations did not. While the bulk CeO2 treatment resulted in significantly higher concentrations of hydrogen peroxide (H2O2) in plant tissues at the vegetative stage, CeO2NPs led to significantly higher H2O2 levels in plant tissues at the floral stage. The activity of superoxide dismutase (SOD) in Brassica rapa also displayed a growth-stage dependent response to different sizes of CeO2 while catalase (CAT) activity was not affected by either size of CeO2 throughout the life cycle of Brassica rapa. Altogether, the results demonstrated that plant responses to CeO2 exposure varied with the particle sizes and the growth stages of plants.

WebBioBank: a new platform for integrating clinical forms and shared neurosignal analyses to support multi-centre studies in Parkinson's Disease.

BACKGROUND: The web-based systems available for multi-centre clinical trials do not combine clinical data collection (Electronic Health Records, EHRs) with signal processing storage and analysis tools. However, in pathophysiological research, the correlation between clinical data and signals is crucial for uncovering the underlying neurophysiological mechanisms. A specific example is the investigation of the mechanisms of action for Deep Brain Stimulation (DBS) used for Parkinson's Disease (PD); the neurosignals recorded from the DBS target structure and clinical data must be investigated. OBJECTIVE: The aim of this study is the development and testing of a new system dedicated to a multi-centre study of Parkinson's Disease that integrates biosignal analysis tools and data collection in a shared and secure environment. METHODS: We designed a web-based platform (WebBioBank) for managing the clinical data and biosignals of PD patients treated with DBS in different clinical research centres. Homogeneous data collection was ensured in the different centres (Operative Units, OUs). The anonymity of the data was preserved using unique identifiers associated with patients (ID BAC). The patients' personal details and their equivalent ID BACs were archived inside the corresponding OU and were not uploaded on the web-based platform; data sharing occurred using the ID BACs. The system allowed researchers to upload different signal processing functions (in a .dll extension) onto the web-based platform and to combine them to define dedicated algorithms. RESULTS: Four clinical research centres used WebBioBank for 1year. The clinical data from 58 patients treated using DBS were managed, and 186 biosignals were uploaded and classified into 4 categories based on the treatment (pharmacological and/or electrical). The user's satisfaction mean score exceeded the satisfaction threshold. CONCLUSIONS: WebBioBank enabled anonymous data sharing for a clinical study conducted at multiple centres and demonstrated the capabilities of the signal processing chain configuration as well as its effectiveness and efficiency for integrating the neurophysiological results with clinical data in multi-centre studies, which will allow the future collection of homogeneous data in large cohorts of patients.