Search

Summary: URBAN is a multicentric, ambispective study evaluating the effectiveness and safety of obinutuzumab‐based immuno‐chemotherapy and maintenance in patients with untreated advanced follicular lymphoma (FL). The study began before the COVID‐19 emergency declaration in Italy. It is currently ongoing for follow‐up, and the enrolment timeline encompassed different stages of the pandemic, various vaccination roll‐out phases and prevalence of SARS‐CoV‐2 variants. Outcomes of interest of the present sub‐analysis included SARS‐CoV‐2 infection rates and COVID‐19‐related hospitalizations/deaths. At data cut‐off, 86 (28.8%) and 213 patients (71.2%) were treated before and during/after the COVID‐19 outbreak respectively; 294 (98.3%) completed the induction, 31 (10.4%) completed maintenance and 170 (56.9%) were still on maintenance. Overall, 245 patients (81.9%) received at least one SARS‐CoV‐2 vaccine dose: 13.5%, 31.4% and 55.1% received one, two and three doses respectively. We observed a substantial decrease in COVID‐19‐related mortality rates in pre‐ versus post‐vaccination phases, along with a reduction in COVID‐19‐related outcomes due to the shift from alpha/delta to omicron variant predominance. No differences emerged between patients given maintenance or not, although the schedule was modified in 65% of cases. To our knowledge, URBAN represents the largest dataset of COVID‐19‐related outcomes in FL patients extensively exposed to obinutuzumab. ClinicalTrials.gov identifier: NCT04034056. [ABSTRACT FROM AUTHOR]

This report highlights a science outreach effort for prisons launched by the Spanish National Research Council (CSIC) in collaboration with the NGO Solidarios para el Desarrollo. The Microbiology‐focused part of the initiative aims at educating inmates on some basic facts, in order to raise awareness about microorganisms and their impact on daily life. The outline of the talks, inspired by the International Initiative for Microbial Literacy, aims to encourage this collective to move from passive listeners into active participants, helping them understand that Earth is a microbial planet, and that their bodies harbour vast microbiomes that affect their health and social interactions. The talks introduce Microbiology using simple metaphors and emphasize the role of beneficial microorganisms. By explaining the power of microscopes, inmates are shown the hidden microbial world that surrounds them, sparking interest and curiosity. The talks also cover microbial biotechnology, using examples such as bioplastics, anti‐cavity bacteria, and skin microorganisms designed for acne prevention. Overall, this outreach initiative seeks to provide inmates with valuable scientific knowledge, fostering curiosity and critical thinking. Despite the challenges of delivering such content in a prison setting, the initiative demonstrates that even marginalized groups can benefit from microbiological literacy, helping them to both endure their terms and eventually reintegrate into society. [ABSTRACT FROM AUTHOR]

Background and purpose: Quantitative muscle magnetic resonance imaging (MRI) is a promising non‐invasive method in the diagnostic workup as well as follow‐up of neuromuscular disorders. The aim of this study was to correlate quantitative MRI (qMRI) parameters to histopathological changes in skeletal muscle tissue and thus to verify the data from our pilot study. Methods: Twenty‐six patients (eight females, 46.4 ± 15.1 years) were examined within 72 h before and within 24 h after a skeletal muscle biopsy using quantitative muscle MRI. Post‐biopsy MRI was employed to pinpoint the exact localization of the biopsy. qMRI parameters including fat fraction, water T2 relaxation time and diffusion metrics including fractional anisotropy, mean diffusivity, axial diffusivity and radial diffusivity were extracted from the localization of the biopsy and correlated with histopathological findings. Additionally, three different segmentation masks were applied to the qMRI dataset, to evaluate whether the whole muscle represents the exact biopsy location. Results: Fat fraction and water T2 relaxation time in qMRI correlated significantly with the fat fraction in the muscle biopsy and histopathological inflammatory markers. Fractional anisotropy correlated with the quantity of type 2 fibres, whilst mean diffusivity correlated with p62. No differences were found using different segmentation masks in qMRI. Conclusions: In this follow‐up study, the results from our previous study were verified regarding the correlation of qMRI parameters with histopathological features in muscle biopsies, indicating that qMRI serves as a suitable non‐invasive method in the follow‐up of patients with neuromuscular disorders. If post‐biopsy MRI is not available, whole muscle volume can be used for histopathological correlations. [ABSTRACT FROM AUTHOR]

The canonical arsRBC genes of the ars1 operon in Pseudomonas putida KT2440, which confer tolerance to arsenate and arsenite, are followed by a series of additional ORFs culminating in phoN1. The phoN1 gene encodes an acetyltransferase that imparts resistance to the glutamine synthetase inhibitor herbicide phosphinothricin (PPT). The co‐expression of phoN1 and ars genes in response to environmental arsenic, along with the physiological effects, was analysed through transcriptomics of cells exposed to the oxyanion and phenotypic characterization of P. putida strains deficient in different components of the bifan motif governing arsenic resistance in this bacterium. Genetic separation of arsRBC and phoN1 revealed that their associated phenotypes operate independently, indicating that their natural co‐regulation is not functionally required for simultaneous response to the same signal. The data suggest a scenario of associative evolution, akin to Pavlovian conditioning, where two unrelated but frequently co‐occurring signals result in one regulating the other's response – even if there is no functional link between the signal and the response. Such surrogate regulatory events may provide an efficient solution to complex regulatory challenges and serve as a genetic patch to address transient gaps in evolving regulatory networks. [ABSTRACT FROM AUTHOR]

Quantitative muscle magnetic resonance imaging (qMRI) is a valuable methodology for assessing muscular injuries and neuromuscular disorders. Notably, muscle diffusion tensor imaging (DTI) gives insights into muscle microstructural and macrostructural characteristics. However, the long‐term reproducibility and robustness of these measurements remain relatively unexplored. The purpose of this prospective longitudinal cohort study was to assess the long‐term robustness and range of variation of qMRI parameters, especially DTI metrics, in the lower extremity muscles of healthy controls under real‐life conditions. Twelve volunteers (seven females, age 44.1 ± 12.1 years, body mass index 23.3 ± 2.0 kg/m2) underwent five leg muscle MRI sessions every 20 ± 4 weeks over a total period of 1.5 years. A multiecho gradient‐echo Dixon‐based sequence, a multiecho spin‐echo T2‐mapping sequence, and a spin‐echo echo planar imaging diffusion‐weighted sequence were acquired bilaterally with a Philips 3‐T Achieva MR System using a 16‐channel torso coil. Fifteen leg muscles were segmented in both lower extremities. qMRI parameters, including fat fraction (FF), water T2 relaxation time, and the diffusion metrics fractional anisotropy (FA) and mean diffusivity (MD), were evaluated. Coefficients of variance (wsCV) and intraclass correlation coefficients (ICCs) were calculated to assess the reproducibility of qMRI parameters. The standard error of measurement (SEM) and the minimal detectable change (MDC) were calculated to determine the range of variation. All tests were applied to all muscles and, subsequently, to each muscle separately. wsCV showed good reproducibility (≤ 10%) for all qMRI parameters in all muscles. The ICCs revealed excellent agreement between time points (FF = 0.980, water T2 = 0.941, FA = 0.952, MD = 0.948). Random measurement errors assessed by SEM and the MDC were low (< 12%). In conclusion, in this study, we showed that qMRI parameters in healthy volunteers living normal lives are stable over 18 months, thereby defining a benchmark for the expected range of variation over time. [ABSTRACT FROM AUTHOR]

Limb‐girdle muscular dystrophy (LGMD) type R1 (LGMDR1) is the most common subtype of LGMD in Europe. Prospective longitudinal data, including clinical assessments and new biomarkers such as quantitative magnetic resonance imaging (qMRI), are needed to evaluate the natural course of the disease and therapeutic options. We evaluated eight thigh and seven leg muscles of 13 LGMDR1 patients (seven females, mean age 36.7 years, body mass index 23.9 kg/m2) and 13 healthy age‐ and gender‐matched controls in a prospective longitudinal design over 1 year. Clinical assessment included testing for muscle strength with quick motor function measure (QMFM), gait analysis and patient questionnaires (neuromuscular symptom score, activity limitation [ACTIVLIM]). MRI scans were performed on a 3‐T MRI scanner, including a Dixon‐based sequence, T2 mapping and diffusion tensor imaging. The qMRI values of fat fraction (FF), water T2 relaxation time (T2), fractional anisotropy, mean diffusivity, axial diffusivity and radial diffusivity were analysed. Within the clinical outcome measures, significant deterioration between baseline and follow‐up was found for ACTIVLIM (p = 0.029), QMFM (p = 0.012). Analysis of qMRI parameters of the patient group revealed differences between time points for both FF and T2 when analysing all muscles (FF: p < 0.001; T2: p = 0.016). The highest increase of fat replacement was found in muscles with an FF of between 10% and 50% at baseline. T2 in muscles with low‐fat replacement increased significantly. No significant differences were found for the diffusion metrics. Significant correlations between qMRI metrics and clinical assessments were found at baseline and follow‐up, while only T2 changes in thigh muscles correlated with changes in ACTIVLIM over time (ρ = −0.621, p < 0.05). Clinical assessments can show deterioration of the general condition of LGMDR1 patients. qMRI measures can give additional information about underlying pathophysiology. Further research is needed to establish qMRI outcome measures for clinical trials. [ABSTRACT FROM AUTHOR]

The article discusses the outcomes of infants with very late relapse of acute lymphoblastic leukaemia initially treated in Interfant-06. It highlights the characteristics and outcomes of six children who experienced a very late relapse of infant ALL, providing detailed information on their initial diagnosis, relapse, treatment, and follow-up. The study shows that all patients achieved a second complete remission after a lymphoid-style salvage regimen, with five patients receiving allogeneic hematopoietic stem cell transplantation and experiencing promising long-term results. The findings suggest that infants with very late relapses may have a more favorable outcome compared to those who relapse within the first year after diagnosis, emphasizing the importance of effective first-line therapies in reducing relapse rates. [Extracted from the article]

Advances in the understanding of cytokines have revolutionized mechanistic treatments for chronic inflammatory and autoimmune diseases, as exemplified by rheumatoid arthritis. We conducted a systematic literature review on the role of cytokines and chemokines in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN). Ovid Medline, EMBASE and Web of Science were searched until August 31, 2022 for human studies investigating cytokines levels in CIDP or MMN. Fifty‐five articles on 1061 CIDP patients and 86 MMN patients were included, with a median of 18 patients per study (range 3–71). Studies differed in the inclusion criteria, type of assay, manufacturer, control subjects, and tested biological material. Only a minority of studies reported data on disease activity. Interleukin (IL)‐6, IL‐17, CXCL10, and tumor necrosis factor alpha (TNF‐α), were elevated in CIDP compared to controls in most of the studies. IL‐6 and TNF‐α levels are also correlated with disability. In MMN patients, IL‐1Ra was elevated in the majority of the reports. While acknowledging the challenges in comparing studies and the various limitations of the studies, including small patient numbers, particularly in MMN, our review suggests that IL‐6, IL‐17, CXCL10, and TNF‐α might play a role in CIDP pathogenesis. Larger studies are needed in MMN. [ABSTRACT FROM AUTHOR]

Background and purpose: There are different criteria for the diagnosis of different variants of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). The 2021 European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) guidelines provide specific clinical criteria for each CIDP variant even if their therapeutical impact has not been investigated. Methods: We applied the clinical criteria for CIDP variants of the 2021 EAN/PNS guidelines to 369 patients included in the Italian CIDP database who fulfilled the 2021 EAN/PNS electrodiagnostic criteria for CIDP. Results: According to the 2021 EAN/PNS clinical criteria, 245 patients achieved a clinical diagnosis of typical CIDP or CIDP variant (66%). We identified 106 patients with typical CIDP (29%), 62 distal CIDP (17%), 28 multifocal or focal CIDP (7%), four sensory CIDP (1%), 27 sensory‐predominant CIDP (7%), 10 motor CIDP (3%), and eight motor‐predominant CIDP (2%). Patients with multifocal, distal, and sensory CIDP had milder impairment and symptoms. Patients with multifocal CIDP had less frequently reduced conduction velocity and prolonged F‐wave latency and had lower levels of cerebrospinal fluid protein. Patients with distal CIDP more frequently had reduced distal compound muscle action potentials. Patients with motor CIDP did not improve after steroid therapy, whereas those with motor‐predominant CIDP did. None of the patients with sensory CIDP responded to steroids, whereas most of those with sensory‐predominant CIDP did. Conclusions: The 2021 EAN/PNS criteria for CIDP allow a better characterization of CIDP variants, permitting their distinction from typical CIDP and more appropriate treatment for patients. [ABSTRACT FROM AUTHOR]

Analyses of inequalities related to prevention and cancer therapeutics/care show disparities between countries with different economic standing, and within countries with high Gross Domestic Product. The development of basic technological and biological research provides clinical and prevention opportunities that make their implementation into healthcare systems more complex, mainly due to the growth of Personalized/Precision Cancer Medicine (PCM). Initiatives like the USA‐Cancer Moonshot and the EU‐Mission on Cancer and Europe's Beating Cancer Plan are initiated to boost cancer prevention and therapeutics/care innovation and to mitigate present inequalities. The conference organized by the Pontifical Academy of Sciences in collaboration with the European Academy of Cancer Sciences discussed the inequality problem, dependent on the economic status of a country, the increasing demands for infrastructure supportive of innovative research and its implementation in healthcare and prevention programs. Establishing translational research defined as a coherent cancer research continuum is still a challenge. Research has to cover the entire continuum from basic to outcomes research for clinical and prevention modalities. Comprehensive Cancer Centres (CCCs) are of critical importance for integrating research innovations to preclinical and clinical research, as for ensuring state‐of‐the‐art patient care within healthcare systems. International collaborative networks between CCCs are necessary to reach the critical mass of infrastructures and patients for PCM research, and for introducing prevention modalities and new treatments effectively. Outcomes and health economics research are required to assess the cost‐effectiveness of new interventions, currently a missing element in the research portfolio. Data sharing and critical mass are essential for innovative research to develop PCM. Despite advances in cancer research, cancer incidence and prevalence is growing. Making cancer research infrastructures accessible for all patients, considering the increasing inequalities, requires science policy actions incentivizing research aimed at prevention and cancer therapeutics/care with an increased focus on patients' needs and cost‐effective healthcare. [ABSTRACT FROM AUTHOR]

Colony formation is key to many ecological and biotechnological processes. In its early stages, colony formation involves the concourse of a number of physical and biological parameters for generation of a distinct 3D structure—the specific influence of which remains unclear. We focused on a thus far neglected aspect of the process, specifically the consequences of the differential pressure experienced by cells in the middle of a colony versus that endured by bacteria located in the growing periphery. This feature was characterized experimentally in the soil bacterium Pseudomonas putida. Using an agent‐based model we recreated the growth of microcolonies in a scenario in which pressure was the only parameter affecting proliferation of cells. Simulations exposed that, due to constant collisions with other growing bacteria, cells have virtually no free space to move sideways, thereby delaying growth and boosting chances of overlapping on top of each other. This scenario was tested experimentally on agar surfaces. Comparison between experiments and simulations suggested that the inside/outside differential pressure determines growth, both timewise and in terms of spatial directions, eventually moulding colony shape. We thus argue that—at least in the case studied—mere physical pressure of growing cells suffices to explain key dynamics of colony formation. [ABSTRACT FROM AUTHOR]

Background: Simplexvirus humanalpha1 (HuAHV‐1) are common anthropozoonosis reported in marmosets but rare in howler monkeys (Alouatta sp.). Methods: Necropsy of two brown‐howler monkeys (A. caraya) and one red‐howler monkey (A. guariba clamitans) from different zoo collections were performed. Fragments of all organs were examined through microscopy. Samples were submitted to IHC for Simplexvirus humanalpha 2 (HuAHV‐2) [sin. Herpesvirus simplex type 2] and PCR. Results: Grossly, only the A. guariba showed liver lesions characterized by multifocal, pinpoint white areas corresponding microscopically as random necrotizing herpetic hepatitis and ulcerative glossitis. Both A. caraya showed necrotizing meningoencephalitis with Cowdry A‐type body inclusions within neurons and astrocytes. Immunolabeling for HuAHV‐1/2 was observed in the tongue, liver, and brain. HuAHV‐1 was confirmed in all samples by PCR, Sanger sequencing, and phylogenetic analyses. Conclusion: Necrotizing meningoencephalitis was appreciated in 2/3 of animals, and it is associated with neurologic signs. Along with ulcerative glossitis, a hallmark lesion in marmosets, it was present in one animal. Regarding herpetic hepatitis, it is not frequent in monkeys and occurs mainly in immunocompromised animals. HuAHV‐1 infection was confirmed corroborating with a human source. This is the second report on captive black‐howler monkeys and the first gross, histologic, immunohistochemical, and molecular description of herpetic hepatitis and ulcerative glossitis in red‐howler monkeys (A. guariba). [ABSTRACT FROM AUTHOR]

European cancer research stakeholders met in October 2022 in Heidelberg, Germany, at the 5th Gago conference on European Cancer Policy, to discuss the current cancer research and cancer care policy landscape in Europe. Meeting participants highlighted gaps in the existing European programmes focusing on cancer research, including Europe's Beating Cancer Plan (EBCP), the Mission on Cancer (MoC), Understanding Cancer (UNCAN.eu), and the joint action CRANE, and put forward the next priorities, in the form of the Heidelberg Manifesto for cancer research. This meeting report presents all discussions that shed light on how infrastructures can be effectively shaped for translational, prevention, clinical and outcomes cancer research, with a focus on implementation and sustainability and while engaging patients and the public. In addition, we summarize recommendations on how to introduce frameworks for the digitalization of European cancer research. Finally, we discuss what structures, commitment, and resources are needed to establish a collaborative cancer research environment in Europe to achieve the scale required for innovation. [ABSTRACT FROM AUTHOR]

The biodegradative capacity of bacteria in their natural habitats is affected by water availability. In this work, we have examined the activity and effector specificity of the transcriptional regulator XylR of the TOL plasmid pWW0 of Pseudomonas putida mt‐2 for biodegradation of m‐xylene when external water potential was manipulated with polyethylene glycol PEG8000. By using non‐disruptive luxCDEAB reporter technology, we noticed that the promoter activated by XylR (Pu) restricted its activity and the regulator became more effector‐specific towards head TOL substrates when cells were grown under water subsaturation. Such a tight specificity brought about by water limitation was relaxed when intracellular osmotic stress was counteracted by the external addition of the compatible solute glycine betaine. With these facts in hand, XylR variants isolated earlier as effector‐specificity responders to the non‐substrate 1,2,4‐trichlorobenzene under high matric stress were re‐examined and found to be unaffected by water potential in vivo. All these phenomena could be ultimately explained as the result of water potential‐dependent conformational changes in the A domain of XylR and its effector‐binding pocket, as suggested by AlphaFold prediction of protein structures. The consequences of this scenario for the evolution of specificities in regulators and the emergence of catabolic pathways are discussed. [ABSTRACT FROM AUTHOR]

Background: Tauopathies that include e.g. frontotemporal dementia and Alzheimer's disease, are neurodegenerative diseases characterized by accumulation of hyperphosphorylated Tau in the brain. Tau is a tempting drug target for tauopathies but no Tau‐targeting therapies are in clinical use. We have recently shown that small‐molecular inhibitors of prolyl oligopeptidase (PREP) can activate protein phosphatase 2A (PP2A) by regulating PREP‐PP2A interaction. PP2A is the main phosphatase regulating Tau, and therefore, we decided to test the efficacy of a reference PREP inhibitor, KYP‐2047, and novel PREP ligands on cellular and animal models of tauopathies. Method: The compounds, KYP‐2047 and HUP‐46, 55 and 59 (1, 5 and 10 μM), were first screened in the GFP‐2N4R‐Tau transfected HEK‐293 cells where the Tau aggregation was induced by small‐dose okadaic acid (OA; 10 nM), a PP2A inhibitor. The results were verified by using 2N4R‐Tau transfected HEK‐293 cells with 10 nM OA. After the treatment the cells were fractioned to RIPA soluble and SDS‐fractions, and total Tau and S262 phosphorylated Tau (pS262 Tau) levels were studied by Western blot (WB). Finally, KYP‐2047 and HUP‐46 were tested in PS19 Tau transgenic mouse. PS19 mice were treated with the ligands for 4 weeks (10 mg/kg/day, Alzet minipump i.p.) starting from 5.5 months old when the behavioral deficits were observed. After the treatment, the mice behavior was tested by Barnes Maze and locomotor activity assay, and total Tau, pS262 Tau and PP2A levels were studied. Result: In the GFP‐Tau aggregation assay, all compounds decreased the GFP signal as an indicative of Tau aggregation with 10 mM concentration but HUP‐46 was the most effective (Fig. 1). WB that showed that PREP ligands had the most significant effect on total Tau and pS262 Tau in the SDS‐fraction. In the PS19 mice, KYP‐2047 restored normal behavior in Barnes maze and locomotor activity assay. HUP‐46 had similar effect but did not reach significance (Fig. 2). However, both compounds reduced significantly total Tau and pS262 Tau levels in mouse hippocampus and cortex, and activated PP2A (Fig. 3). Conclusion: Small‐molecular PREP ligands, such as KYP‐2047 and HUP‐46 have disease‐modifying effects on cellular and animal models of tauopathies. [ABSTRACT FROM AUTHOR]

That emergence of new functions depends on genetic drifts at the margins of an existing gene leaves empty an enormous DNA sequence space for creation of truly novel functions. One of the most conspicuous examples of evolution in action is the awesome spectacle of how environmental microorganisms manage to face and eventually metabolize xenobiotic compounds with synthetic chemical structures that have not been in the Biosphere before we release them - in many cases with bad long-term consequences. However, it is in fact perplexing that de novo gene birth (i.e., creation of new genes from otherwise non-coding DNA sequences) has hardly been investigated in bacteria: Virtually all studies on the issue have taken place in eukaryotic cells and animals (Ruiz-Orera et al., [22]). Prokaryotes are extraordinarily innovative to repurpose existing genes and DNA sequences upon genetic drift (see above). [Extracted from the article]

Summary: The ability of T7 RNA polymerase (RNAPT7) fusions to cytosine deaminases (CdA) for entering C➔T changes in any DNA segment downstream of a T7 promoter was exploited for hyperdiversification of defined genomic portions of Pseudomonas putida KT2440. To this end, test strains were constructed in which the chromosomally encoded pyrF gene (the prokaryotic homologue of yeast URA3) was flanked by T7 transcription initiation and termination signals and also carried plasmids expressing constitutively either high‐activity (lamprey's) or low‐activity (rat's) CdA‐RNAPT7 fusions. The DNA segment‐specific mutagenic action of these fusions was then tested in strains lacking or not uracil‐DNA glycosylase (UDG), that is ∆ung/ung+ variants. The resulting diversification was measured by counting single nucleotide changes in clones resistant to 5‐fluoroorotic acid (5FOA), which otherwise is transformed by wild‐type PyrF into a toxic compound. Although the absence of UDG dramatically increased mutagenic rates with both CdA‐RNAPT7 fusions, the most active variant – pmCDA1 – caused extensive appearance of 5FOA‐resistant colonies in the wild‐type strain not limited to C➔T but including also a range of other changes. Furthermore, the presence/absence of UDG activity swapped cytosine deamination preference between DNA strands. These qualities provided the basis of a robust system for continuous evolution of preset genomic portions of P. putida and beyond. [ABSTRACT FROM AUTHOR]

Summary: The potential of LacI/Ptrc, XylS/Pm, AlkS/PalkB, CprK/PDB3 and ChnR/PchnB regulatory nodes, recruited from both Gram‐negative and Gram‐positive bacteria, as the source of parts for formatting expression cargoes following the Standard European Vector Architecture (SEVA) has been examined. The five expression devices, which cover most known regulatory configurations in bacteria were assembled within exactly the same plasmid backbone and bearing the different functional segments arrayed in an invariable DNA scaffold. Their performance was then analysed in an Escherichia coli strain of reference through the readout of a fluorescence reporter gene that contained strictly identical translation signal elements. This approach allowed us to describe and compare the cognate expression systems with quantitative detail. The constructs under scrutiny diverged considerably in their capacity, expression noise, inducibility and ON/OFF ratios. Inspection of such a variance exposed the different constraints that rule the optimal arrangement of functional DNA segments in each case. The data highlighted also the ease of standardizing inducer‐responsive devices subject to transcriptional activation as compared to counterparts based on repressors. The study resulted in a defined collection of formatted expression cargoes lacking any cross talk while offering a panoply of choices to potential users and help interoperability of the specific constructs. [ABSTRACT FROM AUTHOR]

B Methods: b This open-label, phase 3 trial, with blinded centralized PET assessment, accrued untreated pts aged 18-60 with advanced-stage HL (IIB extranodal and/or bulky, III, IV) at 46 FIL Centers. B Introduction: b PET-adapted ABVD with deferred intensification is the favored therapy for most patients with advanced Hodgkin Lymphoma (HL), while upfront intensification ("first hit") with escBEACOPP remains an option in the high-risk disease. FRONTLINE INTENSIFIED ABVD DEMONSTRATES SUPERIOR EFFICACY THAN PET-ADAPTED ABVD IN ADVANCED HODGKIN LYMPHOMA: THE FIL-ROUGE PHASE 3 TRIAL BY THE FONDAZIONE ITALIANA LINFOMI. [Extracted from the article]

Background: The 2018 Lipids in Parenteral Nutrition summit involved a panel of experts in clinical nutrition, lipid metabolism, and pharmacology, to assess the current state of knowledge and develop expert consensus statements regarding the use of intravenous lipid emulsions in various patient populations and clinical settings. The main purpose of the consensus statements is to assist healthcare professionals by providing practical guidance on common clinical questions related to the provision of lipid emulsions as part of parenteral nutrition (PN).Methods: The summit was designed to allow interactive discussion and consensus development. The resulting consensus statements represent the collective opinion of the members of the expert panel, which was informed and supported by scientific evidence and clinical experience.Results: The current article summarizes the key discussion topics from the summit and provides a set of consensus statements designed to complement existing evidence-based guidelines. Lipid emulsions are a major component of PN, serving as a condensed source of energy and essential fatty acids. In addition, lipids modulate a variety of biologic functions, including inflammatory and immune responses, coagulation, and cell signaling. A growing body of evidence suggests that lipid emulsions containing ω-3 fatty acids from fish oil confer important clinical benefits via suppression of inflammatory mediators and activation of pathways involved in the resolution of inflammation.Conclusions: This article provides a set of expert consensus statements to complement formal PN guideline recommendations. [ABSTRACT FROM AUTHOR]

In hospitalized patients, lipid emulsions are an integral part of balanced parenteral nutrition. Traditionally, a single lipid source, soybean oil, has been given to patients and was usually regarded as just a source of energy and to prevent essential fatty-acid deficiency. However, mixtures of different lipid emulsions have now become widely available, including mixtures of soybean oil, medium-chain triglycerides, olive oil, and fish oil. Fish oil is high in the ω-3 polyunsaturated fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). There is a growing body of evidence that these ω-3 fatty acids can exert beneficial immunomodulatory, anti-inflammatory, and inflammation-resolution effects across a wide range of patient groups including surgical, cancer, and critically ill patients. At least in part, these effects are realized via potent specialized pro-resolution mediators (SPMs). Moreover, parenteral nutrition including ω-3 fatty acids can result in additional clinical benefits over the use of standard lipid emulsions, such as reductions in infection rates and length of hospital and intensive care unit stay. Clinical and experimental evidence is reviewed regarding lipid emulsion use in a variety of hospitalized patient groups, including surgical, critically ill, sepsis, trauma, and acute pancreatitis patients. Practical aspects of lipid emulsion use in critically ill patients are also considered, such as how to determine and fulfill energy expenditure, how and when to consider parenteral nutrition, duration of infusion, and safety monitoring. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to test whether a newly designed polypharmacy‐based scale would perform better than Charlson's Comorbidity Index (CCI) to predict outcomes in chronic complex adult patients after a reference Emergency Department (ED) visit. Methods: We built a polypharmacy‐based scale with prespecified drug families. The primary outcome was 6‐month mortality after the reference ED visit. Predefined secondary outcomes were need for hospital admission, 30‐day readmission, and 30‐day and 90‐day mortality. We evaluated the ability of the CCI and the polypharmacy‐based scale to independently predict 6‐month mortality using logistic regression, receiver operating characteristic (ROC) curves, and cumulative survival curves using Kaplan–Meier estimates and the log‐rank test for three‐category distributions of the polypharmacy‐based scale and the CCI. Finally, we sought to replicate our results in two different external validation cohorts. Results: We included 201 patients (53.7% women, mean age = 81.4 years), 162 of whom were admitted to the hospital at the reference ED visit. In separate multivariable analyses accounting for gender, age and main diagnosis at discharge, both the polypharmacy‐based scale (P <.001) and the CCI (P =.005) independently predicted 6‐month mortality. The polypharmacy‐based scale performed better in the ROC analyses (area under the curve [AUC] = 0.838, 95% confidence interval [CI] = 0.780–0.896) than the CCI (AUC = 0.628, 95% CI = 0.548–0.707). In the 6‐month cumulative survival analysis, the polypharmacy‐based scale showed statistical significance (P <.001), whereas the CCI did not (P =.484). We replicated our results in the validation cohorts. Conclusions: Our polypharmacy‐based scale performed significantly better than the CCI to predict 6‐month mortality in chronic complex patients after a reference ED visit. [ABSTRACT FROM AUTHOR]

Background: Anthropogenic disturbances are the main threats to nonhuman primates conservation, and infectious diseases may also play a key role in primate population decline. This study aimed to determine the main causes of death in neotropical primates. Methods: A retrospective study of post‐mortem examinations was conducted on 146 neotropical primates between January 2000 and December 2018. Results: Conclusive diagnoses were obtained in 68.5% of the cases, of which 59 corresponded to non‐infectious causes and 41 to infectious diseases. Trauma was the main cause of death (54/100), with anthropogenic stressors caused by blunt force trauma injuries (collision with vehicles) and puncture wound injuries associated with interspecific aggression (dog predation) were the most common factors. Other causes of death included bacterial diseases (27%), followed by parasitic diseases (12%), neoplasms (2%), and viral diseases (2%). Conclusions: Free‐ranging primates were mostly affected by non‐infectious causes, while captive primates were by infectious conditions. [ABSTRACT FROM AUTHOR]

Background: Coronavirus disease 2019 acute respiratory distress syndrome (COVID‐19 ARDS) is a disease that often requires invasive ventilation. Little is known about COVID‐19 ARDS sequelae. We assessed the mid‐term lung status of COVID‐19 survivors and investigated factors associated with pulmonary sequelae. Methods: All adult COVID‐19 patients admitted to the intensive care unit from 25th February to 27th April 2020 were included. Lung function was evaluated through chest CT scan and pulmonary function tests (PFT). Logistic regression was used to identify predictors of persisting lung alterations. Results: Forty‐nine patients (75%) completed lung assessment. Chest CT scan was performed after a median (interquartile range) time of 97 (89–105) days, whilst PFT after 142 (133–160) days. The median age was 58 (52–65) years and most patients were male (90%). The median duration of mechanical ventilation was 11 (6–16) days. Median tidal volume/ideal body weight (TV/IBW) was 6.8 (5.71–7.67) ml/Kg. 59% and 63% of patients showed radiological and functional lung sequelae, respectively. The diffusion capacity of carbon monoxide (DLCO) was reduced by 59%, with a median per cent of predicted DLCO of 72.1 (57.9–93.9) %. Mean TV/IBW during invasive ventilation emerged as an independent predictor of persistent CT scan abnormalities, whilst the duration of mechanical ventilation was an independent predictor of both CT and PFT abnormalities. The extension of lung involvement at hospital admission (evaluated through Radiographic Assessment of Lung Edema, RALE score) independently predicted the risk of persistent alterations in PFTs. Conclusions: Both the extent of lung parenchymal involvement and mechanical ventilation protocols predict morphological and functional lung abnormalities months after COVID‐19. [ABSTRACT FROM AUTHOR]

Background: Intrahepatic cholangiocarcinoma (iCCA) is the second most frequent liver cancer. The overall survival of iCCA and other biliary tract cancers (BTC) remains poor. Recently, the ABC‐06 trial reported the superiority of FOLFOX vs clinical observation as a second‐line treatment. Still, the survival benefit was less than expected. We hypothesized that the pattern of progression of iCCA can drive post‐progression survival (PPS), similar to hepatocellular carcinoma. Methods: Multicentre retrospective evaluation of consecutive iCCA patients who progressed after frontline systemic treatment with gemcitabine as monotherapy or in combination with platinum. Radiological assessment of progression was evaluated according to RECIST 1.1. The progression pattern was divided according to the presence/absence of new extrahepatic lesions (NEH). Results: We included 206 patients from 5 centres. The median OS was 14.1 months and its independent predictors (hazard ratio [HR], 95% confidence interval [CI]) were previous surgery 0.699 [0.509‐0.961], performance status >2.445 [1.788‐3.344], permanent first‐line discontinuation 16.072 [5.102‐50.633], registration of ascites 2.226 [1.448‐3.420] or bilirubin >3 mg/dl 3.004 [1.935‐4.664] during the follow‐up, and disease progression 2.523 [1.261‐5.050]. The appearance of NEH independently predicted OS 2.18 [1.55‐3.06] in patients with radiological progression. Amongst 138 patients eligible for second‐line treatment, PPS was 16.8 and 5.9 months in cases without and with NEH, respectively (P =.001). Progression owing to NEH lesions was an independent predictor of PPS 1.873 [1.333‐2.662], together with performance status, time to progression to the frontline treatment, bilirubin >3 mg/dl and ascites. Conclusions: PPS of iCCA is influenced by progression pattern, with important implications for second‐line trial design and analysis. [ABSTRACT FROM AUTHOR]

In Arabidopsis thaliana, perception of chitin from fungal cell walls is mediated by three LysM‐containing Receptor‐Like Kinases (LYKs): CERK1, which is absolutely required for chitin perception, and LYK4 and LYK5, which act redundantly. The role in plant innate immunity of a fourth LYK protein, LYK2, is currently not known. Here we show that CERK1, LYK2 and LYK5 are dispensable for basal susceptibility to B. cinerea but are necessary for chitin‐induced resistance to this pathogen. LYK2 is dispensable for chitin perception and early signalling events, though it contributes to callose deposition induced by this elicitor. Notably, LYK2 is also necessary for enhanced resistance to B. cinerea and Pseudomonas syringae induced by flagellin and for elicitor‐induced priming of defence gene expression during fungal infection. Consistently, overexpression of LYK2 enhances resistance to B. cinerea and P. syringae and results in increased expression of defence‐related genes during fungal infection. LYK2 appears to be required to establish a primed state in plants exposed to biotic elicitors, ensuring a robust resistance to subsequent pathogen infections. Arabidopsis thaliana LYK2 is not involved in the direct perception of chitin, but it is necessary for elicitor‐induced resistance to pathogens and priming of defence response. [ABSTRACT FROM AUTHOR]

Purpose: We examined the ability of the P(v‐a)CO2/Da‐vO2 ratio combined with elevated lactate levels to predict early allograft dysfunction (EAD). Materials and methods: Patients were classified into four groups according to lactate levels and P(v‐a)CO2/Da‐vO2 ratio: Group 1; lactate >2.0 mmol/L and P(v‐a)CO2/Da‐vO2 ratio >1.0; Group 2; lactate >2.0 mmol/L and P(v‐a)CO2/Da‐vO2 ratio <1.0; group 3; lactate<2.0 mmol/L and P(v‐a)CO2/Da‐vO2 ratio >1.0; group 4; lactate<2.0 mmol/L and P(v‐a)CO2/Da‐vO2 ratio <1.0. We defined EAD according to Olthoff criteria. Results: One‐hundred and fifty patients were included. EAD occurred in 41 patients (27.3%), and was associated with worse graft survival at 1 year (92% vs. 73%; P = ,003) as well as a higher re‐transplantation rate (4,6% vs. 17,1%; P = ,019). The multivariate analysis revealed that P(v‐a)CO2/Da‐vO2 ratio at T6 [OR 7.05(CI95% 2.77–19.01, P<.001)] was an independent predictor for EAD. Belonging to group 1 at 6 h was associated with worse clinical outcomes but no association was found with 1‐year graft survival or 1‐year patient survival. Conclusions: In this single center, prospective, observational study in patients who received an OLT, we found that elevated lactate levels combined with a high Cv‐aCO2/Da‐vO2 after 6 h was associated with the development of EAD and worse clinical outcomes in the early postoperative period. [ABSTRACT FROM AUTHOR]

Summary: Adaptive laboratory evolution (ALE) is a general and effective strategy for optimizing the design of engineered genetic circuits and upgrading metabolic phenotypes. However, the specific characteristics of each microorganism typically ask for exclusive conditions that need to be adjusted to the biological chassis at stake. In this work, we have adopted a do‐it‐yourself (DIY) approach to implement a flexible and automated framework for performing ALE experiments with the environmental bacterium and metabolic engineering platform Pseudomonas putida. The setup includes a dual‐chamber semi‐continuous log‐phase bioreactor design combined with an anti‐biofilm layout to manage specific traits of this bacterium in long‐term cultivation experiments. As a way of validation, the prototype was instrumental for selecting fast‐growing variants of a P. putida strain engineered to metabolize D‐xylose as sole carbon and energy source after running an automated 42 days protocol of iterative regrowth. Several genomic changes were identified in the evolved population that pinpointed the role of RNA polymerase in controlling overall physiological conditions during metabolism of the new carbon source. [ABSTRACT FROM AUTHOR]

Background: COVID-19 long-term sequelae are ill-defined since only a few studies have explored the long-term consequences of this disease so far. Aims: To evaluate the 6-month respiratory outcome and exercise capacity of COVID-19 acute respiratory failure (ARF) patients treated with continuous positive airway pressure (CPAP) during the first wave of the ongoing COVID-19 pandemic. Methods: A retrospective observational study included COVID-19 patients with ARF. Interventions included CPAP during hospitalisation and 6-month follow up. Frailty assessment was carried out through frailty index (FI), pO2/FiO2 during hospitalisation and at follow up, respiratory parameters, 6-min walking test (6MWT) and the modified British Medical Research Council (mMRC) and Borg scale at follow up. Results: More than half of the patients had no dyspnoea according to the mMRC scale. Lower in-hospital pO2/FiO2 correlated with higher Borg scale levels after 6MWT (- 0.27; P 0.04) at the follow-up visit. FI was positively correlated with length of hospitalisation (- 0.3; P 0.03) and negatively with the 6MWT distance walked (- 0.36; P 0.004). Conclusions: Robust and frail patients with COVID-19 ARF treated with CPAP outside the intensive care unit setting had good respiratory parameters and exercise capacity at 6-month follow up, although more severe patients had slightly poorer respiratory performance compared with patients with higher PaO2/FiO2 and lower FI. [ABSTRACT FROM AUTHOR]

Early signalling events in response to elicitation include reversible protein phosphorylation and re‐localization of plasma membrane (PM) proteins. Oligogalacturonides (OGs) are a class of damage‐associated molecular patterns (DAMPs) that act as endogenous signals to activate the plant immune response. Previous data on early phosphoproteome changes in Arabidopsis thaliana upon OG perception uncovered the immune‐related phospho‐regulation of several membrane proteins, among which PCaP1, a PM‐anchored protein with actin filament–severing activity, was chosen for its potential involvement in OG‐ and flagellin‐triggered responses. Here, we demonstrate that PCaP1 is required for late, but not early, responses induced by OGs and flagellin. Moreover, pcap1 mutants, unlike the wild type, are impaired in the recovery of full responsiveness to a second treatment with OGs performed 24 h after the first one. Localization studies on PCaP1 upon OG treatment in plants expressing a functional PCaP1‐GFP fusion under the control of PCaP1 promoter revealed fluorescence on the PM, organized in densely packed punctate structures, previously reported as microdomains. Fluorescence was found to be associated also with endocytic vesicles, the number of which rapidly increased after OG treatment, suggesting both an endocytic turnover of PCaP1 for maintaining its homeostasis at the PM and an OG‐induced endocytosis. The A. thaliana plasma membrane (PM)‐anchored protein, PCaP1, is involved in elicitor‐induced protection against the necrotrophic fungus B. cinerea. (GFP)‐PCaP1 organization into PM microdomains and its oligogalacturonide‐induced endocytosis point to a role of PCaP1 and its turn‐over in the sensing/transduction response to elicitors. [ABSTRACT FROM AUTHOR]

Summary: The self‐sufficient cytochrome P450 RhF and its homologues belonging to the CYP116B subfamily have attracted considerable attention due to the potential for biotechnological applications based in their ability to catalyse an array of challenging oxidative reactions without requiring additional protein partners. In this work, we showed for the first time that a CYP116B self‐sufficient cytochrome P450 encoded by the ohpA gene harboured by Cupriavidus pinatubonensis JMP134, a β‐proteobacterium model for biodegradative pathways, catalyses the conversion of 2‐hydroxyphenylacetic acid (2‐HPA) into homogentisate. Mutational analysis and HPLC metabolite detection in strain JMP134 showed that 2‐HPA is degraded through the well‐known homogentisate pathway requiring a 2‐HPA 5‐hydroxylase activity provided by OhpA, which was additionally supported by heterologous expression and enzyme assays. The ohpA gene belongs to an operon including also ohpT, coding for a substrate‐binding subunit of a putative transporter, whose expression is driven by an inducible promoter responsive to 2‐HPA in presence of a predicted OhpR transcriptional regulator. OhpA homologues can be found in several genera belonging to Actinobacteria and α‐, β‐ and γ‐proteobacteria lineages indicating a widespread distribution of 2‐HPA catabolism via homogentisate route. These results provide first time evidence for the natural function of members of the CYP116B self‐sufficient oxygenases and represent a significant input to support novel kinetic and structural studies to develop cytochrome P450‐based biocatalytic processes. [ABSTRACT FROM AUTHOR]

Background: COVID‐19 disease can lead to severe functional impairments after discharge. We assessed the quality of life of invasively ventilated COVID‐19 ARDS survivors. Methods: We carried out a prospective follow‐up study of the patients admitted to the Intensive Care Units (ICUs) of a teaching hospital. Patients affected by COVID‐19 ARDS who required invasive ventilation and were successfully discharged home were assessed through the telephone administration of validated tests. We explored survival, functional outcomes, return to work, quality of life, cognitive and psychological sequelae. The main variables of interest were the following: demographics, severity scores, laboratory values, comorbidities, schooling, working status, treatments received during ICU stay, complications, and psychological, cognitive, functional outcomes. Results: Out of 116 consecutive invasively ventilated patients, overall survival was 65/116 (56%) with no death occurring after hospital discharge. Forty‐two patients were already discharged home with a median follow‐up time of 61 (51‐71) days after ICU discharge and 39 of them accepted to be interviewed. Only one patient (1/39) experienced cognitive decline. The vast majority of patients reported no difficulty in walking (32/35:82%), self‐care (33/39:85%), and usual activities (30/39:78%). All patients were either malnourished (15/39:38%) or at risk for malnutrition (24/39:62%). Exertional dyspnea was present in 20/39 (51%) patients. 19/39 (49%) reported alterations in senses of smell and/or taste either before or after hospitalization. Conclusions: Invasively ventilated COVID‐19 ARDS survivors have an overall good recovery at a 2‐months follow‐up which is better than what was previously reported in non‐COVID‐19 ARDS patients. [ABSTRACT FROM AUTHOR]

Summary: A revised model of the aromatic binding A domain of the σ54‐dependent regulator XylR of Pseudomonas putida mt‐2 was produced based on the known 3D structures of homologous regulators PoxR, MopR and DmpR. The resulting frame was instrumental for mapping a number of mutations known to alter effector specificity, which were then reinterpreted under a dependable spatial reference. Some of these changes involved the predicted aromatic binding pocket but others occurred in distant locations, including dimerization interfaces and putative zinc binding site. The effector pocket was buried within the protein structure and accessible from the outside only through a narrow tunnel. Yet, several loop regions of the A domain could provide the flexibility required for widening such a tunnel for passage of aromatic ligands. The model was experimentally validated by treating the cells in vivo and the purified protein in vitro with benzyl bromide, which reacts with accessible nucleophilic residues on the protein surface. Structural and proteomic analyses confirmed the predicted in/out distribution of residues but also supported two additional possible scenarios of interaction of the A domain with aromatic effectors: a dynamic interaction of the fully structured yet flexible protein with the aromatic partner and/or inducer‐assisted folding of the A domain. [ABSTRACT FROM AUTHOR]

We have reached a watershed moment in Europe in our efforts to ensure increased survival and better outcomes for cancer patients. The EU Cancer Mission and the European Beating Cancer Plan together provide an unrivalled opportunity to make significant inroads into a disease that kills over 1.7 million European citizens annually. Harnessing these twin pillars of cancer research and cancer control can be transformative for the European cancer community and in particular for the European cancer patient. However, from a research perspective, in order to fully realise these benefits, we need to ensure that all aspects of the cancer continuum are addressed. Previous research efforts have focussed more on the diagnosis and treatment of cancer, whereas cancer survivorship, to date, has been overlooked. Here, we aim to redress this balance, by identifying the key challenges in cancer survivorship research that need to be addressed and proposing a series of recommended solutions, which, if acted upon, would deliver significant benefits for the nearly 20 million cancer survivors in Europe. To achieve this, we propose the development of a clearly articulated and sustainably funded European Cancer Survivorship Research and Innovation Plan. Embedding this plan within the framework of the EU Cancer Mission would be transformative for cancer survivors and society. [ABSTRACT FROM AUTHOR]

Summary: Reliable biomarkers are needed to avoid diagnostic delay and its devastating effects in patients with primary central nervous system (CNS) lymphoma (PCNSL). We analysed the discriminating sensitivity and specificity of myeloid differentiation primary response (88) (MYD88) L265P mutation (mut‐MYD88) and interleukin‐10 (IL‐10) in cerebrospinal fluid (CSF) of both patients with newly diagnosed (n = 36) and relapsed (n = 27) PCNSL and 162 controls (118 CNS disorders and 44 extra‐CNS lymphomas). The concordance of MYD88 mutational status between tumour tissue and CSF sample and the source of ILs in PCNSL tissues were also investigated. Mut‐MYD88 was assessed by TaqMan‐based polymerase chain reaction. IL‐6 and IL‐10 messenger RNA (mRNA) was assessed on PCNSL biopsies using RNAscope technology. IL levels in CSF were assessed by enzyme‐linked immunosorbent assay. Mut‐MYD88 was detected in 15/17 (88%) PCNSL biopsies, with an 82% concordance in paired tissue‐CSF samples. IL‐10 mRNA was detected in lymphomatous B cells in most PCNSL; expression of IL‐6 transcripts was negligible. In CSF samples, mut‐MYD88 and high IL‐10 levels were detected, respectively, in 72% and 88% of patients with newly diagnosed PCNSL and in 1% of controls; conversely, IL‐6 showed a low discriminating sensitivity and specificity. Combined analysis of MYD88 and IL‐10 exhibits a sensitivity and specificity to distinguish PCNSL of 94% and 98% respectively. Similar figures were recorded in patients with relapsed PCNSL. In conclusion, high detection rates of mut‐MYD88 and IL‐10 in CSF reflect, respectively, the MYD88 mutational status and synthesis of this IL in PCNSL tissue. These biomarkers exhibit a very high sensitivity and specificity in detecting PCNSL both at initial diagnosis and relapse. Implications of these findings in patients with lesions unsuitable for biopsy deserve to be investigated. [ABSTRACT FROM AUTHOR]

Recognition at the plasma membrane of danger signals (elicitors) belonging to the classes of the microbe/pathogen‐ and damage‐associated molecular patterns is a key event in pathogen sensing by plants and is associated with a rapid activation of immune responses. Different cellular compartments, including plasma membrane, chloroplasts, nuclei and mitochondria, are involved in the immune cellular program. However, how pathogen sensing is transmitted throughout the cell remains largely to be uncovered. Arabidopsis NPK1‐related Proteins (ANPs) are mitogen‐activated protein kinase kinase kinases previously shown to have a role in immunity. In this article, we studied the in vivo intracellular dynamics of ANP1‐ and ANP3‐GFP fusions and found that under basal physiological conditions both proteins are present in the cytosol, while ANP3 is also localized in mitochondria. After elicitor perception, both proteins are present also in the plastids and nuclei, revealing a localization pattern that is so far unique. The N‐terminal region of the protein kinases is responsible for their localization in mitochondria and plastids. Moreover, we found that the localization of ANPs coincides with the sites of elicitor‐induced ROS accumulation and that plants lacking ANP function do not accumulate intracellular ROS. Upon danger sensing, the subcellular localization of the Arabidopsis NPK1‐related Protein kinases changes and coincides with sites of elicitor‐induced ROS accumulation, such as plastids and nuclei. anp mutants do not accumulate ROS in those organelles hinting that ANPs are required for this process. [ABSTRACT FROM AUTHOR]

Objective: This study compares microvascular reactivity (MR) in chronic Chagas disease (CD) patients with healthy individuals, matched for sex and age. In addition, we evaluated the association between MR and left ventricular ejection fraction (LVEF) in patients. Methods: Acetylcholine iontophoresis was performed on the forearm skin, using laser speckle contrast imaging, to evaluate endothelium‐dependent vasodilation. Clinical data were obtained from medical records. Results: Thirty‐six patients were compared to 25 healthy individuals (controls). Vasodilation was higher in controls, when compared to patients (p <.0001). There was a significant association between LVEF, stratified into quartiles, and MR (p‐value for linear trend =.002). In addition, there was no difference in MR between patients with normal LVEF and the control group. In patients, MR was independent of the presence of arterial hypertension or diabetes. Conclusions: We have shown for the first time that the reduction of MR is associated with a decrease of LVEF in a cohort of chronic CD patients. The results were not affected by comorbidities, such as hypertension or diabetes. The evaluation of systemic endothelial function may be useful to tailor therapeutic and preventive approaches, targeted at systolic left ventricular failure associated with chronic CD cardiomyopathy. [ABSTRACT FROM AUTHOR]

Oligogalacturonides (OGs) are fragments of pectin released from the plant cell wall during insect or pathogen attack. They can be perceived by the plant as damage signals, triggering local and systemic defence responses. Here, we analyse the dynamics of local and systemic responses to OG perception in tomato roots or shoots, exploring their impact across the plant and their relevance in pathogen resistance. Targeted and untargeted metabolomics and gene expression analysis in plants treated with purified OGs revealed that local responses were transient, while distal responses were stronger and more sustained. Remarkably, changes were more conspicuous in roots, even upon foliar application of the OGs. The treatments differentially activated the synthesis of defence‐related hormones and secondary metabolites including flavonoids, alkaloids and lignans, some of them exclusively synthetized in roots. Finally, the biological relevance of the systemic defence responses activated upon OG perception was confirmed, as the treatment induced systemic resistance to Botrytis cinerea. Overall, this study shows the differential regulation of tomato defences upon OGs perception in roots and shoots and reveals the key role of roots in the coordination of the plant responses to damage sensing. Oligogalacturonide perception in tomato roots or shoots triggers differential transient local responses, but also a myriad of systemic responses at the metabolic, transcriptomic and enzymatic level leading to pathogen resistance. The results highlight the key role of roots in the regulation of these systemic responses. [ABSTRACT FROM AUTHOR]

We report final results of a phase II trial addressing efficacy and feasibility of lenalidomide maintenance in patients with chemosensitive relapse of diffuse large B-cell lymphoma (DLBCL) not eligible for or failed after autologous stem cell transplantation (ASCT). Patients with relapsed DLBCL who achieved at least a partial response to salvage chemoimmunotherapy were enrolled and treated with lenalidomide 25 mg/day for 21 of 28 days for 2 years or until progression or unacceptable toxicity. Primary endpoint was 1-year PFS. Forty-six of 48 enrolled patients were assessable. Most patients had IPI ≥2, advanced stage and extranodal disease before the salvage treatment that led to trial registration; 28 (61%) patients were older than 70 years. Lenalidomide was well tolerated. With the exception of neutropenia, grade-4 toxicities occurred in <1% of courses. Three patients died of complications during maintenance and three died due to second cancers at 32 to 64 months. There were 13 SAEs recorded in 12 patients; all these patients but two recovered. Lenalidomide was interrupted due to toxicity in other 6 patients, and 25 patients required dose reduction (transient in 21). At 1 year from registration, 31 patients were progression free. After a median follow-up of 65 (range 39-124) months, 22 patients remain progression free, with a 5-year PFS of 48% ± 7%. The duration of response to lenalidomide was longer than response to prior treatment in 30 (65%) patients. Benefit was observed both in de novo and transformed DLBCL, germinal-center-B-cell and nongerminal-center-B-cell subtypes. Twenty-six patients are alive (5-year OS 62% ± 7%). With the limitations of a nonrandomized design, these long-term results suggest that lenalidomide maintenance might bring benefit to patients with chemosensitive relapse of DLBCL not eligible for or failed after ASCT. Lenalidomide was associated with durable disease control and was well tolerated in this elderly population. Further investigations on immunomodulatory drugs as maintenance in these high-risk patients are warranted. [ABSTRACT FROM AUTHOR]

Sex-specific differences have been definitively demonstrated in cardiovascular (CV) diseases. These differences can also impact on the effects of CV therapies. Female sex is recognized as an independent predictor of thromboembolic risk, particularly in older patients. Most of strokes are due to atrial fibrillation (AF). Women affected by AF have higher stroke risk compared to men. The introduction of novel oral anticoagulants (NOACs) for long-term anticoagulation completely changed the anticoagulant therapeutic approach and follow-up of patients affected by nonvalvular atrial fibrillation (NVAF). CHA2DS2-VASc stroke risk scoring in use in the current international guidelines attributes 1 point to "female sex". Besides, no anticoagulation is indicated for AF female patients without other risk factors. Interestingly, NOACs seem to normalize the differences between males and females both in terms of safety and efficacy, whereas residual higher stroke risk and systemic embolism persist in AF women treated with vitamin K antagonist anticoagulants VKA with optimal time in therapeutic range. Based on the CHA2DS2-VASc score, NOACs represent the preferred choice in NVAF patients. Moreover, complete evaluation of apparently lower risk factor along with concomitant clinical conditions in AF patients appears mandatory, particularly for female patients, in order to achieve the most appropriate anticoagulant treatment, either in male or in female patients. The present review was performed to review sex differences in AF-related thromboembolic risk reported in the literature and possibly highlight current knowledge gaps in prevention and management that need further research. [ABSTRACT FROM AUTHOR]

Serendipity cannot be planned but is favoured by researcher interactions. Inviting colleagues from other institutions to partake in seminars or consortial research meetings holds immense significance in the realms of information sharing, strategic research planning and, perhaps most importantly, in stimulating creativity through brainstorming and exploring the vast expanse of I idea space i . [Extracted from the article]

Background. Probiotic oral intake, via modulation of the microbiota-gut-brain axis, can impact brain activity, mood, and behavior; therefore, it may be beneficial against psychological distress and anxiety disorders. Inflammatory cytokines can influence the onset and progression of several neurodegenerative mood disorders, and the IL-1β rs16944 SNP is related to high cytokine levels and potentially affects mood disorders. The aim of this study was to examine the combined effect of IL-1β polymorphism and probiotic administration in mood disorder phenotypes in the Italian population. Methods. 150 subjects were randomized into two different groups, probiotic oral suspension group (POSG) and placebo control group (PCG), and received the relative treatment for 12 weeks. Psychological profile assessment by Hamilton Anxiety Rating Scale (HAM-A), Body Uneasiness Test (BUT), and Symptom Checklist 90-Revised (SCL90R) was administered to all volunteers. Genotyping was performed on DNA extracted from salivary samples. Results. After 12 weeks of intervention, a significant reduction of HAM-A total score was detected in the POSG (p < 0.01), compared to the PCG. Furthermore, IL-1β carriers have moderate risk to develop anxiety (OR = 5.90), and in POSG IL-1β carriers, we observed a reduction of HAM-A score (p = 0.02). Conclusions. Consumption of probiotics mitigates anxiety symptoms, especially in healthy adults with the minor A allele of rs16944 as a risk factor. Our results encourage the use of probiotics in anxiety disorders and suggest genetic association studies for psychobiotic-personalized therapy. [ABSTRACT FROM AUTHOR]

The affinity engineering is a key step to increase the efficacy of therapeutic monoclonal antibodies and yeast surface display is the most widely used and powerful affinity maturation approach, achieving picomolar binding affinities. In this study, we provide an optimization of the yeast surface display methodology, applied to the generation of potentially therapeutic high affinity antibodies targeting the immune checkpoint PD-L1. In this approach, we coupled a 10-cycle error-prone mutagenesis of heavy chain complementarity determining region 3 of an anti‐PD-L1 scFv, previously identified by phage display, with high-throughput sequencing, to generate scFv-yeast libraries with high mutant frequency and diversity. In addition, we set up a novel, faster and effective selection scheme by fluorescence-activated cell sorting, based on a fast drop of the antigen concentration between the first and the last selection cycles, unlike the gradual decrease typical of current selection protocols. In this way we isolated 6 enriched mutated scFv-yeast clones overall, showing an affinity improvement for soluble PD-L1 protein compared to the parental scFv. As a proof of the potency of the novel approach, we confirmed that the antibodies converted from all the mutated scFvs retained the affinity improvement. Remarkably, the best PD-L1 binder among them also bound with a higher affinity to PD-L1 expressed in its native conformation on human-activated lymphocytes, and it was able to stimulate lymphocyte proliferation in vitro more efficiently than its parental antibody. This optimized technology, besides the identification of a new potential checkpoint inhibitor, provides a tool for the quick isolation of high affinity binders. [ABSTRACT FROM AUTHOR]

Summary: What is known and objectives: Inadequate management of chronic medication puts patients at risk and causes unnecessary suspension of surgical procedures. The objective of the study was to calculate the rate of cancellation of elective surgical procedures due to inadequate management of chronic medications and to analyse the underlying causes of cancellation. Methods: We designed an analytic, observational, retrospective study of all elective surgical procedures performed from July to October 2017 in a tertiary hospital. The main variable was the percentage of surgeries cancelled owing to inadequate management of chronic medications. Other variables recorded included demographic characteristics, time between the preanaesthesia evaluation and surgery, drug involved, and the reason for incorrect management of the medication. Results: During the study period, 5415 surgical procedures were programmed, and 793 (14.6%) were cancelled. Cancellations due to inadequate patient preparation accounted for 5.3% (42 cases), and 19 were related to incorrect medication management (2.4% of the total number of cancellations). The 19 patients, who were mostly men (73.7%), had a median age of 76 years (IQR 68‐81). The drugs involved were acenocoumarol (6), enoxaparin (4), clopidogrel (4), direct‐acting oral anticoagulants (2), acetylsalicylic acid (1), tocilizumab (1) and leflunomide (1). The reasons for drug mishandling were poor understanding of the anaesthesiology recommendations (15) and lack of a preanaesthesia evaluation (4). What is new and conclusion: Inadequate management of chronic medications (2.4%) is not the most frequent reason for cancellation, although it is one of the easiest to avoid. Based on our results, starting in October 2017, the Pharmacy Department began to offer a pharmaceutical service to patients with doubts about the preoperative management of chronic medications. [ABSTRACT FROM AUTHOR]