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In ancient Greek, relative pronouns are, as a rule, subject to wh-movement and obligatorily surface at the left edge of the relative clause. However, the archaic poet Pindar sometimes allows material belonging to the relative clause to appear in front of the relative pronoun, which is then postponed within its clause. In this paper, I survey all relative clauses in the surviving texts by Pindar and study the possible differences in semantics and syntax between relative clauses with initial and postponed relative pronouns, which turn out to be indistinguishable in both respects. I suggest that postponed relative pronouns do move syntactically to the Spec of their relative clause but are then optionally treated as postpositive words and surface in second position in the relative clause. Phonological arguments, based on the distributional properties of postpositive words and on the metrical makeup of Pindar’s texts, are put forward to show how postponed relative pronouns select a host at the left edge of the relative clause and incorporate phonologically to it. The informational status of relative pronouns as ratified (given) topics triggers their phonological demoting, which turns them into postpositive words, a regular process in ancient Greek. Approaching the position of relative pronouns as a conflict between syntactic and (informationally driven) phonological alignment explains why Pindar’s strategy for relativization remained rare in ancient Greek and eventually disappeared: It took one specific poetic genre to allow phonology to outrank syntax.

In vitro incubation of nanomaterials with plasma offer insights on biological interactions, but cannot fully explain the in vivo fate of nanomaterials. Here, we use a library of polymer nanoparticles to show how physicochemical characteristics influence blood circulation and early distribution. For particles with different diameters, surface hydrophilicity appears to mediate early clearance. Densities above a critical value of approximately 20 poly(ethylene glycol) chains (MW 5 kDa) per 100 nm 2 prolong circulation times, irrespective of size. In knockout mice, clearance mechanisms are identified for nanoparticles with low and high steric protection. Studies in animals deficient in the C3 protein showed that complement activation could not explain differences in the clearance of nanoparticles. In nanoparticles with low poly(ethylene glycol) coverage, adsorption of apolipoproteins can prolong circulation times. In parallel, the low-density-lipoprotein receptor plays a predominant role in the clearance of nanoparticles, irrespective of poly(ethylene glycol) density. These results further our understanding of nanopharmacology. Understanding the interaction between nanoparticles and biomolecules is crucial for improving current drug-delivery systems. Here, the authors shed light on the essential role of the surface and other physicochemical properties of a library of nanoparticles on their in vivo pharmacokinetics.

Bone is a favorable microenvironment for tumor growth and a frequent destination for metastatic cancer cells. Targeting cancers within the bone marrow remains a crucial oncologic challenge due to issues of drug availability and microenvironment-induced resistance. Herein, we engineered bone-homing polymeric nanoparticles (NPs) for spatiotemporally controlled delivery of therapeutics to bone, which diminish off-target effects and increase local drug concentrations. The NPs consist of poly(d , l -lactic-co-glycolic acid) (PLGA), polyethylene glycol (PEG), and bisphosphonate (or alendronate, a targeting ligand). The engineered NPs were formulated by blending varying ratios of the synthesized polymers: PLGA- b -PEG and alendronate-conjugated polymer PLGA- b -PEG-Ald, which ensured long circulation and targeting capabilities, respectively. The bone-binding ability of Ald-PEG-PLGA NPs was investigated by hydroxyapatite binding assays and ex vivo imaging of adherence to bone fragments. In vivo biodistribution of fluorescently labeled NPs showed higher retention, accumulation, and bone homing of targeted Ald-PEG-PLGA NPs, compared with nontargeted PEG-PLGA NPs. A library of bortezomib-loaded NPs (bone-targeted Ald-Bort-NPs and nontargeted Bort-NPs) were developed and screened for optimal physiochemical properties, drug loading, and release profiles. Ald-Bort-NPs were tested for efficacy in mouse models of multiple myeloma (MM). Results demonstrated significantly enhanced survival and decreased tumor burden in mice pretreated with Ald-Bort-NPs versus Ald-Empty-NPs (no drug) or the free drug. We also observed that bortezomib, as a pretreatment regimen, modified the bone microenvironment and enhanced bone strength and volume. Our findings suggest that NP-based anticancer therapies with bone-targeting specificity comprise a clinically relevant method of drug delivery that can inhibit tumor progression in MM.

B cells and T cells collaborate in multiple sclerosis (MS) pathogenesis. IgH [MOG] mice possess a B cell repertoire skewed to recognize myelin oligodendrocyte glycoprotein (MOG). Here, we show that upon immunization with the T cell-obligate autoantigen, MOG [35-55] , IgH [MOG] mice develop rapid and exacerbated experimental autoimmune encephalomyelitis (EAE) relative to wildtype (WT) counterparts, characterized by aggregation of T and B cells in the IgH [MOG] meninges and by CD4 + T helper 17 (Th17) cells in the CNS. Production of the Th17 maintenance factor IL-23 is observed from IgH [MOG] CNS-infiltrating and meningeal B cells, and in vivo blockade of IL-23p19 attenuates disease severity in IgH [MOG] mice. In the CNS parenchyma and dura mater of IgH [MOG] mice, we observe an increased frequency of CD4 + PD-1 + CXCR5 - T cells that share numerous characteristics with the recently described T peripheral helper (Tph) cell subset. Further, CNS-infiltrating B and Tph cells from IgH [MOG] mice show increased reactive oxygen species (ROS) production. Meningeal inflammation, Tph-like cell accumulation in the CNS and B/Tph cell production of ROS were all reduced upon p19 blockade. Altogether, MOG-specific B cells promote autoimmune inflammation of the CNS parenchyma and meninges in an IL-23-dependent manner. B cells are crucial in multiple sclerosis (MS) pathology but the mechanisms are incompletely understood. In a mouse model of MS, the authors show that B cells make IL-23, and that IL-23 invokes meningeal inflammation and CNS presence of T peripheral helper cells.

Fluorescent labelling is commonly used to monitor the biodistribution of nanomedicines. However, meaningful interpretation of the results requires that the fluorescent label remains attached to the nanomedicine. In this work, we explore the stability of three fluorophores (BODIPY650, Cyanine 5 and AZ647) attached to polymeric hydrophobic biodegradable anchors. Using dual-labelled poly(ethylene glycol)-b-poly(lactic acid) (PEG-PLA) nanoparticles that are both radioactive and fluorescent, we investigated how the properties of the fluorophores impact the stability of the labelling in vitro and in vivo. Results suggest that the more hydrophilic dye (AZ647) is released faster from nanoparticles, and that this instability results in misinterpretation of in vivo data. While hydrophobic dyes are likely more suitable to track nanoparticles in biological environments, quenching of the fluorescence inside the nanoparticles can also introduce artefacts. Altogether, this work raises awareness about the importance of stable labelling methods when investigating the biological fate of nanomedicines.

Adjuvant radiotherapy after prostatectomy was recently challenged by early salvage radiotherapy, which highlighted the need for biomarkers to improve risk stratification. Therefore, we developed an MRI ADC map-derived radiomics model to predict biochemical recurrence (BCR) and BCR-free survival (bRFS) after surgery. Our goal in this work was to externally validate this radiomics-based prediction model. Experimental Design: A total of 195 patients with a high recurrence risk of prostate cancer (pT3-4 and/or R1 and/or Gleason’s score > 7) were retrospectively included in two institutions. Patients with postoperative PSA (Prostate Specific Antigen) > 0.04 ng/mL or lymph node involvement were excluded. Radiomics features were extracted from T2 and ADC delineated tumors. A total of 107 patients from Institution 1 were used to retrain the previously published model. The retrained model was then applied to 88 patients from Institution 2 for external validation. BCR predictions were evaluated using AUC (Area Under the Curve), accuracy, and bRFS using Kaplan–Meier curves. Results: With a median follow-up of 46.3 months, 52/195 patients experienced BCR. In the retraining cohort, the clinical prediction model (combining the number of risk factors and postoperative PSA) demonstrated moderate predictive power (accuracy of 63%). The radiomics model (ADC-based SZEGLSZM) predicted BCR with an accuracy of 78% and allowed for significant stratification of patients for bRFS (p < 0.0001). In Institution 2, this radiomics model remained predictive of BCR (accuracy of 0.76%) contrary to the clinical model (accuracy of 0.56%). Conclusions: The recently developed MRI ADC map-based radiomics model was validated in terms of its predictive accuracy of BCR and bRFS after prostatectomy in an external cohort.

Background Adjuvant chemotherapy (AC) improves the prognosis after pancreatic ductal adenocarcinoma (PDAC) resection. However, previous studies have shown that a large proportion of patients do not receive or complete AC. This national study examined the risk factors for the omission or interruption of AC. Methods Data of all patients who underwent pancreatic surgery for PDAC in France between January 2012 and December 2017 were extracted from the French National Administrative Database. We considered “omission of adjuvant chemotherapy” (OAC) all patients who failed to receive any course of gemcitabine within 12 postoperative weeks and “interruption of AC” (IAC) was defined as less than 18 courses of AC. Results A total of 11 599 patients were included in this study. Pancreaticoduodenectomy was the most common procedure (76.3%), and 31% of the patients experienced major postoperative complications. OACs and IACs affected 42% and 68% of the patients, respectively. Ultimately, only 18.6% of the cohort completed AC. Patients who underwent surgery in a high-volume centers were less affected by postoperative complications, with no impact on the likelihood of receiving AC. Multivariate analysis showed that age ≥ 80 years, Charlson comorbidity index (CCI) ≥ 4, and major complications were associated with OAC (OR = 2.19; CI 95% [1.79–2.68]; OR = 1.75; CI 95% [1.41–2.18] and OR = 2.37; CI 95% [2.15–2.62] respectively). Moreover, age ≥ 80 years and CCI 2–3 or ≥ 4 were also independent risk factors for IAC (OR = 1.54, CI 95% [1.1–2.15]; OR = 1.43, CI 95% [1.21–1.68]; OR = 1.47, CI 95% [1.02–2.12], respectively). Conclusion Sequence surgery followed by chemotherapy is associated with a high dropout rate, especially in octogenarian and comorbid patients.

Retinoic acid (RA), the active derivative of vitamin A, has been implicated in various steps of cardiovascular development. The retinaldehyde dehydrogenase 2 (RALDH2) enzyme catalyzes the second oxidative step in RA biosynthesis and its loss of function creates a severe embryonic RA deficiency. Raldh2⁻/⁻ knockout embryos fail to undergo heart looping and have impaired atrial and sinus venosus development. To understand the mechanism(s) producing these changes, we examined the contribution of the second heart field (SHF) to pharyngeal mesoderm, atria, and outflow tract in Raldh2⁻/⁻ embryos. RA deficiency alters SHF gene expression in two ways. First, Raldh2⁻/⁻ embryos exhibited a posterior expansion of anterior markers of the SHF, including Tbx1, Fgf8, and the Mlc1v-nlacZ-24/Fgf10 reporter transgene as well as of Islet1. This occurred at early somite stages, when cardiac defects became irreversible in an avian vitamin A-deficiency model, indicating that endogenous RA is required to restrict the SHF posteriorly. Explant studies showed that this expanded progenitor population cannot differentiate properly. Second, RA up-regulated cardiac Bmp expression levels at the looping stage. The contribution of the SHF to both inflow and outflow poles was perturbed under RA deficiency, creating a disorganization of the heart tube. We also investigated genetic cross-talk between Nkx2.5 and RA signaling by generating double mutant mice. Strikingly, Nkx2.5 deficiency was able to rescue molecular defects in the posterior region of the Raldh2⁻/⁻ mutant heart, in a gene dosage-dependent manner.

Background: Pembrolizumab is a monoclonal antibody (mAb) approved for treating Non-Small Cell Lung Cancer (NSCLC), melanoma and lymphomas. Commercialized in single-size (100 mg/4 mL) vials, the pembrolizumab solution contains no preservative. As such, the manufacturer recommends using pembrolizumab vials only once, and thus, to rapidly dispose of any unused portion. Thus, appreciable amounts of this costly product are wasted. Objective: To evaluate the physical, chemical and microbiological stability of pembrolizumab vial leftovers stored at room temperature or at 4 °C, 7 and 14 days after first vial puncturing. Methods: Following pH assessments, submicronic aggregation and turbidity of pembrolizumab were measured by dynamic light scattering (DLS) and spectrophotometry, respectively. In addition, SE-HPLC (size-exclusion high-performance liquid chromatography), IEX-HPLC (ion exchange HPLC) and peptide mapping HPLC served to respectively evaluate aggregation and fragmentation, distribution of charge and primary structure of pembrolizumab. Incubation at 37 °C for 48 h of pembrolizumab vial leftovers on blood agar plates was used to determine their microbiological stability. Results: Physical, chemical and microbiological stability of pembrolizumab leftovers was demonstrated for at least two full weeks. Conclusions: These results argue forcefully in favor of allowing prolongation of pembrolizumab vial leftovers usage well beyond a single day.

Secretory phospholipase A 2 -IIA (sPLA 2 -IIA) is a bactericidal enzyme that hydrolyzes membrane phospholipids, releasing lipid metabolites that can affect inflammation. sPLA 2 -IIA exhibits poor activity toward eukaryotic cells but preferentially targets gram-positive bacterial membranes. While sPLA 2 -IIA is constitutively expressed in the intestine and upregulated by inflammation in various bodily fluids, its precise physiological substrates remain debated. Intriguingly, sPLA 2 -IIA can modulate the intestinal lipidome without altering the microbiota composition. Here, we investigated whether sPLA 2 -IIA could use membranes from bacterial extracellular vesicles (bEVs) as alternative substrates to modulate immune signaling. We found that bEVs from both Staphylococcus aureus and Escherichia coli could mitigate the bactericidal effects of sPLA 2 -IIA on gram-positive bacteria. Enzymatic hydrolysis of bacteria, bEVs and fecal extracellular vesicles released distinct lipid metabolites and differentially impacted Toll-like receptor activation. These findings suggest that sPLA 2 -IIA can use bEVs as substrates and modulate inflammatory signaling through the generation of pathogen-associated molecular patterns, thus linking bacterial lipid metabolism to host immune response. Secretory phospholipase A2-IIA, a bactericidal enzyme whose main expression is in the intestine, uses bacterial extracellular vesicles as substrates to release lipid metabolites and affect immune pathways.