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Objective:The aim of this randomised controlled trial was to evaluate the effectiveness of a short, highly structured parent based language intervention group programme for 2-year-old children with specific expressive language delay (SELD, without deficits in receptive language).Methods:61 children with SELD (mean age 24.7 months, SD 0.9) were selected between October 2003 and February 2006 during routine developmental check-ups in general paediatric practices, using a German parent-report screening questionnaire (adapted from the MacArthur Communicative Development Inventories). Standardised instruments were used to assess the language and non-verbal cognitive abilities of these children and of 36 other children with normal language development (reference group; mean age 24.6 months, SD 0.8). 58 children with SELD were sequentially randomly assigned to an intervention group (n = 29) or a 12-month waiting group (n = 29). In the intervention group, mothers participated in the 3-month Heidelberg Parent-based Language Intervention (HPLI). All children were reassessed 6 and 12 months after pretest. Assessors were blind to allocation and previous results.Results:47 children were included in the analysis. At the age of 3 years, 75% of the children in the intervention group showed normal expressive language abilities in contrast to 44% in the waiting group. Only 8% of the children in the intervention group versus 26% in the waiting group met the criteria for specific language impairment (t score ⩽35).Conclusions:By applying the short, highly structured HPLI in children with SELD, the rate of treatment for language impairment at the age of 3 years can be significantly reduced.

The granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells vaccine (GVAX) has antitumour activity against prostate cancer; preclinical studies have shown potent synergy when combined with ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen 4. We aimed to assess the safety of combined treatment with GVAX and ipilimumab in patients with metastatic castration-resistant prostate cancer (mCRPC). We did an open-labelled, single-centre, dose-escalation study of ipilimumab concurrent with a fixed dose of GVAX, with a subsequent expansion phase, both at the VU University Medical Centre (Amsterdam, Netherlands). Eligible patients had documented mCRPC and had not been previously treated with chemotherapy. All patients received a 5×108 cell priming dose of GVAX intradermally on day 1 with subsequent intradermal injections of 3×108 cells every 2 weeks for 24 weeks. The vaccinations were combined with intravenous ipilimumab every 4 weeks. We enrolled patients in cohorts of three; each cohort received an escalating dose of ipilimumab at 0·3, 1·0, 3·0, or 5·0 mg/kg. Our primary endpoint was safety. This study is registered with ClinicalTrials.gov, number NCT01510288. We enrolled 12 patients into our dose-escalation cohort. We did not record any severe immune-related adverse events at the first two dose levels. At the 3·0 mg/kg dose level, one patient had grade 2 and two patients grade 3 hypophysitis; at the 5·0 mg/kg dose level, two patients had grade 3 hypophysitis and one patient developed grade 4 sarcoid alveolitis (a dose-limiting toxic effect). Due to observed clinical activity and toxic events, we decided to expand the 3·0 mg/kg dose level, rather than enrol a further three patients at the 5·0 mg/kg level. 16 patients were enrolled in the expansion cohort, two of whom developed grade 2 hypophysitis, three colitis (one grade 1 and two grade 2), and one grade 3 hepatitis—all immune-related adverse events. The most common adverse events noted in all 28 patients were injection-site reactions (grade 1–2 events seen in all patients), fatigue (grade 1–2 in 20 patients, grade 3 in two), and pyrexia (grade 1–2 in 15 patients, grade 3 in one). 50% or greater declines in prostate-specific antigen from baseline was recorded in seven patients (25%); all had received 3·0 mg/kg or 5·0 mg/kg ipilimumab. GVAX combined with 3·0 mg/kg ipilimumab is tolerable and safe for patients with mCRPC. Further research on the combined treatment of patients with mCRPC with vaccination and ipilimumab is warranted. Cell Genesys Inc, Prostate Cancer Foundation, Dutch Cancer Society (KWF-VU 2006-3697), and Foundation Stichting VUmc Cancer Center Amsterdam.

Checkpoint inhibitor (CPI) therapies provide limited benefit to patients with tumors of low immune reactivity. T cell-inducing vaccines hold promise to exert long-lasting disease control in combination with CPI therapy. Safety, tolerability and recommended phase 2 dose (RP2D) of an individualized, heterologous chimpanzee adenovirus (ChAd68) and self-amplifying mRNA (samRNA)-based neoantigen vaccine in combination with nivolumab and ipilimumab were assessed as primary endpoints in an ongoing phase 1/2 study in patients with advanced metastatic solid tumors (NCT03639714). The individualized vaccine regimen was safe and well tolerated, with no dose-limiting toxicities. Treatment-related adverse events (TRAEs) >10% included pyrexia, fatigue, musculoskeletal and injection site pain and diarrhea. Serious TRAEs included one count each of pyrexia, duodenitis, increased transaminases and hyperthyroidism. The RP2D was 10 12 viral particles (VP) ChAd68 and 30 µg samRNA. Secondary endpoints included immunogenicity, feasibility of manufacturing and overall survival (OS). Vaccine manufacturing was feasible, with vaccination inducing long-lasting neoantigen-specific CD8 T cell responses. Several patients with microsatellite-stable colorectal cancer (MSS-CRC) had improved OS. Exploratory biomarker analyses showed decreased circulating tumor DNA (ctDNA) in patients with prolonged OS. Although small study size limits statistical and translational analyses, the increased OS observed in MSS-CRC warrants further exploration in larger randomized studies. An individualized, heterologous chimpanzee adenovirus (ChAd68) and self-amplifying mRNA-based neoantigen vaccine is safe and well tolerated in patients, warranting further studies to test its potential to rescue response to checkpoint blockade in tumors of low immune reactivity.

Most trauma patients require intensive care treatment and are susceptible to developing persistent inflammation and immunosuppression, potentially leading to multi organ dysfunction syndrome (MODS) and dependence on long term care facilities. T cells undergo changes in numbers and function post trauma. T cell dysfunction in polytraumatized patients was characterized using functional immunomonitoring to predict individual clinical outcome. Moreover, the potential to reverse T cell dysfunction using Interleukin (IL)-7 was examined. Blood samples were drawn from healthy individuals and prospectively enrolled polytrauma patients (Injury Severity Score ≥ 18) on admission, 8, 24 and 48 hours, 5 and 10 days after. CD3/28-stimulated cytokine production of T cells in whole blood was assessed via Enzyme Linked Immuno Spot (ELISpot). T cell subsets were quantified via counting and flow cytometry. Unfavorable physical performative outcome was defined as death or new functional disability necessitating long term care. Secondary outcomes were the development of MODS and in-hospital mortality. IL-7 was added ex vivo to test reversibility of cytokine disturbances. 34 patients were enrolled. The different outcome groups showed no difference in injury severity. Patients with favorable physical performative outcome revealed higher functional T cell specific Interferon γ (IFN-γ) and IL-17 (8 hours) and lower IL-10 production (day 5) and higher CD8 T cell concentrations. Patients without MODS development showed a higher IFN-γ (day 10), higher IL-2 (8 hours) and higher IL-17 production (admission, day 5). There were no differences regarding in-hospital mortality. Systemic blood IFN-γ, IL-2 and IL-10 concentrations only correlated with MODS (24 hours). Systemic CD8 T cell numbers correlated with functional IFN-γ production. Whole blood stimulation with IL-7 increased functional T cell IFN-γ release. Our study reveals an early characteristic overall T cell dysfunction of pro-inflammatory (IFN-γ, IL-2, IL-17) and immunosuppressive (IL-10) subtypes in polytraumatized patients. Our data indicates that rather the functional capacity of T cells to release cytokines, but not systemic cytokine concentrations can be used to predict outcome post trauma. We assume that the early stimulation of pro- and anti-inflammatory T cells benefits polytraumatized patients. Potentiation of functional IFN-γ release might be achieved by IL-7 administration.

Histone post-translational modifications (PTMs) often serve as distinct recognition sites for the recruitment of chromatin-associated proteins (CAPs) for epigenome regulation. While CAP:PTM interactions are extensively studied using histone peptides, this cannot represent the regulatory potential of multisite binding on intact nucleosomes. To overcome this limitation, we applied Nucleosome Mass Spectrometry (Nuc-MS), a native Top-Down MS approach that enables the controlled disassembly and proteoform analysis of CAP:nucleosome (CAP:nuc) complexes. As proof of principle, we show the BPTF plant homeodomain (PHD)-bromodomain (BD) native tandem reader binds synergistically to both PTM classes in fully defined ([H3K4me3K9acK14acK18ac]2) nucleosomes. We then extend to explore the engagement of BRD4 (native BD1-BD2), DNMT3A-MPP8 (chimeric PWWP-CD), and Populus trichocarpa Short Half Life (PtSHL) (native bromodomain-adjacent homology (BAH-PHD) tandem readers with endogenous HeLa nucleosomes. In the resulting enrichment profiles, BRD4 favors di- and triacetylated histone H4 proteoforms, whereas DNMT3A-MPP8 and PtSHL recover distinct hypermethylated H3 proteoforms. Of note, PtSHL enriches a potential {H3K4me3K27me3} cis combinatorial that expands the biology of this bivalent signature previously only described in trans. By directly characterizing CAP:nuc complex composition, Nuc-MS informs on the nucleoforms driving binding and thus identifies primary candidates for direct biochemical, structural, and genomic studies.

We report here on the presence of two different nonvolatile resistive switching mechanisms in Pt-Pr0.67Ca0.33MnO3-Pt sandwich structures based on pulsed electrical transport measurements. As a function of pulse length, amplitude and temperature, the devices show two different switching regimes. The first is positive switching (PS) where a high resistance state (HRS) evolves at positive bias at the top electrode in the voltage range of U 0.5-1.2 V and pulse lengths tp 10−7 s. In addition, we observe a cross over to negative switching (NS) for U > 1 V and tp 10−3 s. Here, the HRS evolves at negative bias applied at the top electrode. We present strong evidence that both switching mechanisms take place at the interface between Pr0.67Ca0.33MnO3 and the top electrode. Based on finite element simulations of the temperature evolution during the electrical pulses, we show that the onset of Joule heating is characteristic of the PS regime, whereas drastic temperature increases of several hundred Kelvin evolve during NS. Based on the observed different timescales, pulse amplitudes and temperature dependences of PS and NS, respectively, we suggest that two different switching mechanisms are involved: a fast, short range exchange of oxygen at the interface with the metallic electrode for PS and a slower, long range redistribution of oxygen in the entire PCMO film for the NS.

Fundamental losses of photovoltaic energy conversion are transmission of sub band gap photons and thermalisation which are the underlying physics of the Shockley-Queisser limit defining maximum conversion efficiency of single-junction solar cells. Strongly correlated materials such as perovskites are promising candidates to exceed this limit by exploiting (i) long wavelength light absorption and (ii) the existence of long-living intraband excitations indicating that harvesting hot excess carriers might be feasible in such systems. In this work, we study pn-heterojunctions produced from Pr1-xCaxMnO3 on SrTi1-yNbyO3 by means of microscopic techniques. Such systems exhibit relevant quantities such as space charge layer width, screening lengths and excess carrier diffusion lengths in the 1-10 nm range which makes the use of standard methods such as electron beam induced current a challenging task. We report scanning transmission electron beam induced current experiments of misfit dislocations at the heterojunction. The dislocation-induced reduction of the charge collection is studied with nanometer spatial resolution. Effects of surface recombination and the heterojunction electric field are discussed.

Immune checkpoint blockade enhances antitumor responses, but can also lead to severe immune-related adverse events (IRAE). To avoid unnecessary exposure to these potentially hazardous agents, it is important to identify biomarkers that correlate with clinical activity and can be used to select patients that will benefit from immune checkpoint blockade. To understand the consequences of CTLA-4 blockade and identify biomarkers for clinical efficacy and/or survival, an exploratory T cell monitoring study was performed in a phase I/II dose escalation/expansion trial ( n  = 28) of combined Prostate GVAX/ipilimumab immunotherapy. Phenotypic T cell monitoring in peripheral blood before and after Prostate GVAX/ipilimumab treatment revealed striking differences between patients who benefited from therapy and patients that did not. Treatment-induced rises in absolute lymphocyte counts, CD4 + T cell differentiation, and CD4 + and CD8 + T cell activation were all associated with clinical benefit. Moreover, significantly prolonged overall survival (OS) was observed for patients with high pre-treatment frequencies of CD4 + CTLA-4 + , CD4 + PD-1 + , or differentiated (i.e., non-naive) CD8 + T cells or low pre-treatment frequencies of differentiated CD4 + or regulatory T cells. Unsupervised clustering of these immune biomarkers revealed cancer-related expression of CTLA-4 + in CD4 + T cells to be a dominant predictor for survival after Prostate GVAX/ipilimumab therapy and to thus provide a putative and much-needed biomarker for patient selection prior to therapeutic CTLA4 blockade.

We report here on the presence of two different nonvolatile resistive switching mechanisms in Pt-Pr sub(0.67) Ca sub(0.33) MnO sub(3)-Pt sandwich structures based on pulsed electrical transport measurements. As a function of pulse length, amplitude and temperature, the devices show two different switching regimes. The first is positive switching (PS) where a high resistance state (HRS) evolves at positive bias at the top electrode in the voltage range of U [approximate] 0.5-1.2 V and pulse lengths t sub(p) [approximate] 10 super(?7) s. In addition, we observe a cross over to negative switching (NS) for U > 1 V and t sub(p)? 10 super(?3) s. Here, the HRS evolves at negative bias applied at the top electrode. We present strong evidence that both switching mechanisms take place at the interface between Pr sub(0.67) Ca sub(0.33) MnO sub(3) and the top electrode. Based on finite element simulations of the temperature evolution during the electrical pulses, we show that the onset of Joule heating is characteristic of the PS regime, whereas drastic temperature increases of several hundred Kelvin evolve during NS. Based on the observed different timescales, pulse amplitudes and temperature dependences of PS and NS, respectively, we suggest that two different switching mechanisms are involved: a fast, short range exchange of oxygen at the interface with the metallic electrode for PS and a slower, long range redistribution of oxygen in the entire PCMO film for the NS.