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Attitude role shift is a sign language strategy to report someone else’s utterance or thought. It has been analyzed either as a kind of demonstration or, alternatively, as a complex construction involving subordination plus a context-shifting operator. The present work reports the results of a sentence-to-picture matching task developed in three different sign languages (Italian Sign Language, French Sign Language and Catalan Sign Language) with the aim of providing experimental evidence about the nature of role shift. The task assessed the comprehension of indexical first-person pronouns in various syntactic contexts with and without role shift. We showed that constructions with role shift, which require context-shifting for the first-person pronoun, are never easier to comprehend than constructions without role shift that do not require context-shifting. In some cases, they are even more difficult. Additionally, we show that, in Italian Sign Language only, sentences in which the role shifted first-person pronoun is in object position are more difficult than sentences in which it is in subject position. We argue that this can be interpreted as an intervention effect and that this is an argument in favor of positing a context-shifting operator in the periphery of the role shift clause. Considering that the population of adult Deaf signers includes, besides native signers, a majority of individuals with a more or less severe delayed first language exposure, the second goal of this paper is to study the effects of age of exposure on comprehension of sentences with role shift. In the three languages under investigation, we found that native signers generally outperformed non-native signers in sentences with role shift and in subordinate clauses without role shift. This confirms that delayed language exposure has a lasting impact on adults’ comprehension of subordinate clauses of various degrees of complexity.

Among the existing sign language assessment tools, only a small number can be used in clinical settings. This contribution aims at presenting three comprehension assessment tests (two lexical and one syntactic) that offer a solid basis to build tools to assess language impairments in deaf signing adults. We provide the material and guidelines, based on psychometric analyses of the items, to make these tests suitable for clinical assessment. They are available for French Sign Language and Italian Sign Language. So far, the three tests were administered to three groups of deaf participants based on age of exposure (AoE) to sign language: native (AoE from birth), early (AoE = from 1 to 5 years), and late (AoE = from 6 to 15 years) signers. The results showed that the three tests are easy for the typical deaf signing population, and therefore, they can be adapted into tests that assess a deaf signing population with language impairments. Moreover, the results of the syntactic test reveal a categorial difference between native and non-native signers and therefore show the need for baselines that mirror the effect of AoE to sign language when assessing language competence, in particular in clinical assessment.

Total plasma cell-free DNA (cfDNA) levels were recently shown to be prognostic in two large phase III trials of taxane chemotherapy in metastatic castration-resistant prostate cancer (mCRPC). However, whether cfDNA concentration is predictive of treatment outcomes with androgen receptor pathway inhibitors (ARPIs) is unknown. We quantified plasma cfDNA levels at baseline (n = 74) and 4 weeks on treatment (n = 56) in a prospective cohort of mCRPC patients treated with the ARPIs abiraterone acetate or enzalutamide. Elevated total cfDNA concentration (log10) at both baseline (hazard ratio [HR] 5.5, p < 0.001) and week 4 (HR 7.5, p < 0.001) was a significant negative prognostic factor for overall survival (OS), a finding maintained after adjustment for plasma circulating tumour DNA fraction. Unexpectedly, a rise in cfDNA concentration from baseline to week 4 was also associated with significantly improved OS (HR 0.14, p = 0.003). Conversely, patients with >=29.8% decrease in cfDNA from baseline (optimal cut-point) had significantly shorter median OS than the rest of the cohort (10.5 vs 25.7 mo, p = 0.03). Collectively, our findings point to the potential prognostic utility of quantifying cfDNA in mCRPC and in particular suggest that dynamic changes in total cfDNA levels may be a novel early predictive biomarker for therapeutic outcome in ARPI-treated patients. Patient Summary: We measured the levels of total cell-free DNA (cfDNA) in the plasma of patients with metastatic prostate cancer prior to and 4 weeks after starting new hormonal drugs. We found that patients with higher levels of cfDNA or a higher proportion of tumour-derived DNA at baseline had worse outcomes on hormonal therapies. Similarly, higher levels of cfDNA at 4 weeks into therapy were also associated with worse outcomes. However, a rise in total cfDNA levels at 4 weeks compared with baseline was linked with better outcomes. Measuring changes in cfDNA concentration may be a useful and technically straightf

Background: The prognostic significance of DDR alterations in mCRPC remains unclear, with conflicting data from prior reports. Whether DDR alterations are predictive of outcomes with therapeutic agents other than PARP inhibitors in mCRPC is also poorly understood. With increasing use of molecular profiling in mCRPC, understanding the full prognostic and predictive utility of plasma DDR alterations is paramount. Method(s): A next-generation sequencing Predicine liquid biopsy assay was used to profile cfDNA and germline DNA in 407 mCRPC patients (pts) from two independent international cohorts (n=162 Australia, n=245 US). DDR genes profiled were BRCA2, ATM, BRCA1, MLH1 and MSH2. Kaplan-Meier survival estimates and multivariable Cox regression analyses were used to assess associations between DDR alterations and clinical outcomes including PSA response rate (PSA RR), progression-free survival and overall survival (OS). Result(s): Median age was 74 (IQR 67-79), with median follow up 74 months and median OS 23 months. 65/407 (16%) harboured pathogenic DDR alterations, including 21 patients with 1 alteration. Frequency of genomic aberrations are shown in the table. BRCA2 alterations were further classified as heterozygous loss (66%), homozygous loss (14%), monoallelic mutation (11%) and biallelic mutation/loss of heterozygosity (9%). Aberrations in any DDR gene, ATM, MLH1 + MSH2 or BRCA2 were associated with shorter OS on univariable analysis, but only any DDR or BRCA2 aberration remained significant upon adjusting for clinical prognosticators and ctDNA fraction (Table). Pre-treatment BRCA2 aberration was associated with significantly shorter OS and lower PSA RR compared to BRCA2 wt for pts receiving an AR pathway inhibitor (ARPI) (18 vs 32 months, p=0.006; 36 vs 60%, p=0.04 respectively) but not for taxane chemotherapy (17 vs 20 months, p=0.3; 45 vs 66, p=0.1 respectively). Conclusion(s): Detection of an aberration in any DDR gene or BRCA2 was an independent poor prognos

Background: With the evolving use of targeted therapies exploiting genomic vulnerabilities in mCRPC, screening patients for sensitizing alterations is of increasing relevance. However, the influence of age on the detection of relevant genomic alterations is incompletely understood. In this study, we compared the cell-free DNA (cfDNA) profiles of younger (age <70) versus older (age >=70) men with mCRPC and assessed the relative prognostic impact of common genomic alterations. Method(s): A next-generation sequencing-based Predicine cfDNA assay was used to profile 276 mCRPC patients from two independent international cohorts. The frequency of genomic alterations across age categories was compared using the chi-squared test, while circulating tumour DNA fraction (ctDNA%) was compared using the Mann-Whitney U test. Cox proportional hazards analysis with interaction testing was used to assess the association between age, genomic alteration and overall survival. Result(s): The median age of the combined cohort was 72 years (IQR 66-78), with 170 (62%) patients >=70 years old. Despite differences in baseline characteristics (poorer performance status in older patients, higher Gleason score and de novo metastatic disease in younger patients), there was no significant difference in ctDNA% (median 22% vs 30%, p=0.6). We observed similar frequencies of genomic alterations across the 10 most commonly aberrant genes, including AR (<70 vs >=70: 46% vs 49%, p=0.6), TP53 (40% vs 36%, p=0.6), BRCA2 (29% vs 21%, p=0.13) and PTEN (39% vs 35%, p=0.5). This similarity persisted when analysing mutations and copy number alterations in isolation. While driver alterations in both age categories were strongly associated with unfavourable outcomes (Table), an exploratory analysis revealed that copy number gain in PIK3CA may have a worse prognostic impact in younger men (p for interaction = 0.03), with a lesser effect observed in AR gain (p = 0.1) and MYC gain (p = 0.1). Conclusion(s): The genom

177Lu-PSMA-617 is an effective therapy for metastatic castration-resistant prostate cancer (mCRPC). However, treatment resistance occurs frequently, and combination therapies may improve outcomes. We report the final safety and efficacy results of a phase I/II study combining 177Lu-PSMA-617 with idronoxil (NOX66), a radiosensitizer, and examine potential clinical, blood-based, and imaging biomarkers. Methods: Fifty-six men with progressive mCRPC previously treated with taxane chemotherapy and novel androgen signaling inhibitor (ASI) were enrolled. Patients received up to 6 doses of 177Lu-PSMA-617 (7.5 GBq) on day 1 in combination with a NOX66 suppository on days 1-10 of each 6-wk cycle. Cohort 1 (n = 8) received 400 mg of NOX66, cohort 2 (n = 24) received 800 mg, and cohort 3 (n = 24) received 1,200 mg. 68Ga-PSMA and 18F-FDG PET/CT were performed at study entry, and semiquantitative imaging analysis was undertaken. Blood samples were collected for analysis of blood-based biomarkers, including androgen receptor splice variant 7 expression. The primary outcomes were safety and tolerability; secondary outcomes included efficacy, pain scores, and xerostomia. Regression analyses were performed to explore the prognostic value of baseline clinical, blood-based, and imaging parameters. Results: Fifty-six of the 100 men screened were enrolled (56%), with a screening failure rate of 26% (26/100) for PET imaging criteria. All men had received prior treatment with ASI and docetaxel, and 95% (53/56) had received cabazitaxel. Ninety-six percent (54/56) of patients received at least 2 cycles of combination NOX66 and 177Lu-PSMA-617, and 46% (26/56) completed 6 cycles. Common adverse events were anemia, fatigue, and xerostomia. Anal irritation attributable to NOX66 occurred in 38%. Forty-eight of 56 had a reduction in prostate-specific antigen (PSA) level (86%; 95% CI, 74%-94%); 34 of 56 (61%; 95% CI, 47%-74%) had a PSA reduction of at least 50%. Median PSA progression-free survival

Transglutaminase 2 (TGase 2) represents a multifunctional protein, which is involved in various physiological and pathophysiological processes. The latter also include its participation in the development and progression of malignant neoplasms, which is often accompanied by an in-creased protein synthesis. Besides the elucidation of the molecular functions of TGase 2 in tumor cells, knowledge of its concentration that is available for targeting by theranostic agents repre-sents a valuable information. Herein, we describe the application of a recently developed fluo-rescence anisotropy (FA)-based assay for the quantitative expression profiling of TGase 2 by means of transamidase-active enzyme in cell lysates. The assay is based on the incorporation of rhodamine B‑isonipecotyl‑cadaverine (R-I-Cad) into N,N-dimethylated casein (DMC), which results in an increase of FA signal over time. It was shown that this reaction is not only catalyzed by TGase 2 but also by TGases 1, 3, and 6 and factor XIIIa using recombinant proteins. Therefore, control measurements in the presence of a selective irreversible TGase 2 inhibitor were manda-tory to ascertain the specific contribution of TGase 2 to the overall FA rate. To validate the assay regarding the quality of quantification, spike/recovery and linearity of dilution experiments were performed. A total of 25 cancer and 5 non-cancer cell lines were characterized with this as-say method in terms of their activatable TGase 2 concentration (fmol/µg protein lysate) and the results were compared to protein synthesis data obtained by western blotting. Moreover, com-plementary protein quantification methods using a biotinylated irreversible TGase 2 inhibitor as activity-based probe and a commercially available ELISA were applied for selected cell lines to further validate the results obtained by the FA-based assay. Overall, the present study demonstrates that the FA-based assay using the substrate pair R-I-Cad and DMC represents a facile

Primärdaten zum FA-Assay, activity-based ELISA und ELISA

Who is a native signer? Since around 95% of deaf infants are born into a hearing family, deaf signers are exposed to a sign language at various moments of their life, and not only from birth. Moreover, the linguistic input they are exposed to is not always a fully fledged natural sign language. In this situation, is the notion of native signer as someone exposed to language from birth of any use? We review the results of the first large-scale cross-linguistic investigation on the effects of age of exposure to sign language. This research involved about 45 Deaf adult signers in each of three sign languages (Catalan Sign Language, French Sign Language, and Italian Sign Language). Across the three languages, participants were divided into three groups – those exposed from birth, those between 1 and 5 years of age, and those exposed between 6 and 15 years of age – and received a battery of tests designed for each language targeting various aspects of morphosyntactic competence. In particular, the tests focused on both those morphosyntactic phenomena that are known from the spoken language literature to be good detectors of language impairment or delay (i.e., wh-interrogatives and relative clauses) and on morphosyntactic phenomena that are sign language specific (i.e., role shift and directional verbs). The results showed a clear effect of being native, with significant differences across languages and tests between signers exposed to sign language from birth and those exposed in the 1st years of life. This confirms the life-long importance of language exposure from birth and the reliability of the notion of “nativeness”, at least for syntax. On the other hand, while in most domains the differences observed between populations might be differences in performance, for some specific constructions, signers belonging to the three groups may have different grammars. This latter finding challenges the generalized use of native signers’ grammar as the baseline for language desc

OBJECTIVES: The aim of the study was to assess the feasibility of a national pre-exposure prophylaxis (PrEP) programme using smartphone-compatible data collection. METHODS: This was a multicentre cohort study (NCT03893188) enrolling individuals interested in PrEP in Switzerland. All centres participate in the SwissPrEPared programme, which uses smartphone-compatible data collection. Feasibility was assessed after centres had enrolled at least one participant. Participants were HIV-negative individuals presenting for PrEP counselling. Outcomes were participation (number enrolled/number eligible), enrolment rates (number enrolled per month), retention at first follow-up (number with first follow-up/number enrolled), and uptake (proportion attending first visit as scheduled). Participant characteristics were compared between those retained after baseline assessment and those who dropped out. RESULTS: Between April 2019 and January 2020, 987 individuals were assessed for eligibility, of whom 969 were enrolled (participation: 98.2%). The median enrolment rate was 86 per month [interquartile range (IQR) 52-137]. Retention at first follow-up and uptake were both 80.7% (782/969 and 532/659, respectively). At enrolment, the median age was 40 (IQR 33-47) years, 95% were men who have sex with men, 47% had a university degree, and 75.5% were already taking PrEP. Most reported multiple casual partners (89.2%), previous sexually transmitted infections (74%) and sexualized drug use (73.1%). At baseline, 25.5% tested positive for either syphilis, gonorrhoea or chlamydia. Participants who dropped out were at lower risk of HIV infection than those retained after baseline assessment. CONCLUSIONS: In a national PrEP programme using smartphone-compatible data collection, participation, retention and uptake were high. Participants retained after baseline assessment were at considerable risk of HIV infection. Younger, less educated individuals were underrepresented in the SwissPrEPared co

Background: Effective two-drug regimens could decrease long-term drug exposure and toxicity with HIV-1 antiretroviral therapy (ART). We therefore aimed to evaluate the efficacy and safety of a two-drug regimen compared with a three-drug regimen for the treatment of HIV-1 infection in ART-naive adults. Methods: We conducted two identically designed, multicentre, double-blind, randomised, non-inferiority, phase 3 trials: GEMINI-1 and GEMINI-2. Both studies were done at 192 centres in 21 countries. We included participants (≥18 years) with HIV-1 infection and a screening HIV-1 RNA of 500 000 copies per mL or less, and who were naive to ART. We randomly assigned participants (1:1) to receive a once-daily two-drug regimen of dolutegravir (50 mg) plus lamivudine (300 mg) or a once-daily three-drug regimen of dolutegravir (50 mg) plus tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg). Both drug regimens were administered orally. We masked participants and investigators to treatment assignment: dolutegravir was administered as single-entity tablets (similar to its commercial formulation, except with a different film colour), and lamivudine tablets and tenofovir disoproxil fumarate and emtricitabine tablets were over-encapsulated to visually match each other. Primary endpoint was the proportion of participants with HIV-1 RNA of less than 50 copies per mL at week 48 in the intention-to-treat-exposed population, using the Snapshot algorithm and a non-inferiority margin of −10%. Safety analyses were done on the safety population. GEMINI-1 and GEMINI-2 are registered with ClinicalTrials.gov, numbers NCT02831673 and NCT02831764, respectively. Findings: Between July 18, 2016, and March 31, 2017, 1441 participants across both studies were randomly assigned to receive either the two-drug regimen (n=719) or three-drug regimen (n=722). At week 48 in the GEMINI-1 intention-to-treat-exposed population, 320 (90%) of 356 participants receiving the two-drug regimen and 332