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Novel immunotherapeutics against LGR5 to target multiple cancer types.
No full textWe have developed and validated a highly specific, versatile antibody to the extracellular domain of human LGR5 (α-LGR5). α-LGR5 detects LGR5 overexpression in >90% of colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B-ALL tumour cells and was used to generate an Antibody-Drug Conjugate (α-LGR5-ADC), Bispecific T-cell Engager (α-LGR5-BiTE) and Chimeric Antigen Receptor (α-LGR5-CAR). α-LGR5-ADC was the most effective modality for targeting LGR5+ cancer cells in vitro and demonstrated potent anti-tumour efficacy in a murine model of human NALM6 pre-B-ALL driving tumour attrition to less than 1% of control treatment. α-LGR5-BiTE treatment was less effective in the pre-B-ALL cancer model yet promoted a twofold reduction in tumour burden. α-LGR5-CAR-T cells also showed specific and potent LGR5+ cancer cell killing in vitro and effective tumour targeting with a fourfold decrease in pre-B-ALL tumour burden relative to controls. Taken together, we show that α-LGR5 can not only be used as a research tool and a biomarker but also provides a versatile building block for a highly effective immune therapeutic portfolio targeting a range of LGR5-expressing cancer cells
Raw trace element data obtained by LA-ICP-MS for analysed tephra across 751-763 CE from one proximal site in Iceland
No full textRaw Trace element data of analysed proximal samples from Iceland across the period 751-763 CE. Tephra (ash) samples were taken from a soil outcrop in Iceland [Atley, Iceland; 63.67295°N/18.68231°W] for candidate events. Trace element data was obtained by LA-ICP-MS at the University of St Andrews using a beam diameter of 20µm, laser energy of 3.5 J cm-2 (4 Hz repetition rate), 30-s ablation time and 20-s background measurement
A suicide attentional bias as implicit cognitive marker of suicide vulnerability in a high-risk sample.
Get PDFINTRODUCTION
Suicide risk assessment based on self-report questionnaires is considered as problematic because risk states are dynamic and at-risk individuals may conceal suicidal intentions for several reasons. Therefore, recent research efforts increasingly focus on implicit risk markers such as the suicide attentional bias (SAB) measured with the Suicide Stroop Task (SST). However, most SST studies failed to demonstrate a SAB in individuals with suicide risk and repeatedly demonstrated insufficient psychometrics of the SST. This study aimed to investigate a SAB using a modified SST (M-SST) and to test its psychometric properties.
METHOD
We compared n = 61 healthy controls and a high-risk inpatient sample of n = 40 suicide ideators and n = 40 suicide attempters regarding interference scores of positive, negative and suicide-related words. Interference scores were calculated by subtracting the mean reaction time (mean RT) of the neutral words from the mean RT of the suicide-related words (mean RT Suicide -mean RT Neutral), resulting in a suicide-specific interference score. Similarly, interference scores were calculated for the positive and negative words by subtracting the mean RT of neutral words from the mean RT of positive and negative words.
RESULTS
A Group × Interference ANOVA showed a significant interaction effect (p <.001, ηp2 = .09), indicating that group effects significantly vary across interference type. Post hoc comparisons revealed that both ideators and attempters demonstrated greater interferences only for suicide-related words compared to healthy controls, indicating a SAB in patients, while a difference between ideators and attempters was lacking. The suicide interference score classified with an AUC = 0.73, 95% CI [0.65 - 0.82], p <.001, between controls and patients with STBs. The M-SST demonstrated good internal consistency and convergent validity.
DISCUSSION
The study adds evidence to the assumptions of the Cognitive Model of Suicide, viewing a SAB as a cognitive marker of suicide vulnerability independently of the engagement in suicidal behavior. The results' clinical implications are discussed in the context of recommended intervention strategies during an acute suicidal state. Future studies with the M-SST should include non-suicidal patient controls to investigate whether a SAB is uniquely related to suicidality
Long-Term Impact of Lumacaftor/Ivacaftor Treatment on Cystic Fibrosis Disease Progression in Children 2 Through 5 Years of Age Homozygous for F508del-CFTR: A Phase 2, Open-Label Clinical Trial.
No full textRATIONALE
Clinical trials show that lumacaftor/ivacaftor (LUM/IVA) treatment has the potential to modify early cystic fibrosis (CF) disease progression in children as young as 2 years of age.
OBJECTIVE
To assess the long-term impact of LUM/IVA treatment on CF disease progression in children aged 2 through 5 years.
METHODS
This phase 2 trial had two parts: Part 1, a 48-week, randomized, double-blind, placebo-controlled study of LUM/IVA in children aged 2 through 5 years (previously reported) was followed by a 48-week open-label treatment period where all children received LUM/IVA (Part 2; reported here). Endpoints assessed in Part 2 included absolute changes from baseline in chest magnetic resonance imaging (MRI) global score at week 96; weight-for-age, stature-for-age, and body mass index (BMI)-for-age z-scores at week 96; lung clearance index (LCI2.5) through week 96; chest MRI morphological score, chest MRI perfusion score, weight, stature, BMI, and microbiology cultures (oropharyngeal swabs) at week 96; sweat chloride, serum levels of immunoreactive trypsinogen, fecal elastase-1 levels, and fecal calprotectin through week 96; and number of pulmonary exacerbations (PEx), time-to-first PEx, and number of CF-related hospitalizations.
RESULTS
Forty-nine children received ≥1 dose of LUM/IVA in the open-label period (33 in the LUM/IVA to LUM/IVA group and 16 in the placebo to LUM/IVA group); mean exposure 47.1 (SD, 5.2) weeks. The mean absolute change in MRI global score (negative value = improvement) from baseline at Week 96 was -2.7 (SD 7.0; 95% CI, -5.2 to -0.1) in the LUM/IVA to LUM/IVA group and -5.6 (SD 6.9; 95% CI, -9.2 to -1.9) in the placebo to LUM/IVA group. Improvements in LCI2.5, sweat chloride concentration, and markers of pancreatic function and intestinal inflammation were also observed in both groups. Growth parameters remained stable in both groups. The majority of children had adverse events (AEs) considered mild (38.8%) or moderate (40.8%). Two (4.1%) children discontinued LUM/IVA treatment due to AEs (distal intestinal obstruction syndrome [n=1] and alanine aminotransferase increase [n=1]).
CONCLUSION
These findings confirm the potential for early LUM/IVA treatment to alter the trajectory of CF disease progression, including CF lung disease, in children as young as 2 years of age. Clinical trial registration available at www.
CLINICALTRIALS
gov, ID: NCT03625466
HIV-1 subtype-specific drug resistance on dolutegravir-based antiretroviral therapy: protocol for a multicentre study (DTG RESIST).
Get PDFINTRODUCTION
HIV drug resistance poses a challenge to the United Nation's goal of ending the HIV/AIDS epidemic. The integrase strand transfer inhibitor (InSTI) dolutegravir, which has a higher resistance barrier, was endorsed by the WHO in 2019 for first-line, second-line and third-line antiretroviral therapy (ART). This multiplicity of roles of dolutegravir in ART may facilitate the emergence of dolutegravir resistance.
METHODS AND ANALYSIS
Nested within the International epidemiology Databases to Evaluate AIDS (IeDEA), DTG RESIST is a multicentre study of adults and adolescents living with HIV in sub-Saharan Africa, Asia, and South and Central America who experienced virological failure on dolutegravir-based ART. At the time of virological failure, whole blood will be collected and processed to prepare plasma or dried blood spots. Laboratories in Durban, Mexico City and Bangkok will perform genotyping. Analyses will focus on (1) individuals who experienced virological failure on dolutegravir and (2) those who started or switched to such a regimen and were at risk of virological failure. For population (1), the outcome will be any InSTI drug resistance mutations, and for population (2) virological failure is defined as a viral load >1000 copies/mL. Phenotypic testing will focus on non-B subtype viruses with major InSTI resistance mutations. Bayesian evolutionary models will explore and predict treatment failure genotypes. The study will have intermediate statistical power to detect differences in resistance mutation prevalence between major HIV-1 subtypes; ample power to identify risk factors for virological failure and limited power for analysing factors associated with individual InSTI drug resistance mutations.
ETHICS AND DISSEMINATION
The research protocol was approved by the Biomedical Research Ethics Committee at the University of KwaZulu-Natal, South Africa and the Ethics Committee of the Canton of Bern, Switzerland. All sites participate in International epidemiology Databases to Evaluate AIDS and have obtained ethics approval from their local ethics committee to collect additional data.
TRIAL REGISTRATION NUMBER
NCT06285110
Droschken(un)ordnung. Die Reglementierung des Droschkenwesens in den Schweizer Städten Zürich und Luzern
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Oral Acitretin Plus Topical Triamcinolone vs Topical Triamcinolone Monotherapy in Patients With Symptomatic Oral Lichen Planus: A Randomized Clinical Trial.
No full textIMPORTANCE
Symptomatic oral lichen planus (OLP) can be challenging to treat.
OBJECTIVE
To compare the efficacy of oral acitretin plus topical triamcinolone acetonide (TAC), 0.1%, with TAC monotherapy in patients with symptomatic OLP.
DESIGN, SETTING, AND PARTICIPANTS
This monocentric, investigator-initiated, placebo-controlled, investigator- and patient-blinded randomized clinical trial was conducted from December 2018 to June 2020 at the Postgraduate Institute of Medical Education and Research, a tertiary referral center in Chandigarh, India. Sixty-four patients 18 years or older with symptomatic OLP were recruited by consecutive sampling. Data were analyzed from July to December 2020.
INTERVENTION
The patients were randomized to receive either a combination of oral acitretin (25-35 mg/d) and TAC (treatment group) or TAC in combination with placebo (placebo group) for 28 weeks, with an additional 8 weeks of treatment-free follow-up after the end of treatment (36 weeks of total study duration).
MAIN OUTCOMES AND MEASURES
The disease severity and treatment response were assessed using Oral Disease Severity Score (ODSS), Oral Health Impact Profile 14 (OHIP-14), and visual analog scale (VAS). The primary aim was to assess the number of patients achieving ODSS-75 (75% reduction in ODSS compared with baseline) in both groups at 28 weeks and at the end of 36 weeks.
RESULTS
Among 64 patients, 31 in the treatment group and 30 in the placebo group completed the study (mean [SD] age, 50.6 [15.2] years vs 49.2 [14.4] years; male-female ratio, 13:19 vs 16:16). Baseline ODSS, visual analog scale, and Oral Health Impact Profile 14 scores were comparable in both groups. In the intention-to-treat analysis, there was a statistically significant higher number of patients achieving 75% or higher reduction in ODSS in the treatment group compared with the placebo group at the end of 28 weeks (28 [88%] vs 15 [47%], a 41 [95% CI, 20-61] percentage point difference between groups; P .99; Cramér V = 0.07).
CONCLUSION AND RELEVANCE
In this randomized clinical trial, the combination of oral acitretin and TAC was more effective than TAC monotherapy in patients with symptomatic OLP.
TRIAL REGISTRATION
Clinical Trial Registry of India Identifier: CTRI/2018/11/016448
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