Abstract
Summary
Cellular lineage trees can be derived from single-cell RNA sequencing snapshots of differentiating cells. Currently, only datasets with simple topologies are available. To test and ...further develop tools for lineage tree reconstruction, we need test datasets with known complex topologies. PROSSTT can simulate scRNA-seq datasets for differentiation processes with lineage trees of any desired complexity, noise level, noise model and size. PROSSTT also provides scripts to quantify the quality of predicted lineage trees.
Availability and implementation
https://github.com/soedinglab/prosstt.
Supplementary information
Supplementary data are available at Bioinformatics online.
The frustratometer is an energy landscape theory-inspired algorithm that aims at quantifying the location of frustration manifested in protein molecules. Frustration is a useful concept for gaining ...insight to the proteins biological behavior by analyzing how the energy is distributed in protein structures and how mutations or conformational changes shift the energetics. Sites of high local frustration often indicate biologically important regions involved in binding or allostery. In contrast, minimally frustrated linkages comprise a stable folding core of the molecule that is conserved in conformational changes. Here, we describe the implementation of these ideas in a webserver freely available at the National EMBNet node-Argentina, at URL: http://lfp.qb.fcen.uba.ar/embnet/.
Pediatric psychologists are often interested in finding patterns in heterogeneous longitudinal data. Latent variable mixture modeling is an emerging statistical approach that models such ...heterogeneity by classifying individuals into unobserved groupings (latent classes) with similar (more homogenous) patterns. The purpose of the second of a 2-article set is to offer a nontechnical introduction to longitudinal latent variable mixture modeling.
3 latent variable approaches to modeling longitudinal data are reviewed and distinguished.
Step-by-step pediatric psychology examples of latent growth curve modeling, latent class growth analysis, and growth mixture modeling are provided using the Early Childhood Longitudinal Study-Kindergarten Class of 1998-1999 data file.
Latent variable mixture modeling is a technique that is useful to pediatric psychologists who wish to find groupings of individuals who share similar longitudinal data patterns to determine the extent to which these patterns may relate to variables of interest.
In this study we assessed the relationship between the laboratory and field performance of different isofemale lines of Trichogramma pretiosum Riley. In comparative assays, we used three rare ...mitochondrial haplotypes as genetic markers of the isofemale lines, and by introgressing these mitochondrial haplotypes into each of 15 genetically different nuclear lines, also tested the assumption that mitochondria are neutral markers. In a laboratory trial, 45 isofemale lines (15 nuclear genotypes x three mitochondrial haplotypes) were ranked in three categories (best, intermediate and worst) according to the mean offspring production and the proportion of female offspring. Subsequently, lines from each of the three categories were selected for field releases to quantify field parasitism on Ephestia kuehniella. Temporally separate releases were done in a transgenic Bt cornfield, with four plots, each with 50 points of recapture. The points of recapture consisted of trap cards with eggs of E. kuehniella collected daily. The trap cards were maintained in the laboratory at 25°C until the adult wasps emerged, and the maternal identity of the wasps was determined using qPCR and high-resolution melt curve analysis to determine the mitochondrial haplotype. The results showed that these measures of laboratory performance (fecundity and offspring sex ratio) were good predictors of field success in T. pretiosum. We also report strong evidence discrediting the assumption that mitochondria are neutral, in view of the correlation between performance and mitochondrial haplotype.
Non-small-cell lung cancer (NSCLC) is terminal in most patients with locally advanced stage disease. We aimed to assess the antitumour activity and safety of neoadjuvant chemoimmunotherapy for ...resectable stage IIIA NSCLC.
This was an open-label, multicentre, single-arm phase 2 trial done at 18 hospitals in Spain. Eligible patients were aged 18 years or older with histologically or cytologically documented treatment-naive American Joint Committee on Cancer-defined stage IIIA NSCLC that was deemed locally to be surgically resectable by a multidisciplinary clinical team, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received neoadjuvant treatment with intravenous paclitaxel (200 mg/m2) and carboplatin (area under curve 6; 6 mg/mL per min) plus nivolumab (360 mg) on day 1 of each 21-day cycle, for three cycles before surgical resection, followed by adjuvant intravenous nivolumab monotherapy for 1 year (240 mg every 2 weeks for 4 months, followed by 480 mg every 4 weeks for 8 months). The primary endpoint was progression-free survival at 24 months, assessed in the modified intention-to-treat population, which included all patients who received neoadjuvant treatment, and in the per-protocol population, which included all patients who had tumour resection and received at least one cycle of adjuvant treatment. Safety was assessed in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03081689, and is ongoing but no longer recruiting patients.
Between April 26, 2017, and Aug 25, 2018, we screened 51 patients for eligibility, of whom 46 patients were enrolled and received neoadjuvant treatment. At the time of data cutoff (Jan 31, 2020), the median duration of follow-up was 24·0 months (IQR 21·4–28·1) and 35 of 41 patients who had tumour resection were progression free. At 24 months, progression-free survival was 77·1% (95% CI 59·9–87·7). 43 (93%) of 46 patients had treatment-related adverse events during neoadjuvant treatment, and 14 (30%) had treatment-related adverse events of grade 3 or worse; however, none of the adverse events were associated with surgery delays or deaths. The most common grade 3 or worse treatment-related adverse events were increased lipase (three 7%) and febrile neutropenia (three 7%).
Our results support the addition of neoadjuvant nivolumab to platinum-based chemotherapy in patients with resectable stage IIIA NSCLC. Neoadjuvant chemoimmunotherapy could change the perception of locally advanced lung cancer as a potentially lethal disease to one that is curable.
Bristol-Myers Squibb, Instituto de Salud Carlos III, European Union's Horizon 2020 research and innovation programme.
Programmed cell death ligand 1 (PD-L1) is a major immune checkpoint protein that mediates antitumor immune suppression and response. Preliminary data suggest that its detection using ...immunohistochemistry (IHC) in formalin-fixed and paraffin-embedded tissues may predict clinical response to PD-1/PD-L1 therapy. In diagnostic pathology, it is essential to count with a validated IHC that can reliably detect PD-L1-positive cases. The present study was conducted to compare and validate different PD-L1 commercial clones and identify which ones can be reliably used by surgical pathologist to detect PD-L1 expression in human cancer tissues. Eight commercial available PD-L1 clones were tested and compared with a noncommercial PD-L1 antibody clone 5H1. Western blot and IHC using cell lines and human tissues were used to validate these clones. From all PD-L1 antibodies, only the clones E1L3N, E1J2J, SP142, 28-8, 22C3, and SP263 passed the Western blot and IHC validation, providing similar pattern than the clone 5H1 and then they were tested in 259 non-small cell lung cancer cases placed in 9 tissue microarrays. Among all cases, only those with ≥2 cores were included (185 cases). Positive and significant correlation was found between the median PD-L1 H-score in tumor and stroma compartments, for all selected antibodies. Overall, 56 of 185 cases were detected as positive cases in malignant cells expressing membranous PD-L1 by all the clones. However, the clone SP263 identified more PD-L1-positive cases compared with the other clones. Our results show that clones E1L3N, E1J2J, SP142, 28-8, 22C3, and SP263 provide positive membrane staining pattern comparable with clone 5H1. These commercial clones are comparable, but a careful evaluation by the pathologist is necessary to minimize error of positive misinterpretations.
The protein frustratometer is an energy landscape theory-inspired algorithm that aims at localizing and quantifying the energetic frustration present in protein molecules. Frustration is a useful ...concept for analyzing proteins' biological behavior. It compares the energy distributions of the native state with respect to structural decoys. The network of minimally frustrated interactions encompasses the folding core of the molecule. Sites of high local frustration often correlate with functional regions such as binding sites and regions involved in allosteric transitions. We present here an upgraded version of a webserver that measures local frustration. The new implementation that allows the inclusion of electrostatic energy terms, important to the interactions with nucleic acids, is significantly faster than the previous version enabling the analysis of large macromolecular complexes within a user-friendly interface. The webserver is freely available at URL: http://frustratometer.qb.fcen.uba.ar.
We report the first case series of immune checkpoint inhibitors (ICI)-associated colitis successfully treated with fecal microbiota transplantation, with reconstitution of the gut microbiome and a ...relative increase in the proportion of regulatory T-cells within the colonic mucosa. These preliminary data provide evidence that modulation of the gut microbiome may abrogate ICI-associated colitis.
Immune-profiling is becoming an important tool to identify predictive markers for the response to immunotherapy. Our goal was to validate multiplex immunofluorescence (mIF) panels to apply to ...formalin-fixed and paraffin-embedded tissues using a set of immune marker antibodies, with the Opal™ 7 color Kit (PerkinElmer) in the same tissue section. We validated and we described two panels aiming to characterize the expression of PD-L1, PD-1, and subsets of tumor associated immune cells. Panel 1 included pancytokeratin (AE1/AE3), PD-L1, CD4, CD8, CD3, CD68, and DAPI, and Panel 2 included pancytokeratin, PD-1, CD45RO, granzyme B, CD57, FOXP3, and DAPI. After all primary antibodies were tested in positive and negative controls by immunohistochemistry and uniplex IF, panels were developed and simultaneous marker expressions were quantified using the Vectra 3.0™ multispectral microscopy and image analysis InForm™ 2.2.1 software (PerkinElmer).These two mIF panels demonstrated specific co-localization in different cells that can identify the expression of PD-L1 in malignant cells and macrophages, and different T-cell subpopulations. This mIF methodology can be an invaluable tool for tumor tissue immune-profiling to allow multiple targets in the same tissue section and we provide that is accurate and reproducible method when is performed carefully under pathologist supervision.
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