Crizotinib, an anaplastic lymphoma kinase (ALK) inhibitor, is a first-line treatment for ALK translocation–positive advanced non–small cell lung cancer (NSCLC); however, patients eventually progress. ...Immunotherapies, including the programmed death-1 inhibitor nivolumab, have resulted in durable responses and long-term overall survival in patients with NSCLC. We hypothesized that combining targeted therapy with immunotherapy could result in more patients with responses and/or more durable responses. Herein we report data from a study assessing nivolumab plus crizotinib in patients with previously untreated advanced ALK translocation–positive NSCLC.
Group E in CheckMate 370 was a single-arm cohort designed to evaluate the safety of first-line nivolumab (240 mg every 2 weeks) plus crizotinib (250 mg twice daily) in patients with ALK translocation–positive NSCLC. The primary endpoint of safety would be met if ≤20% of patients discontinued treatment due to treatment-related adverse events by week 17. Objective response rate was a secondary endpoint. A planned safety review occurred in November 2016; the data cutoff was May 26, 2017.
Of the first 13 patients treated with nivolumab plus crizotinib, 5 (38%) developed severe hepatic toxicities leading to the discontinuation of the combination. Of these, two patients died and the presence of severe hepatic toxicities may have contributed to death. Enrollment was closed and combination treatment discontinued due to observed grade ≥3 hepatic toxicities. Five patients (38%) had a partial response.
These findings do not support further evaluation of nivolumab 240 mg every 2 weeks plus crizotinib 250 mg twice daily.
Structural variation (SV), involving deletions, duplications, inversions and translocations of DNA segments, is a major source of genetic variability in somatic cells and can dysregulate ...cancer-related pathways. However, discovering somatic SVs in single cells has been challenging, with copy-number-neutral and complex variants typically escaping detection. Here we describe single-cell tri-channel processing (scTRIP), a computational framework that integrates read depth, template strand and haplotype phase to comprehensively discover SVs in individual cells. We surveyed SV landscapes of 565 single cells, including transformed epithelial cells and patient-derived leukemic samples, to discover abundant SV classes, including inversions, translocations and complex DNA rearrangements. Analysis of the leukemic samples revealed four times more somatic SVs than cytogenetic karyotyping, submicroscopic copy-number alterations, oncogenic copy-neutral rearrangements and a subclonal chromothripsis event. Advancing current methods, single-cell tri-channel processing can directly measure SV mutational processes in individual cells, such as breakage-fusion-bridge cycles, facilitating studies of clonal evolution, genetic mosaicism and SV formation mechanisms, which could improve disease classification for precision medicine.
Microbial Translocation (MT) and altered gut microbiota are involved in immune activation and inflammation, whereas immune checkpoint proteins play an important role in maintaining immune ...self-tolerance and preventing excessive immune activation.
This study aims to investigate the relationship between plasma phage load and immune homeostasis in people living with HIV(PLWH).
We recruited 15 antiretroviral therapy (ART)-naive patients, 23 ART-treated (AT) patients, and 34 Healthy Participants (HP) to explore the relationship between the plasma phage load and immune checkpoint proteins. The Deoxyribonucleic Acid (DNA) load of the lambda (λ) phage was detected using fluorescence quantitative Polymerase Chain Reaction (PCR). The Immune Checkpoints (ICPs) were detected using multiplex immunoassay.
Our study demonstrated that the plasma phage load was increased in people living with HIV (PLWH) (P<0.05), but not in the ART-naive and AT groups (P>0.05). Plasma ICPs, including cluster of differentiation 27 (CD27), soluble glucocorticoid-induced Tumor Necrosis Factor (TNF) receptor (sGITR), soluble cluster of differentiation 80 (sCD80), sCD86, soluble glucocorticoidinduced TNF receptor-related ligand (sGITRL), soluble induced T-cell Costimulatory (sICOS), sCD40, soluble toll-like receptor 2 (sTLR2), and sCD28, were markedly decreased among the ARTnaive group (P<0.05) but not in the AT and HP groups (P>0.05). The plasma phage load was positively correlated with ICP and C-reactive protein (CRP) levels in PLWH (P<0.05).
Our study indicated that the plasma phage load in PLWH was positively related to the expression of ICPs and inflammation, which may be used as a promising marker for the immune level of PLWH.
Trends in animal translocation research Evans, Maldwyn J.; Pierson, Jennifer C.; Neaves, Linda E. ...
Ecography (Copenhagen),
March 2023, 2023-03-00, 20230301, Volume:
2023, Issue:
3
Journal Article
Peer reviewed
Open access
Translocations are an important conservation tool that enable the restoration of species and their ecological functions. They are particularly important during the current environmental crisis. We ...used a combination of text‐analysis tools to track the history and evolution of the peer‐reviewed scientific literature on animal translocation science. We compared this corpus with research showcased in the IUCNs Global Conservation Translocation Perspectives, a curated collection of non‐peer‐reviewed reintroduction case studies. We show that the peer‐reviewed literature, in its infancy, was dominated by charismatic species. It then grew in two classical threads: management of the species of concern and management of the environment of the species. The peer‐reviewed literature exhibits a bias towards large charismatic mammals, and while these data are invaluable, expansion to under‐represented groups such as insects and reptiles will be critical to combating biodiversity loss across taxonomic groups. These biases were similar in the Translocation Perspectives, but with some subtle differences. To ensure translocation science can address global issues, we need to overcome barriers that restrict this research to a limited number of countries.
BackgroundChromosomal rearrangements have profound consequences in diverse human genetic diseases. Currently, the detection of balanced chromosomal rearrangements (BCRs) mainly relies on routine ...cytogenetic G-banded karyotyping. However, cryptic BCRs are hard to detect by karyotyping, and the risk of miscarriage or delivering abnormal offspring with congenital malformations in carrier couples is significantly increased. In the present study, we aimed to investigate the potential of single-molecule optical genome mapping (OGM) in unravelling cryptic chromosomal rearrangements.MethodsEleven couples with normal karyotypes that had abortions/affected offspring with unbalanced rearrangements were enrolled. Ultra-high-molecular-weight DNA was isolated from peripheral blood cells and processed via OGM. The genome assembly was performed followed by variant calling and annotation. Meanwhile, multiple detection strategies, including FISH, long-range-PCR amplicon-based next-generation sequencing and Sanger sequencing were implemented to confirm the results obtained from OGM.ResultsHigh-resolution OGM successfully detected cryptic reciprocal translocation in all recruited couples, which was consistent with the results of FISH and sequencing. All high-confidence cryptic chromosomal translocations detected by OGM were confirmed by sequencing analysis of rearrangement breakpoints. Moreover, OGM revealed additional complex rearrangement events such as inverted aberrations, further refining potential genetic interpretation.ConclusionTo the best of our knowledge, this is the first study wherein OGM facilitate the rapid and robust detection of cryptic chromosomal reciprocal translocations in clinical practice. With the excellent performance, our findings suggest that OGM is well qualified as an accurate, comprehensive and first-line method for detecting cryptic BCRs in routine clinical testing.
Background: Chromosomal rearrangements play an important role in infertility. Carriers of chromosomal rearrangements have a lower chance of producing normal or balanced gametes due to abnormal ...segregation of chromosomes at meiosis, which leads to recurrent spontaneous abortions and infertility. Preimplantation genetic testing for structural chromosome rearrangements (PGT-SR) is offered to couples who have balanced chromosomal rearrangements in order to select embryos with a balanced karyotype prior to implantation, thereby increasing the chances of pregnancy. The purpose of the current study was to assess the outcomes of PGT-SR in patients carrying various balanced chromosomal rearrangements and to assess their clinical pregnancy outcome after in vitro fertilization (IVF). Methods: In this study, infertile couples with balanced chromosomal abnormalities undergoing PGT-SR were retrospectively analyzed at a single fertility center from January 2016 to December 2019. Results: PGT-SR was performed on 87 embryos from 22 couples in whom one partner carried a balanced translocation or an inversion. Fifty-seven (65.5%) of these embryos had unbalanced or sporadic aneuploidies, 30 (34.5%) embryos were normal or chromosomally balanced, which were then transferred in 18 couples. A higher rate of unbalanced translocations in comparison to sporadic aneuploidies was observed in couples with reciprocal translocation. The live birth rate per embryo transfer was found to be 66.6% (12/18). Conclusion: PGT-SR is a useful tool in selecting normal or balanced embryos for transfer in IVF, which could lead to a pregnancy by reducing the chance of miscarriages due to chromosome aneuploidy in couples with balanced chromosomal rearrangements. Keywords: Aneuploidy, Balanced chromosomal rearrangements, In vitro fertilization, Inversion, Preimplantation genetic testing, Reciprocal translocation, Recurrent miscarriages, Robertsonian translocation.
Chromosomal NUP98-PHF23 translocation is associated with an aggressive form of acute myeloid leukemia (AML) and poor survival rate. Here, we report the molecular mechanisms by which NUP98-PHF23 ...recognizes the histone mark H3K4me3 and is inhibited by small molecule compounds, including disulfiram that directly targets the PHD finger of PHF23 (PHF23PHD). Our data support a critical role for the PHD fingers of NUP98-PHF23, and related NUP98-KDM5A and NUP98-BPTF fusions in driving leukemogenesis, and demonstrate that blocking this interaction in NUP98-PHF23 expressing AML cells leads to cell death through necrotic and late apoptosis pathways. An overlap of NUP98-KDM5A oncoprotein binding sites and H3K4me3-positive loci at the Hoxa/b gene clusters and Meis1 in ChIP-seq, together with NMR analysis of the H3K4me3-binding sites of the PHD fingers from PHF23, KDM5A and BPTF, suggests a common PHD finger-dependent mechanism that promotes leukemogenesis by this type of NUP98 fusions. Our findings highlight the direct correlation between the abilities of NUP98-PHD finger fusion chimeras to associate with H3K4me3-enriched chromatin and leukemic transformation.
To determine the effect of different translocation characteristics on fertilization rate and blastocyst development in chromosomal translocation patients. This retrospective cohort study was ...conducted at the Third Affiliated Hospital of Zhengzhou University From January 2017 to December 2022.All couples were diagnosed as reciprocal translocation or Robertsonian translocation by karyotype of peripheral blood lymphocytes test. After adjusting for confounding factors, the effect of chromosomal rearrangement characteristics, such as carrier sex, translocation type, chromosome length and break sites, on fertilization rate and embryo development were analysed separately using multiple linear regression. In cases of Robertsonian translocation (RobT), the carrier sex plays an independent role in fertilization rate, and the male carriers was lower than that of female carriers (76.16% vs.86.26%, P = 0.009). In reciprocal translocation (RecT), the carrier sex, chromosome types and break sites had no influence on fertilization rate, blastocyst formation rate (P > 0.05). However, patients with human longer chromosomal (chromosomes 1-5) translocation have a lower available blastocyst formation rate (Group AB vs. Group CD: 41.49%vs.46.01%, P = 0.027). For male carriers, the translocation types was an independent factor affecting the fertilization rate, and the RobT was the negative one (B = - 0.075, P = 0 0.009). In female carriers, we did not observe this difference (P = 0.227). In patients with chromosomal translocation, the fertilization rate may be influenced by carrier sex and translocation type, chromosomes 1-5 translocation may adversely affect the formation of available blastocysts. Break sites have no role in fertilization and blastocyst development.
Rhabdomyosarcoma (RMS) arises from abnormal muscle development. We reported previously that Fragile-X-Related 1 (FXR1), essential to normal myogenesis, was highly expressed in RMS relative to other ...embryonal tumors. This current study explored FXR1 expression across RMS disease characteristics and treatment response.
RMS patients ≤18 years (1980–2019; n = 152) were categorized according to tumor histology, PAX/FOXO1 translocation, and vital status. FXR1 protein expression was compared before and after chemotherapy. Impact of FXR1 expression on relapse-free (RFS) and overall survival (OS) was analyzed.
FXR1 was most intensely expressed in the cytosol of undifferentiated rhabdomyoblasts. At diagnosis, FXR1 expression was ubiquitous and strong across all disease characteristics and foremost associated with worse RFS in translocation-positive patients (p = 0.0411). Among embryonal and translocation-negative RMS, survivors showed a significantly greater decrease in FXR1 expression after chemotherapy (p < 0.001) compared to decedents (p = 0.8). In contrast, alveolar and translocation-positive RMS specimens showed insignificant changes in FXR1 expression across therapy. As expected, alveolar histology, translocation presence, stage, and clinical group associated with worse survival.
FXR1 was expressed strongly across RMS specimens at diagnosis regardless of disease or patient characteristics, and particularly in undifferentiated cells. Reduction in FXR1 expression after chemotherapy associated with improved survival for embryonal and translocation-negative RMS patients.
The translocase of the outer mitochondrial membrane (TOM) complex is the main entry gate for most mitochondrial proteins. The TOM complex is a multisubunit membrane protein complex consisting of a ...β‐barrel protein Tom40 and six α‐helical transmembrane (TM) proteins, receptor subunits Tom20, Tom22, and Tom70, and regulatory subunits Tom5, Tom6, and Tom7. Although nearly 30 years have passed since the main components of the TOM complex were identified and characterized, the structural details of the TOM complex remained poorly understood until recently. Thanks to the rapid development of the cryoelectron microscopy (EM) technology, high‐resolution structures of the yeast TOM complex have become available. The identified structures showed a symmetric dimer containing five different subunits including Tom22. Biochemical and mutational analyses based on the TOM complex structure revealed the presence of different translocation paths within the Tom40 import channel for different classes of translocating precursor proteins. Previous studies including our cross‐linking analyses indicated that the TOM complex in intact mitochondria is present as a mixture of the trimeric complex containing Tom22. Furthermore, the dimeric complex lacking Tom22, and the trimer and dimer may handle different sets of mitochondrial precursor proteins for translocation across the outer membrane. In this Structural Snapshot, we will discuss possible rearrangement of the subunit interactions upon dynamic conversion of the TOM complex between the different subunit assembly states, the Tom22‐containing core dimer and trimer.
The cryoelectron microscopy structures of the mitochondrial protein import gate, the translocase of the outer mitochondrial membrane (TOM) complex, have become available. The yeast TOM complex structure shows the presence of two paths within the import channel for different classes of mitochondrial precursor proteins. This explains how the TOM import channel can handle and translocate ˜ 1000 different precursor proteins with different physical and chemical properties from the cytosol to the mitochondrial interior across the outer membrane.
PDF
