Burkitt lymphoma is characterized by deregulation of MYC, but the contribution of other genetic mutations to the disease is largely unknown. Here, we describe the first completely sequenced genome ...from a Burkitt lymphoma tumor and germline DNA from the same affected individual. We further sequenced the exomes of 59 Burkitt lymphoma tumors and compared them to sequenced exomes from 94 diffuse large B-cell lymphoma (DLBCL) tumors. We identified 70 genes that were recurrently mutated in Burkitt lymphomas, including ID3, GNA13, RET, PIK3R1 and the SWI/SNF genes ARID1A and SMARCA4. Our data implicate a number of genes in cancer for the first time, including CCT6B, SALL3, FTCD and PC. ID3 mutations occurred in 34% of Burkitt lymphomas and not in DLBCLs. We show experimentally that ID3 mutations promote cell cycle progression and proliferation. Our work thus elucidates commonly occurring gene-coding mutations in Burkitt lymphoma and implicates ID3 as a new tumor suppressor gene.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The structure of the human gastrointestinal microbiota can change during pregnancy, which may influence gestational metabolism; however, a mechanism of action remains unclear. Here we observed that ...in wild-type (WT) mice the relative abundance of Actinobacteria and Bacteroidetes increased during pregnancy. Along with these changes, short-chain fatty acids (SCFAs), which are mainly produced through gut microbiota fermentation, significantly changed in both the cecum and peripheral blood throughout gestation in these mice. SCFAs are recognized by G protein-coupled receptors (GPCRs) such as free fatty acid receptor-2 (FFA2), and we have previously demonstrated that the fatty acid receptor-2 gene (Ffar2) expression is higher in pancreatic islets during pregnancy. Using female Ffar2-/- mice, we explored the physiological relevance of signaling through this GPCR and found that Ffar2-deficient female mice developed fasting hyperglycemia and impaired glucose tolerance in the setting of impaired insulin secretion compared with WT mice during, but not before, pregnancy. Insulin tolerance tests were similar in Ffar2-/- and WT mice before and during pregnancy. Next, we examined the role of FFA2 in gestational β-cell mass, observing that Ffar2-/- mice had diminished gestational expansion of β-cells during pregnancy. Interestingly, mouse genotype had no significant impact on the composition of the gut microbiome, but did affect the observed SCFA profiles, suggesting a functional difference in the microbiota. Together, these results suggest a potential link between increased Ffar2 expression in islets and the alteration of circulating SCFA levels, possibly explaining how changes in the gut microbiome contribute to gestational glucose homeostasis.
The Children's Oncology Group (COG) protocol AALL0434 evaluated the safety and efficacy of multi-agent chemotherapy with Capizzi-based methotrexate/pegaspargase (C-MTX) in patients with newly ...diagnosed pediatric T-cell lymphoblastic lymphoma (T-LL) and gained preliminary data using nelarabine in high-risk patients.
The trial enrolled 299 patients, age 1-31 years. High-risk (HR) patients had ≥ 1% minimal detectable disease (MDD) in the bone marrow at diagnosis or received prior steroid treatment. Induction failure was defined as failure to achieve a partial response (PR) by the end of the 4-week induction. All patients received the augmented Berlin-Frankfurt-Muenster (ABFM) C-MTX regimen. HR patients were randomly assigned to receive or not receive 6 5-day courses of nelarabine incorporated into ABFM. Patients with induction failure were nonrandomly assigned to ABFM C-MTX plus nelarabine. No patients received prophylactic cranial radiation; however, patients with CNS3 disease (CSF WBC ≥ 5/μL with blasts or cranial nerve palsies, brain/eye involvement, or hypothalamic syndrome) were ineligible.
At end-induction, 98.8% of evaluable participants had at least a PR. The 4-year event-free survival (EFS) and overall survival (OS) were 84.7% ± 2.3% and 89.0% ± 2.0%. The 4-year disease-free survival (DFS) from end-induction was 85.9% ± 2.6%. There was no difference in DFS observed between the HR and standard-risk groups (
= .29) or by treatment regimen (
= .55). Disease stage, tumor response, and MDD at diagnosis did not demonstrate thresholds that resulted in differences in EFS. Nelarabine did not show an advantage for HR patients. CNS relapse occurred in only 4 patients.
COG AALL0434 produced excellent outcomes in one of the largest trials ever conducted for patients with newly diagnosed T-LL. The COG ABFM regimen with C-MTX provided excellent EFS and OS without cranial radiation.
Mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, can lead to disfiguring lesions, debilitating pruritus and frequent skin infections. This study assessed response to ...brentuximab vedotin in patients with MF in the phase III ALCANZA study.
Baseline CD30 levels and large-cell transformation (LCT) status were centrally reviewed in patients with previously-treated CD30-positive MF using ≥2 skin biopsies obtained at screening; eligible patients required ≥1 biopsy with ≥10% CD30 expression. Patients were categorised as CD30min < 10% (≥1 biopsy with <10% CD30 expression), or CD30min ≥ 10% (all biopsies with ≥10% CD30 expression) and baseline LCT present or absent. Efficacy analyses were the proportion of patients with objective response lasting ≥4 months (ORR4) and progression-free survival (PFS).
Clinical activity with brentuximab vedotin was observed across all CD30 expression levels in patients with ≥1 biopsy showing ≥10% CD30 expression. Superior ORR4 was observed with brentuximab vedotin versus physician’s choice in patients: with CD30min < 10% (40.9% versus 9.5%), with CD30min ≥ 10% (57.1% versus 10.3%), with LCT (64.7% versus 17.6%) and without LCT (38.7% versus 6.5%). Brentuximab vedotin improved median PFS versus physician’s choice in patients: with CD30min < 10% (16.7 versus 2.3 months), with CD30min ≥ 10% (15.5 versus 3.9 months), with LCT (15.5 versus 2.8 months) and without LCT (16.1 versus 3.5 months). Safety profiles were generally comparable across subgroups.
These exploratory analyses demonstrated that brentuximab vedotin improved rates of ORR4 and PFS versus physician’s choice in patients with CD30-positive MF and ≥1 biopsy showing ≥10% CD30 expression, regardless of LCT status.
Clinicaltrials.gov, NCT01578499.
•Patients with mycosis fungoides (MF) have pruritic and infected skin lesions.•Those with advanced-stage disease or large cell transformation have a poor prognosis.•ALCANZA, a phase III study, showed a superior outcome of brentuximab vedotin (BV).•This study assessed responses in the MF subset by CD30 or large cell transformation.•BV was active regardless of baseline CD30 levels/large-cell transformation status.
Clinical treatment of cancer commonly incorporates X‐ray radiation therapy (XRT), and developing spatially precise radiation‐activatable drug delivery strategies may improve XRT efficacy while ...limiting off‐target toxicities associated with systemically administered drugs. Nevertheless, achieving this has been challenging thus far because strategies typically rely on radical species with short lifespans, and the inherent nature of hypoxic and acidic tumor microenvironments may encourage spatially heterogeneous effects. It is hypothesized that the challenge could be bypassed by using scintillating nanoparticles that emit light upon X‐ray absorption, locally forming therapeutic drug depots in tumor tissues. Thus a nanoparticle platform (Scintillating nanoparticle Drug Depot; SciDD) that enables the local release of cytotoxic payloads only after activation by XRT is developed, thereby limiting off‐target toxicity. As a proof‐of‐principle, SciDD is used to deliver a microtubule‐destabilizing payload MMAE (monomethyl auristatin E). With as little as a 2 Gy local irradiation to tumors, MMAE payloads are released effectively to kill tumor cells. XRT‐mediated drug release is demonstrated in multiple mouse cancer models and showed efficacy over XRT alone (p < 0.0001). This work shows that SciDD can act as a local drug depot with spatiotemporally controlled release of cancer therapeutics.
Clinical cancer treatment often involves X‐ray radiation therapy, and spatially precise radiation treatment offers the possibility of improving the therapeutic window of systemic chemotherapies designed to be activated by irradiation. This work presents scintillating nanoparticles that generate light in response to irradiation, uncaging a reservoir of sustained chemotherapy release within tumor tissue while sparing off‐target sites of toxicity.
Iliopsoas tendonitis, typically caused by impingement with the acetabular cup, occurs in up to 18% of patients after total hip arthroplasty (THA) and up to 30% of patients after hip resurfacing ...arthroplasty (HRA). We have developed a simulation for detecting iliopsoas impingement and validated it in a previous study of THA patients. However, due to the difference in incidence between HRA and THA, this study had two aims. First, to validate the simulation in a cohort of HRA patients and, second, to comparethe results of the HRA and THA patients to understand any differences in their etiology. We conducted a retrospective search in an experienced surgeon's database for HRA patients with iliopsoas tendonitisand control patients without iliopsoas tendonitis, resulting in two cohorts of 12 patients. Using CT scans, 3D models of the each patient's prosthetic and bony anatomy were generated, landmarked, and simulated. Regarding validation of the simulation for HRA patients, impingement significantly predicted the probability of iliopsoas tendonitis in logistic regression models and the simulation had a sensitivity of 83%, specificity of 100%, and an AUC ROC curve of 0.95. Unexpectedly, the HRA cohort exhibited less impingement than the THA cohort. Our novel simulation has now been demonstrated to detect iliopsoas impingement and differentiate between the symptomatic and asymptomatic cohorts in investigations of THA and HRA patients. This tool has the potential to be used preoperatively, to guide decisions about optimal cup placement, and postoperatively, to assist in the diagnosis of iliopsoas tendonitis.
This study aims to identify preoperative risk factors for iliopsoas tendonitis after total hip arthroplasty, a complication typically attributed to acetabular cup position and orientation, using a ...validated iliopsoas impingement detection simulation. Analyzing CT scans and X-rays of 448 patients using a validated preoperative planning protocol, patients were simulated for iliopsoas impingement and categorized into at-risk and not at-risk groups based on a prior validation study, with a 23% at-risk incidence. Implementing a propensity score matching algorithm to reduce covariate imbalance, we identified factors that may exacerbate risk of iliopsoas tendonitis. Parameters that were investigated included standing pelvic tilt, functional femoral rotation, and the difference between the planned acetabular cup diameter and native femoral head diameter (ΔC-NFH). Comparing pelvic tilt, we found a significant difference between the groups (at-risk: -6.0°, not at-risk: -0.7°; p << 0.01). A similar trend was noted for ΔC-NFH (at-risk: +5.7 mm, not at-risk: +5.1 mm; p = 0.01). Additional simulations of at-risk patients indicated increased anteversion of the acetabular cup reduces impingement risk more effectively than medialisation. These findings suggest that spinopelvic parameters may exacerbate iliopsoas irritation risk, underscoring their importance in preoperative planning and patient expectation management. Similar findings of a greater than 6 mm difference between cup size and native femoral head diameter being a significant risk for iliopsoas tendonitis have been observed before, underscoring its potential veracity. These results may provide surgeons with a simple threshold that can be used in determining a cup size to reduce the risk of iliopsoas tendonitis.
Iliopsoas impingement occurs in 4% to 30% of patients after undergoing total hip arthroplasty (THA). Despite a relatively high incidence, there are few attempts at modelling impingement between the ...iliopsoas and acetabular component, and no attempts at modelling this in a representative cohort of subjects. The purpose of this study was to develop a novel computational model for quantifying the impingement between the iliopsoas and acetabular component and validate its utility in a case-controlled investigation.
This was a retrospective cohort study of patients who underwent THA surgery that included 23 symptomatic patients diagnosed with iliopsoas tendonitis, and 23 patients not diagnosed with iliopsoas tendonitis. All patients received postoperative CT imaging, postoperative standing radiography, and had minimum six months' follow-up. 3D models of each patient's prosthetic and bony anatomy were generated, landmarked, and simulated in a novel iliopsoas impingement detection model in supine and standing pelvic positions. Logistic regression models were implemented to determine if the probability of pain could be significantly predicted. Receiver operating characteristic curves were generated to determine the model's sensitivity, specificity, and area under the curve (AUC).
Highly significant differences between the symptomatic and asymptomatic cohorts were observed for iliopsoas impingement. Logistic regression models determined that the impingement values significantly predicted the probability of groin pain. The simulation had a sensitivity of 74%, specificity of 100%, and an AUC of 0.86.
We developed a computational model that can quantify iliopsoas impingement and verified its accuracy in a case-controlled investigation. This tool has the potential to be used preoperatively, to guide decisions about optimal cup placement, and postoperatively, to assist in the diagnosis of iliopsoas tendonitis.Cite this article:
2023;4(1):3-12.
Myelofibrosis is a hematopoietic stem cell neoplasm characterized by bone marrow reticulin fibrosis, extramedullary hematopoiesis, and frequent transformation to acute myeloid leukemia. Constitutive ...activation of JAK/STAT signaling through mutations in
, or
is central to myelofibrosis pathogenesis. JAK inhibitors such as ruxolitinib reduce symptoms and improve quality of life, but are not curative and do not prevent leukemic transformation, defining a need to identify better therapeutic targets in myelofibrosis.
A short hairpin RNA library screening was performed on JAK2
-mutant HEL cells. Nuclear-cytoplasmic transport (NCT) genes including
and
were among top candidates. JAK2
-mutant cell lines, human primary myelofibrosis CD34
cells, and a retroviral JAK2
-driven myeloproliferative neoplasms mouse model were used to determine the effects of inhibiting NCT with selective inhibitors of nuclear export compounds KPT-330 (selinexor) or KPT-8602 (eltanexor).
JAK2
-mutant HEL, SET-2, and HEL cells resistant to JAK inhibition are exquisitely sensitive to RAN knockdown or pharmacologic inhibition by KPT-330 or KPT-8602. Inhibition of NCT selectively decreased viable cells and colony formation by myelofibrosis compared with cord blood CD34
cells and enhanced ruxolitinib-mediated growth inhibition and apoptosis, both in newly diagnosed and ruxolitinib-exposed myelofibrosis cells. Inhibition of NCT in myelofibrosis CD34
cells led to nuclear accumulation of p53. KPT-330 in combination with ruxolitinib-normalized white blood cells, hematocrit, spleen size, and architecture, and selectively reduced JAK2
-mutant cells
.
Our data implicate NCT as a potential therapeutic target in myelofibrosis and provide a rationale for clinical evaluation in ruxolitinib-exposed patients with myelofibrosis.
Burkitt lymphoma (BL) is an aggressive, MYC-driven lymphoma comprising 3 distinct clinical subtypes: sporadic BLs that occur worldwide, endemic BLs that occur predominantly in sub-Saharan Africa, and ...immunodeficiency-associated BLs that occur primarily in the setting of HIV. In this study, we comprehensively delineated the genomic basis of BL through whole-genome sequencing (WGS) of 101 tumors representing all 3 subtypes of BL to identify 72 driver genes. These data were additionally informed by CRISPR screens in BL cell lines to functionally annotate the role of oncogenic drivers. Nearly every driver gene was found to have both coding and non-coding mutations, highlighting the importance of WGS for identifying driver events. Our data implicate coding and non-coding mutations in IGLL5, BACH2, SIN3A, and DNMT1. Epstein-Barr virus (EBV) infection was associated with higher mutation load, with type 1 EBV showing a higher mutational burden than type 2 EBV. Although sporadic and immunodeficiency-associated BLs had similar genetic profiles, endemic BLs manifested more frequent mutations in BCL7A and BCL6 and fewer genetic alterations in DNMT1, SNTB2, and CTCF. Silencing mutations in ID3 were a common feature of all 3 subtypes of BL. In vitro, mass spectrometry–based proteomics demonstrated that the ID3 protein binds primarily to TCF3 and TCF4. In vivo knockout of ID3 potentiated the effects of MYC, leading to rapid tumorigenesis and tumor phenotypes consistent with those observed in the human disease.
•We investigated all 3 subtypes of BL by WGS and transcriptome sequencing.•Experimental validation through CRISPR screening and mouse models provides a better functional understanding of BL genetic drivers.
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