exRNA Atlas Analysis Reveals Distinct Extracellular RNA Cargo Types and Their Carriers Present across Human Biofluids.

To develop a map of cell-cell communication mediated by extracellular RNA (exRNA), the NIH Extracellular RNA Communication Consortium created the exRNA Atlas resource (https://exrna-atlas.org). The Atlas version 4P1 hosts 5,309 exRNA-seq and exRNA qPCR profiles from 19 studies and a suite of analysis and visualization tools. To analyze variation between profiles, we apply computational deconvolution. The analysis leads to a model with six exRNA cargo types (CT1, CT2, CT3A, CT3B, CT3C, CT4), each detectable in multiple biofluids (serum, plasma, CSF, saliva, urine). Five of the cargo types associate with known vesicular and non-vesicular (lipoprotein and ribonucleoprotein) exRNA carriers. To validate utility of this model, we re-analyze an exercise response study by deconvolution to identify physiologically relevant response pathways that were not detected previously. To enable wide application of this model, as part of the exRNA Atlas resource, we provide tools for deconvolution and analysis of user-provided case-control studies.

The transcription factor Runx3 guards cytotoxic CD8+ effector T cells against deviation towards follicular helper T cell lineage.

Activated CD8+ T cells differentiate into cytotoxic effector (TEFF) cells that eliminate target cells. How TEFF cell identity is established and maintained is not fully understood. We found that Runx3 deficiency limited clonal expansion and impaired upregulation of cytotoxic molecules in TEFF cells. Runx3-deficient CD8+ TEFF cells aberrantly upregulated genes characteristic of follicular helper T (TFH) cell lineage, including Bcl6, Tcf7 and Cxcr5. Mechanistically, the Runx3-CBFß transcription factor complex deployed H3K27me3 to Bcl6 and Tcf7 genes to suppress the TFH program. Ablating Tcf7 in Runx3-deficient CD8+ TEFF cells prevented the upregulation of TFH genes and ameliorated their defective induction of cytotoxic genes. As such, Runx3-mediated Tcf7 repression coordinately enforced acquisition of cytotoxic functions and protected the cytotoxic lineage integrity by preventing TFH-lineage deviation.

Evolution and impact of subclonal mutations in chronic lymphocytic leukemia.

Clonal evolution is a key feature of cancer progression and relapse. We studied intratumoral heterogeneity in 149 chronic lymphocytic leukemia (CLL) cases by integrating whole-exome sequence and copy number to measure the fraction of cancer cells harboring each somatic mutation. We identified driver mutations as predominantly clonal (e.g., MYD88, trisomy 12, and del(13q)) or subclonal (e.g., SF3B1 and TP53), corresponding to earlier and later events in CLL evolution. We sampled leukemia cells from 18 patients at two time points. Ten of twelve CLL cases treated with chemotherapy (but only one of six without treatment) underwent clonal evolution, predominantly involving subclones with driver mutations (e.g., SF3B1 and TP53) that expanded over time. Furthermore, presence of a subclonal driver mutation was an independent risk factor for rapid disease progression. Our study thus uncovers patterns of clonal evolution in CLL, providing insights into its stepwise transformation, and links the presence of subclones with adverse clinical outcomes.

Mechanism of EBV inducing anti-tumour immunity and its therapeutic use.

Tumour-associated antigens (TAAs) comprise a large set of non-mutated cellular antigens recognized by T cells in human and murine cancers. Their potential as targets for immunotherapy has been explored for more than two decades1, yet the origins of TAA-specific T cells remain unclear. While tumour cells may be an important source of TAAs for T cell priming2, several recent studies suggest that infection with some viruses, including Epstein-Barr virus and influenza virus can elicit T cell responses against abnormally expressed cellular antigens that function as TAAs3,4. However, the cellular and molecular basis of such responses remains undefined. Here we show that expression of the Epstein-Barr virus signalling protein LMP1 in B cells provokes T cell responses to multiple TAAs. LMP1 signalling leads to overexpression of many cellular antigens previously shown to be TAAs, their presentation on major histocompatibility complex classes I (MHC-I) and II (MHC-II) (mainly through the endogenous pathway) and the upregulation of costimulatory ligands CD70 and OX40L, thereby inducing potent cytotoxic CD4+ and CD8+ T cell responses. These findings delineate a mechanism of infection-induced anti-tumour immunity. Furthermore, by ectopically expressing LMP1 in tumour B cells from patients with cancer and thereby enabling them to prime T cells, we develop a general approach for rapid production of autologous cytotoxic CD4+ T cells against a wide range of endogenous tumour antigens, such as TAAs and neoantigens, for treating B cell malignancies. This work stresses the need to revisit classical concepts concerning viral and tumour immunity, which will be critical to fully understand the impact of common infections on human health and to improve the rational design of immune approaches to treatment of cancers.

Resting EEG Periodic and Aperiodic Components Predict Cognitive Decline Over 10 Years.

Measures of intrinsic brain function at rest show promise as predictors of cognitive decline in humans, including EEG metrics such as individual α peak frequency (IAPF) and the aperiodic exponent, reflecting the strongest frequency of α oscillations and the relative balance of excitatory/inhibitory neural activity, respectively. Both IAPF and the aperiodic exponent decrease with age and have been associated with worse executive function and working memory. However, few studies have jointly examined their associations with cognitive function, and none have examined their association with longitudinal cognitive decline rather than cross-sectional impairment. In a preregistered secondary analysis of data from the longitudinal Midlife in the United States (MIDUS) study, we tested whether IAPF and aperiodic exponent measured at rest predict cognitive function (N = 235; age at EEG recording M = 55.10, SD = 10.71) over 10 years. The IAPF and the aperiodic exponent interacted to predict decline in overall cognitive ability, even after controlling for age, sex, education, and lag between data collection time points. Post hoc tests showed that "mismatched" IAPF and aperiodic exponents (e.g., higher exponent with lower IAPF) predicted greater cognitive decline compared to "matching" IAPF and aperiodic exponents (e.g., higher exponent with higher IAPF; lower IAPF with lower aperiodic exponent). These effects were largely driven by measures of executive function. Our findings provide the first evidence that IAPF and the aperiodic exponent are joint predictors of cognitive decline from midlife into old age and thus may offer a useful clinical tool for predicting cognitive risk in aging.

Respiratory syncytial virus infection provides protection against severe acute respiratory syndrome coronavirus challenge.

Respiratory infections are a major health burden worldwide. Respiratory syncytial virus (RSV) is among the leading causes of hospitalization in both young children and older adults. The onset of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and the public health response had a profound impact on the normal seasonal outbreaks of other respiratory viruses. However, little is known about how a prior respiratory virus infection impacts SARS-CoV-2 disease outcomes. In this study, we examine the impact of a previous RSV infection on the disease severity of a subsequent SARS-CoV-2 challenge in BALB/c mice. Mice infected with RSV, followed by a SARS-CoV-2 challenge, 30 days later, exhibited decreased weight loss and increased survival as compared to control groups. Our results suggest a prior RSV infection can provide protection against a subsequent SARS-CoV-2 infection. IMPORTANCE: Severe acute respiratory syndrome coronavirus 2 and respiratory syncytial virus are respiratory viruses that are a major health burden worldwide. Severe acute respiratory syndrome coronavirus 2 and respiratory syncytial virus frequently have peak seasonal outbreaks during the winter months, and are capable of causing severe respiratory disease, often leading to hospitalization. The 2019 pandemic brought attention to the importance of understanding how co-circulating viruses can impact the disease severity of other respiratory viruses. It is known that many hospitalized patients are undergoing multiple viral infections at once, yet not much has been studied to understand the impact this has on other respiratory viruses or patients. How co-circulating viruses impact one another can provide critical knowledge for future interventions of hospitalized patients and potential vaccination strategies.

Genetic events associated with venetoclax resistance in CLL identified by whole-exome sequencing of patient samples.

Although BCL2 mutations are reported as later occurring events leading to venetoclax resistance, many other mechanisms of progression have been reported though remain poorly understood. Here, we analyze longitudinal tumor samples from 11 patients with disease progression while receiving venetoclax to characterize the clonal evolution of resistance. All patients tested showed increased in vitro resistance to venetoclax at the posttreatment time point. We found the previously described acquired BCL2-G101V mutation in only 4 of 11 patients, with 2 patients showing a very low variant allele fraction (0.03%-4.68%). Whole-exome sequencing revealed acquired loss(8p) in 4 of 11 patients, of which 2 patients also had gain (1q21.2-21.3) in the same cells affecting the MCL1 gene. In vitro experiments showed that CLL cells from the 4 patients with loss(8p) were more resistant to venetoclax than cells from those without it, with the cells from 2 patients also carrying gain (1q21.2-21.3) showing increased sensitivity to MCL1 inhibition. Progression samples with gain (1q21.2-21.3) were more susceptible to the combination of MCL1 inhibitor and venetoclax. Differential gene expression analysis comparing bulk RNA sequencing data from pretreatment and progression time points of all patients showed upregulation of proliferation, B-cell receptor (BCR), and NF-κB gene sets including MAPK genes. Cells from progression time points demonstrated upregulation of surface immunoglobulin M and higher pERK levels compared with those from the preprogression time point, suggesting an upregulation of BCR signaling that activates the MAPK pathway. Overall, our data suggest several mechanisms of acquired resistance to venetoclax in CLL that could pave the way for rationally designed combination treatments for patients with venetoclax-resistant CLL.

Growth dynamics in naturally progressing chronic lymphocytic leukaemia.

How the genomic features of a patient's cancer relate to individual disease kinetics remains poorly understood. Here we used the indolent growth dynamics of chronic lymphocytic leukaemia (CLL) to analyse the growth rates and corresponding genomic patterns of leukaemia cells from 107 patients with CLL, spanning decades-long disease courses. We found that CLL commonly demonstrates not only exponential expansion but also logistic growth, which is sigmoidal and reaches a certain steady-state level. Each growth pattern was associated with marked differences in genetic composition, the pace of disease progression and the extent of clonal evolution. In a subset of patients, whose serial samples underwent next-generation sequencing, we found that dynamic changes in the disease course of CLL were shaped by the genetic events that were already present in the early slow-growing stages. Finally, by analysing the growth rates of subclones compared with their parental clones, we quantified the growth advantage conferred by putative CLL drivers in vivo.

Overcoming doxorubicin resistance in triple-negative breast cancer using the class I-targeting HDAC inhibitor bocodepsin/OKI-179 to promote apoptosis.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with a poor prognosis. Doxorubicin is part of standard curative therapy for TNBC, but chemotherapy resistance remains an important clinical challenge. Bocodepsin (OKI-179) is a small molecule class I histone deacetylase (HDAC) inhibitor that promotes apoptosis in TNBC preclinical models. The purpose of this study was to investigate the combination of bocodepsin and doxorubicin in preclinical TNBC models and evaluate the impact on terminal cell fate, including apoptosis and senescence. METHODS: TNBC cell lines were treated with doxorubicin and CellTiter-Glo was used to assess proliferation and determine doxorubicin sensitivity. Select cell lines were treated with OKI-005 (in vitro version of bocodepsin) and doxorubicin and assessed for proliferation, apoptosis as measured by Annexin V/PI, and cell cycle by flow cytometry. Immunoblotting was used to assess changes in mediators of apoptosis, cell cycle arrest, and senescence. Senescence was measured by the senescence-associated ß-galactosidase assay. An MDA-MB-231 xenograft in vivo model was treated with bocodepsin, doxorubicin, or the combination and assessed for inhibition of tumor growth. shRNA knockdown of p53 was performed in the CAL-51 cell line and proliferation, apoptosis and senescence were assessed in response to combination treatment. RESULTS: OKI-005 and doxorubicin resulted in synergistic antiproliferative activity in TNBC cells lines regardless of p53 mutation status. The combination led to increased apoptosis and decreased senescence. In vivo, the combination resulted in increased tumor growth inhibition compared to either single agent. shRNA knock-down of p53 led to increased doxorubicin-induced senescence that was decreased with the addition of OKI-005 in vitro. CONCLUSION: The addition of bocodepsin to doxorubicin resulted in synergistic antiproliferative activity in vitro, improved tumor growth inhibition in vivo, and promotion of apoptosis which makes this a promising combination to overcome doxorubicin resistance in TNBC. Bocodepsin is currently in clinical development and has a favorable toxicity profile compared to other HDAC inhibitors supporting the feasibility of evaluating this combination in patients with TNBC.

Expanding the landscape of oncogenic drivers and treatment options in acral and mucosal melanomas by targeted genomic profiling.

Despite advancements in treating cutaneous melanoma, patients with acral and mucosal (A/M) melanomas still have limited therapeutic options and poor prognoses. We analyzed 156 melanomas (101 cutaneous, 28 acral, and 27 mucosal) using the Foundation One cancer-gene specific clinical testing platform and identified new, potentially targetable genomic alterations (GAs) in specific anatomic sites of A/M melanomas. Using novel pre-clinical models of A/M melanoma, we demonstrate that several GAs and corresponding oncogenic pathways associated with cutaneous melanomas are similarly targetable in A/M melanomas. Other alterations, including MYC and CRKL amplifications, were unique to A/M melanomas and susceptible to indirect targeting using the BRD4 inhibitor JQ1 or Src/ABL inhibitor dasatinib, respectively. We further identified new, actionable A/M-specific alterations, including an inactivating NF2 fusion in a mucosal melanoma responsive to dasatinib in vivo. Our study highlights new molecular differences between cutaneous and A/M melanomas, and across different anatomic sites within A/M, which may change clinical testing and treatment paradigms for these rare melanomas.

All tidal wetlands are blue carbon ecosystems.

Managing coastal wetlands is one of the most promising activities to reduce atmospheric greenhouse gases, and it also contributes to meeting the United Nations Sustainable Development Goals. One of the options is through blue carbon projects, in which mangroves, saltmarshes, and seagrass are managed to increase carbon sequestration and reduce greenhouse gas emissions. However, other tidal wetlands align with the characteristics of blue carbon. These wetlands are called tidal freshwater wetlands in the United States, supratidal wetlands in Australia, transitional forests in Southeast Asia, and estuarine forests in South Africa. They have similar or larger potential for atmospheric carbon sequestration and emission reductions than the currently considered blue carbon ecosystems and have been highly exploited. In the present article, we suggest that all wetlands directly or indirectly influenced by tides should be considered blue carbon. Their protection and restoration through carbon offsets could reduce emissions while providing multiple cobenefits, including biodiversity.

Doxycycline sclerotherapy of aneurysmal and unicameral bone cysts in the appendicular skeleton and pelvis: Single center 14-year experience.

PURPOSE: To evaluate the safety, effectiveness, and patient satisfaction of doxycycline sclerotherapy for aneurysmal bone cysts (ABCs) and unicameral bone cysts (UBCs). MATERIALS AND METHODS: This is an institutional review board-approved single center retrospective review of all ABCs and UBCs of the appendicular skeleton and pelvis completing doxycycline sclerotherapy and having at least 2 years of follow-up from 2007 to 2021. Radiographic outcomes in a patient cohort were assessed with a modified Neer score. Patient-reported outcome surveys (PROs) were completed by a subgroup of the cohort assessing pain after treatment (Likert scale), functional outcomes (Patient-Reported Outcomes Measurement Instrumentation System, PROMIS), and overall patient satisfaction (adapted from Musculoskeletal Tumor Society, MSTS). RESULTS: Seventy-seven lesions met inclusion criteria, with 55 (71%) receiving Bone Void Filler (BVF) in addition to doxycycline. Of the 77 lesions, 76 (99%) were successfully treated. Twelve lesions (16%) recurred but resolved with additional doxycycline treatment. One lesion failed sclerotherapy, requiring surgical excision. Of the 383 total treatments performed, 17 resulted in SIR classified adverse events (9 with grade 1, 7 with grade 2, and 1 with grade 3). Twenty-five of the 77 cases (32%) completed PROs with 20 (80%) having little to no pain and 15 (60%) having no functional impairment after completing treatment. The PROs documented high levels of satisfaction, with all patients agreeing that they would undergo doxycycline sclerotherapy again if given the option. CONCLUSION: Doxycycline sclerotherapy is a safe and effective stand-alone treatment for ABCs and UBCs.

Prediction of Nanoparticle Photoreactivity in Mixtures of Surface Foulants Requires Kinetic (Non-equilibrium) Adsorption Considerations.

The adsorption of foulants on photocatalytic nanoparticles can suppress their reactivity in water treatment applications by scavenging reactive species at the photocatalyst surface, screening light, or competing for surface sites. These inhibitory effects are commonly modeled using the Langmuir-Hinshelwood model, assuming that adsorbed layer compositions follow Langmuirian (equilibrium) competitive adsorption. However, this assumption has not been evaluated in complex mixtures of foulants. This study evaluates the photoreactivity of titanium dioxide (TiO2) nanoparticles toward a target compound, phenol, in the presence of two classes of foulants ─ natural organic matter (NOM) and a protein, bovine serum albumin (BSA) ─ and mixtures of the two. Langmuir adsorption models predict that BSA should strongly influence the nanoparticle photoreactivity because of its higher adsorption affinity relative to phenol and NOM. However, model evaluation of the experimental phenol decay rates suggested that neither the phenol nor foulant surface coverages are governed by Langmuirian competitive adsorption. Rather, a reactivity model incorporating kinetic predictions of adsorbed layer compositions (favoring NOM adsorption) outperformed Langmuirian models in providing accurate, unbiased predictions of phenol degradation rates. This research emphasizes the importance of using first-principles models that account for adsorption kinetics when assumptions of equilibrium adsorption do not apply.

Respiratory Syncytial Virus Provides Protection against a Subsequent Influenza A Virus Infection.

Respiratory infections are a leading cause of morbidity and mortality. The presence of multiple heterologous virus infections is routinely observed in a subset of individuals screened for the presence of respiratory viruses. However, the impact overlapping infections has on disease severity and the host immune response is not well understood. Respiratory syncytial virus (RSV) and influenza A virus (IAV) are two of the most common respiratory infections observed in hospitalized patients, particularly in the very young and aged populations. In this study, we examined how the order in which BALB/c mice were infected with both RSV and IAV impacts disease severity. RSV infection prior to an IAV infection was associated with decreased weight loss and increased survival as compared with IAV infection alone. In contrast, IAV infection prior to an RSV infection was associated with similar morbidity and mortality as compared with an IAV infection alone. Our results suggest that the order in which viral infections are acquired plays a critical role in the outcome of disease severity and the host immune response.

Pediatric Foot: Development, Variants, and Related Pathology.

Pediatric foot development throughout childhood and adolescence can present a diagnostic dilemma for radiologists because imaging appearances may be confused with pathology. Understanding pediatric foot development and anatomical variants, such as accessory ossification centers, is essential to interpret musculoskeletal imaging in children correctly, particularly because many of these variants are incidental but others can be symptomatic. We first briefly review foot embryology. After describing common accessory ossification centers of the foot, we explain the different patterns of foot maturation with attention to irregular ossification and bone marrow development. Common pediatric foot variants and pathology are described, such as tarsal coalitions and fifth metatarsal base fractures. We also discuss pediatric foot alignment and various childhood foot alignment deformities.

Assessing the reliability of biomechanical variables during a horizontal deceleration task in healthy adults.

Horizontal deceleration technique is an underpinning factor to musculoskeletal injury risk and performance in multidirectional sport. This study primarily assessed within- and between-session reliability of biomechanical and performance-based aspects of a horizontal deceleration technique and secondarily investigated the effects of limb dominance on reliability. Fifteen participants completed four horizontal decelerations on each leg during test and retest sessions. A three-dimensional motion analysis system was used to collect kinetic and kinematic data. Completion time, ground contact time, rate of horizontal deceleration, minimum centre of mass height, peak eccentric force, impulse ratio, touchdown distance, sagittal plane foot and knee angles at initial contact, maximum sagittal plane thorax angle, and maximum knee flexion moment were assessed. Coefficients of variation (COV) and intraclass correlation coefficients (ICC) were used to assess within- and between-session reliability, respectively. Seven variables showed "great" within-session reliability bilaterally (COV ≤9.13%). ICC scores were 'excellent' (≥0.91; n = 4), or 'good' (0.76-0.89; n = 7), bilaterally. Limb dominance affected five variables; three were more reliable for the dominant leg. This horizontal deceleration task was reliable for most variables, with little effect of limb dominance on reliability. This deceleration task may be reliably used to assess and track changes in deceleration technique in healthy adults.

A decision support tool to help identify blue carbon sites for restoration.

Blue carbon ecosystems (BCEs), such as mangroves, saltmarshes, and seagrasses, are important nature-based solutions for climate change mitigation and adaptation but are threatened by degradation. Effective BCE restoration requires strategic planning and site selection to optimise outcomes. We developed a Geographic Information System (GIS)-based multi-criteria decision support tool to identify suitable areas for BCE restoration along the 2512 km-long coastline of Victoria, Australia. High-resolution spatial data on BCE distribution, coastal geomorphology, hydrodynamics, and land tenure were integrated into a flexible spatial model that distinguishes between passive and active restoration suitability. The tool was applied to identify high-priority locations for mangrove, saltmarsh, and seagrass restoration across different scenarios. Results indicate substantial potential for BCE restoration in Victoria, with 33,253 ha of suitable area identified, mostly (>97%) on public land, which aligned with the selection criteria used in the tool. Restoration opportunities are concentrated in bays and estuaries where historical losses have been significant. The mapped outputs provide a decision-support framework for regional restoration planning, while the tool itself can be adapted to other geographies. By integrating multiple spatial criteria and distinguishing between passive and active restoration, our approach offers a new method for targeting BCE restoration and informing resource allocation. The identified restoration potential will also require collaboration with coastal managers and communities, and consideration of socio-economic factors. With further refinements, such as incorporating multi-criteria decision analysis techniques, GIS-based tools can help catalyse strategic blue carbon investments and contribute to climate change mitigation and adaptation goals at different spatial scales. This study highlights the value of spatial identification for BCE restoration and provides a transferable framework for other regions.

Activation of the MAPK pathway mediates resistance to PI3K inhibitors in chronic lymphocytic leukemia.

Inhibitors of Bruton tyrosine kinase (BTK) and phosphatidylinositol 3-kinase δ (PI3Kδ) that target the B-cell receptor (BCR) signaling pathway have revolutionized the treatment of chronic lymphocytic leukemia (CLL). Mutations associated with resistance to BTK inhibitors have been identified, but limited data are available on mechanisms of resistance to PI3Kδ inhibitors. Here we present findings from longitudinal whole-exome sequencing of cells from patients with multiply relapsed CLL (N = 28) enrolled in trials of PI3K inhibitors. The nonresponder subgroup was characterized by baseline activating mutations in MAP2K1, BRAF, and KRAS genes in 60% of patients. PI3Kδ inhibition failed to inhibit ERK phosphorylation (pERK) in nonresponder CLL cells with and without mutations, whereas treatment with a MEK inhibitor rescued ERK inhibition. Overexpression of MAP2K1 mutants in vitro led to increased basal and inducible pERK and resistance to idelalisib. These data demonstrate that MAPK/ERK activation plays a key role in resistance to PI3Kδ inhibitors in CLL and provide a rationale for therapy with a combination of PI3Kδ and ERK inhibitors.

miR-29 modulates CD40 signaling in chronic lymphocytic leukemia by targeting TRAF4: an axis affected by BCR inhibitors.

B-cell receptor (BCR) signaling and T-cell interactions play a pivotal role in chronic lymphocytic leukemia (CLL) pathogenesis and disease aggressiveness. CLL cells can use microRNAs (miRNAs) and their targets to modulate microenvironmental interactions in the lymph node niches. To identify miRNA expression changes in the CLL microenvironment, we performed complex profiling of short noncoding RNAs in this context by comparing CXCR4/CD5 intraclonal cell subpopulations (CXCR4dimCD5bright vs CXCR4brightCD5dim cells). This identified dozens of differentially expressed miRNAs, including several that have previously been shown to modulate BCR signaling (miR-155, miR-150, and miR-22) but also other candidates for a role in microenvironmental interactions. Notably, all 3 miR-29 family members (miR-29a, miR-29b, miR-29c) were consistently down-modulated in the immune niches, and lower miR-29(a/b/c) levels associated with an increased relative responsiveness of CLL cells to BCR ligation and significantly shorter overall survival of CLL patients. We identified tumor necrosis factor receptor-associated factor 4 (TRAF4) as a novel direct target of miR-29s and revealed that higher TRAF4 levels increase CLL responsiveness to CD40 activation and downstream nuclear factor-κB (NF-κB) signaling. In CLL, BCR represses miR-29 expression via MYC, allowing for concurrent TRAF4 upregulation and stronger CD40-NF-κB signaling. This regulatory loop is disrupted by BCR inhibitors (bruton tyrosine kinase [BTK] inhibitor ibrutinib or phosphatidylinositol 3-kinase [PI3K] inhibitor idelalisib). In summary, we showed for the first time that a miRNA-dependent mechanism acts to activate CD40 signaling/T-cell interactions in a CLL microenvironment and described a novel miR-29-TRAF4-CD40 signaling axis modulated by BCR activity.

A glial blueprint for gliomagenesis.

Gliomas are heterogeneous tumours derived from glial cells and remain the deadliest form of brain cancer. Although the glioma stem cell sits at the apex of the cellular hierarchy, how it produces the vast cellular constituency associated with frank glioma remains poorly defined. We explore glioma tumorigenesis through the lens of glial development, starting with the neurogenic-gliogenic switch and progressing through oligodendrocyte and astrocyte differentiation. Beginning with the factors that influence normal glial linage progression and diversity, a pattern emerges that has useful parallels in the development of glioma and may ultimately provide targetable pathways for much-needed new therapeutics.