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ABSTRACT: Rearrangements that place the oncogenes MYC, BCL2, or BCL6 adjacent to superenhancers are common in mature B-cell lymphomas. Lymphomas with diffuse large B-cell lymphoma (DLBCL) or high-grade morphology with both MYC and BCL2 rearrangements are classified as high-grade B-cell lymphoma with MYC and BCL2 rearrangements ("double hit"; HGBCL-DH-BCL2) and are associated with aggressive disease and poor outcomes. Although it is established that MYC rearrangements involving immunoglobulin (IG) loci are associated with inferior outcomes relative to those involving other non-IG superenhancers, the frequency of and mechanisms driving IG vs non-IG MYC rearrangements have not been elucidated. Here, we used custom targeted capture and/or whole-genome sequencing to characterize oncogene rearrangements across 883 mature B-cell lymphomas including Burkitt lymphoma, follicular lymphoma, DLBCL, and HGBCL-DH-BCL2 tumors. We demonstrate that, although BCL2 rearrangement topology is consistent across entities, HGBCL-DH-BCL2 have distinct MYC rearrangement architecture relative to tumors with single MYC rearrangements or with both MYC and BCL6 rearrangements (HGBCL-DH-BCL6), including both a higher frequency of non-IG rearrangements and different architecture of MYC::IGH rearrangements. The distinct MYC rearrangement patterns in HGBCL-DH-BCL2 occur on the background of high levels of somatic hypermutation across MYC partner loci in HGBCL-DH-BCL2, creating more opportunity to form these rearrangements. Furthermore, because 1 IGH allele is already disrupted by the existing BCL2 rearrangement, the MYC rearrangement architecture in HGBCL-DH-BCL2 likely reflects selective pressure to preserve both BCL2 and B-cell receptor expression. These data provide new mechanistic explanations for the distinct patterns of MYC rearrangements observed across different lymphoma entities.
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Reordenamiento Génico , Proteínas Proto-Oncogénicas c-bcl-2 , Proteínas Proto-Oncogénicas c-myc , Humanos , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-myc/genética , Linfoma de Células B/genética , Linfoma de Células B/patología , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patologíaRESUMEN
Deans of medical schools have diverse roles and responsibilities. In this article, we use the career development trajectories of neurologists who have become education deans in student affairs and curriculum to offer advice to aspiring clinician educators of all levels and backgrounds. Although their roles differ, the advice they share is universal and essential for the career development of future clinician educators. ANN NEUROL 2024.
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Mantle cell lymphoma (MCL) is clinically and biologically heterogeneous. While various prognostic features have been proposed, none currently impact therapy selection, particularly in older patients, for whom treatment is primarily dictated by age and comorbidities. Herein, we undertook a comprehensive comparison of clinicopathological features in a cohort of patients 60 years and older, uniformly treated with bendamustine and rituximab, with a median survival of >8 years. The strongest prognostic indicators in this cohort were a high-risk call by a simplified MCL international prognostic index (s-MIPI) (HR: 3.32, 95% CI: 1.65-6.68 compared to low risk), a high-risk call by MCL35 (HR: 10.34, 95% CI: 2.37-45.20 compared to low risk) and blastoid cytology (HR: 4.21, 95% CR: 1.92-9.22 compared to classic). Patients called high risk by both the s-MIPI and MCL35 had the most dismal prognosis (HR: 11.58, 95% CI: 4.10-32.72), while those with high risk by either had a moderate but clinically relevant prognosis (HR: 2.95, 95% CI: 1.49-5.82). A robust assay to assess proliferation, such as MCL35, along with stringent guidelines for cytological evaluation of MCL, in combination with MIPI, may be a strong path to risk-stratify older MCL patients in future clinical trials.
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Linfoma de Células del Manto , Adulto , Humanos , Anciano , Linfoma de Células del Manto/patología , Rituximab/efectos adversos , Clorhidrato de Bendamustina/uso terapéutico , Biomarcadores , Pronóstico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Peripheral T-cell lymphomas (PTCLs) are heterogenous T-cell neoplasms often associated with epigenetic dysregulation. We investigated de novo DNA methyltransferase 3A (DNMT3A) mutations in common PTCL entities, including angioimmunoblastic T-cell lymphoma and novel molecular subtypes identified within PTCL-not otherwise specified (PTCL-NOS) designated as PTCL-GATA3 and PTCL-TBX21. DNMT3A-mutated PTCL-TBX21 cases showed inferior overall survival (OS), with DNMT3A-mutated residues skewed toward the methyltransferase domain and dimerization motif (S881-R887). Transcriptional profiling demonstrated significant enrichment of activated CD8+ T-cell cytotoxic gene signatures in the DNMT3A-mutant PTCL-TBX21 cases, which was further validated using immunohistochemistry. Genomewide methylation analysis of DNMT3A-mutant vs wild-type (WT) PTCL-TBX21 cases demonstrated hypomethylation in target genes regulating interferon-γ (IFN-γ), T-cell receptor signaling, and EOMES (eomesodermin), a master transcriptional regulator of cytotoxic effector cells. Similar findings were observed in a murine model of PTCL with Dnmt3a loss (in vivo) and further validated in vitro by ectopic expression of DNMT3A mutants (DNMT3A-R882, -Q886, and -V716, vs WT) in CD8+ T-cell line, resulting in T-cell activation and EOMES upregulation. Furthermore, stable, ectopic expression of the DNMT3A mutants in primary CD3+ T-cell cultures resulted in the preferential outgrowth of CD8+ T cells with DNMT3AR882H mutation. Single-cell RNA sequencing(RNA-seq) analysis of CD3+ T cells revealed differential CD8+ T-cell subset polarization, mirroring findings in DNMT3A-mutated PTCL-TBX21 and validating the cytotoxic and T-cell memory transcriptional programs associated with the DNMT3AR882H mutation. Our findings indicate that DNMT3A mutations define a cytotoxic subset in PTCL-TBX21 with prognostic significance and thus may further refine pathological heterogeneity in PTCL-NOS and suggest alternative treatment strategies for this subset.
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Interferón gamma , Linfoma de Células T Periférico , Animales , Interferón gamma/genética , Linfoma de Células T Periférico/patología , Metiltransferasas/genética , Ratones , Mutación , Pronóstico , Receptores de Antígenos de Linfocitos T/genéticaRESUMEN
With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an unprecedented scale. Although the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet, the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification, and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses, and epigenetic profiling will be discussed because these will likely become important future tools for implementing precision medicine approaches in clinical decision making for patients with lymphoid malignancies.
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Linfoma , Neoplasias , Humanos , Linfoma/diagnóstico , Linfoma/genética , Linfoma/terapia , Genómica/métodos , Medicina de Precisión , Secuenciación de Nucleótidos de Alto Rendimiento , Toma de Decisiones ClínicasRESUMEN
Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.
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Neoplasias Hematológicas , Linfoma , Comités Consultivos , Consenso , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Humanos , Linfoma/patología , Organización Mundial de la SaludRESUMEN
To bridge the knowledge gap between (a) our (instantaneous-to-seasonal-scale) process understanding of plants and water and (b) our projections of long-term coupled feedbacks between the terrestrial water and carbon cycles, we must uncover what the dominant dynamics are linking fluxes of water and carbon. This study uses the simplest empirical dynamical systems models-two-dimensional linear models-and observation-based data from satellites, eddy covariance towers, weather stations, and machine-learning-derived products to determine the dominant sub-annual timescales coupling carbon uptake and (normalized) evaporation fluxes. We find two dominant modes across the Contiguous United States: (1) a negative correlation timescale on the order of a few days during which landscapes dry after precipitation and plants increase their carbon uptake through photosynthetic upregulation. (2) A slow, seasonal-scale positive covariation through which landscape drying leads to decreased growth and carbon uptake. The slow (positively correlated) process dominates the joint distribution of local water and carbon variables, leading to similar behaviors across space, biomes, and climate regions. We propose that vegetation cover/leaf area variables link this behavior across space, leading to strong emergent spatial patterns of water/carbon coupling in the mean. The spatial pattern of local temporal dynamics-positively sloped tangent lines to a convex long-term mean-state curve-is surprisingly strong, and can serve as a benchmark for coupled Earth System Models. We show that many such models do not represent this emergent mean-state pattern, and hypothesize that this may be due to lack of water-carbon feedbacks at daily scales.
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Ciclo del Carbono , Estaciones del Año , Estados Unidos , Agua/metabolismo , Modelos Teóricos , Ecosistema , Fotosíntesis , Ciclo Hidrológico , Plantas/metabolismo , Carbono/análisis , Carbono/metabolismoRESUMEN
To address the current and long-term unmet health needs of the growing population of non-Hodgkin lymphoma (NHL) patients, we established the Lymphoma Epidemiology of Outcomes (LEO) cohort study (NCT02736357; https://leocohort.org/). A total of 7735 newly diagnosed patients aged 18 years and older with NHL were prospectively enrolled from 7/1/2015 to 5/31/2020 at 8 academic centers in the United States. The median age at diagnosis was 62 years (range, 18-99). Participants came from 49 US states and included 538 Black/African-Americans (AA), 822 Hispanics (regardless of race), 3386 women, 716 age <40 years, and 1513 rural residents. At study baseline, we abstracted clinical, pathology, and treatment data; banked serum/plasma (N = 5883, 76.0%) and germline DNA (N = 5465, 70.7%); constructed tissue microarrays for four major NHL subtypes (N = 1189); and collected quality of life (N = 5281, 68.3%) and epidemiologic risk factor (N = 4489, 58.0%) data. Through August 2022, there were 1492 deaths. Compared to population-based SEER data (2015-2019), LEO participants had a similar distribution of gender, AA race, Hispanic ethnicity, and NHL subtype, while LEO was underrepresented for patients who were Asian and aged 80 years and above. Observed overall survival rates for LEO at 1 and 2 years were similar to population-based SEER rates for indolent B-cell (follicular and marginal zone) and T-cell lymphomas, but were 10%-15% higher than SEER rates for aggressive B-cell subtypes (diffuse large B-cell and mantle cell). The LEO cohort is a robust and comprehensive national resource to address the role of clinical, tumor, host genetic, epidemiologic, and other biologic factors in NHL prognosis and survivorship.
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Linfoma no Hodgkin , Calidad de Vida , Humanos , Femenino , Estados Unidos/epidemiología , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Linfoma no Hodgkin/diagnóstico , Linfocitos B/patología , PronósticoRESUMEN
BACKGROUND: Open subpectoral biceps tenodesis (OSBT) with cortical button fixation has been shown to deliver acceptable results in the short and intermediate term for long head of the biceps (LHB) pathology with the benefit of smaller bone tunnel diameter and a reduced risk of postoperative humeral shaft fracture. The primary purpose of this study was to determine whether OSBT with cortical button fixation results in significant improvements in patient reported outcomes (PROs) from pre-operative to long-term final follow-up. METHODS: A retrospective analysis of patients who underwent OSBT with cortical button fixation at a single institution between the years of 2012 and 2014 was conducted and PROs were collected in the intermediate (> 2 years follow-up) and long term (> 9 years follow-up). PROs were measured pre-operatively, at intermediate follow-up, and at long-term follow-up using three validated questionnaires: American Shoulder and Elbow Surgeons (ASES) score, Disabilities of the Arm, Shoulder, and Hand (DASH) score, and Oxford Shoulder Score (OSS). Patients were additionally asked at final follow-up if they would undergo the same procedure again if they needed it. RESULTS: Twenty-nine (29) patients with a mean age of 51.16 ± 9.06 years at the time of surgery were included in the study at final follow-up. Mean final follow-up time was 10.2 ± 0.5 years (range: 9.2-11.1 years). All PROs (ASES, OSS, and DASH) demonstrated statistically significant improvements from pre-operative to final follow-up with p < 0.01 for each. The proportions of patients exceeding established values for minimum clinically important difference (MCID) were 96.55%, 93.10%, and 75.86% for ASES, OSS, and DASH respectively. Only one patient had required re-operation as of final follow-up. None experienced humeral fractures post-operatively. A significant majority (89.66%; p < 0.01) of patients reported that they would undergo the same procedure again if they needed it. Fifty-three (53) patients were included in the study at intermediate follow-up with a mean follow-up time of 3.5 ± 1.4 years (range: 2-5.3 years). There were no statistically significant differences in any of the PRO measures from intermediate to long-term follow-up. CONCLUSION: This study reported a minimum 9-year follow-up of patients undergoing OSBT with cortical button fixation for the management of LHBT pathology in the setting of concomitant shoulder procedures. All patients had significantly improved functional outcomes assessed with ASES, OSS, and DASH and no obvious differences in median group scores were found between patients assessed at intermediate (mean 3.5 years) and final (mean 10.2 years) follow-up. No infections, fractures, or fixation failures were reported.
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Drylands of the southwestern United States are rapidly warming, and rainfall is becoming less frequent and more intense, with major yet poorly understood implications for ecosystem structure and function. Thermography-based estimates of plant temperature can be integrated with air temperature to infer changes in plant physiology and response to climate change. However, very few studies have evaluated plant temperature dynamics at high spatiotemporal resolution in rainfall pulse-driven dryland ecosystems. We address this gap by incorporating high-frequency thermal imaging into a field-based precipitation manipulation experiment in a semi-arid grassland to investigate the impacts of rainfall temporal repackaging. All other factors held constant, we found that fewer/larger precipitation events led to cooler plant temperatures (1.4°C) compared to that of many/smaller precipitation events. Perennials, in particular, were 2.5°C cooler than annuals under the fewest/largest treatment. We show these patterns were driven by: increased and consistent soil moisture availability in the deeper soil layers in the fewest/largest treatment; and deeper roots of perennials providing access to deeper plant available water. Our findings highlight the potential for high spatiotemporal resolution thermography to quantify the differential sensitivity of plant functional groups to soil water availability. Detecting these sensitivities is vital to understanding the ecohydrological implications of hydroclimate change.
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Ecosistema , Termografía , Lluvia , Plantas , Suelo , Agua/análisis , Cambio ClimáticoRESUMEN
Chromosome region maintenance protein 1 (CRM1) mediates protein export from the nucleus and is a new target for anticancer therapeutics. Broader application of KPT-330 (selinexor), a first-in-class CRM1 inhibitor recently approved for relapsed multiple myeloma and diffuse large B-cell lymphoma, have been limited by substantial toxicity. We discovered that salicylates markedly enhance the antitumor activity of CRM1 inhibitors by extending the mechanisms of action beyond CRM1 inhibition. Using salicylates in combination enables targeting of a range of blood cancers with a much lower dose of selinexor, thereby potentially mitigating prohibitive clinical adverse effects. Choline salicylate (CS) with low-dose KPT-330 (K+CS) had potent, broad activity across high-risk hematological malignancies and solid-organ cancers ex vivo and in vivo. The K+CS combination was not toxic to nonmalignant cells as compared with malignant cells and was safe without inducing toxicity to normal organs in mice. Mechanistically, compared with KPT-330 alone, K+CS suppresses the expression of CRM1, Rad51, and thymidylate synthase proteins, leading to more efficient inhibition of CRM1-mediated nuclear export, impairment of DNA-damage repair, reduced pyrimidine synthesis, cell-cycle arrest in S-phase, and cell apoptosis. Moreover, the addition of poly (ADP-ribose) polymerase inhibitors further potentiates the K+CS antitumor effect. K+CS represents a new class of therapy for multiple types of blood cancers and will stimulate future investigations to exploit DNA-damage repair and nucleocytoplasmic transport for cancer therapy in general.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Colina/análogos & derivados , Reparación del ADN/efectos de los fármacos , Hidrazinas/farmacología , Carioferinas/antagonistas & inhibidores , Linfoma no Hodgkin/tratamiento farmacológico , Proteínas de Neoplasias/antagonistas & inhibidores , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Puntos de Control de la Fase S del Ciclo Celular/efectos de los fármacos , Salicilatos/farmacología , Triazoles/farmacología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Colina/administración & dosificación , Colina/efectos adversos , Colina/farmacología , Replicación del ADN/efectos de los fármacos , ADN de Neoplasias/efectos de los fármacos , Combinación de Medicamentos , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Hidrazinas/administración & dosificación , Hidrazinas/efectos adversos , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/patología , Linfoma no Hodgkin/genética , Linfoma no Hodgkin/patología , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Ftalazinas/administración & dosificación , Ftalazinas/farmacología , Piperazinas/administración & dosificación , Piperazinas/farmacología , Distribución Aleatoria , Salicilatos/administración & dosificación , Salicilatos/efectos adversos , Triazoles/administración & dosificación , Triazoles/efectos adversos , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína Exportina 1RESUMEN
Vegetation cover creates competing effects on land surface temperature: it typically cools through enhancing energy dissipation and warms via decreasing surface albedo. Global vegetation has been previously found to overall net cool land surfaces with cooling contributions from temperate and tropical vegetation and warming contributions from boreal vegetation. Recent studies suggest that dryland vegetation across the tropics strongly contributes to this global net cooling feedback. However, observation-based vegetation-temperature interaction studies have been limited in the tropics, especially in their widespread drylands. Theoretical considerations also call into question the ability of dryland vegetation to strongly cool the surface under low water availability. Here, we use satellite observations to investigate how tropical vegetation cover influences the surface energy balance. We find that while increased vegetation cover would impart net cooling feedbacks across the tropics, net vegetal cooling effects are subdued in drylands. Using observations, we determine that dryland plants have less ability to cool the surface due to their cooling pathways being reduced by aridity, overall less efficient dissipation of turbulent energy, and their tendency to strongly increase solar radiation absorption. As a result, while proportional greening across the tropics would create an overall biophysical cooling feedback, dryland tropical vegetation reduces the overall tropical surface cooling magnitude by at least 14%, instead of enhancing cooling as suggested by previous global studies.
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Cambio Climático , Plantas , TemperaturaRESUMEN
The increasing frequency and intensity of climate extremes and complex ecosystem responses motivate the need for integrated observational studies at low latency to determine biosphere responses and carbon-climate feedbacks. Here, we develop a satellite-based rapid attribution workflow and demonstrate its use at a 1-2-month latency to attribute drivers of the carbon cycle feedbacks during the 2020-2021 Western US drought and heatwave. In the first half of 2021, concurrent negative photosynthesis anomalies and large positive column CO2 anomalies were detected with satellites. Using a simple atmospheric mass balance approach, we estimate a surface carbon efflux anomaly of 132 TgC in June 2021, a magnitude corroborated independently with a dynamic global vegetation model. Integrated satellite observations of hydrologic processes, representing the soil-plant-atmosphere continuum (SPAC), show that these surface carbon flux anomalies are largely due to substantial reductions in photosynthesis because of a spatially widespread moisture-deficit propagation through the SPAC between 2020 and 2021. A causal model indicates deep soil moisture stores partially drove photosynthesis, maintaining its values in 2020 and driving its declines throughout 2021. The causal model also suggests legacy effects may have amplified photosynthesis deficits in 2021 beyond the direct effects of environmental forcing. The integrated, observation framework presented here provides a valuable first assessment of a biosphere extreme response and an independent testbed for improving drought propagation and mechanisms in models. The rapid identification of extreme carbon anomalies and hotspots can also aid mitigation and adaptation decisions.
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Sequías , Ecosistema , Atmósfera , Ciclo del Carbono , Suelo , Plantas , Carbono , Cambio ClimáticoRESUMEN
Activated B cell (ABC) type diffuse large B cell lymphoma (DLBCL), double hit lymphoma (DHL) and double expressor lymphoma (DEL) have poor outcomes to frontline R-CHOP but impact of these molecular features on outcomes of relapsed/refractory (R/R) disease is not well-characterized. We evaluated the association of diagnostic cell of origin (COO), double hit and double expressor status with overall survival after first relapse in DLBCL patients who were enrolled into the Molecular Epidemiology Resource (MER) cohort. COO was available from immunohistochemistry (IHC) using Hans criteria or gene expression profiling (GEP) (Nanostring) on the diagnostic FFPE biopsy. Of 373 pts with R/R DLBCL, 278 had COO by IHC: 152 were GCB, 107 were non-GCB. One hundred and fourty had COO by GEP: 44 were ABC, 65 were GCB and 13 were unclassifiable. Nineteen out of 163 (12%) were DHL; 30 out of 135 (22%) had DEL. COO, either by IHC (2 years OS GCB: 45% [CI95 : 38-54] vs. non-GCB: 44% [CI95 :36-55], p > 0.05) or GEP (2 years OS ABC: 42% [CI95 : 29-59] vs. GCB: 40% [CI95 : 30-54], p > 0.05), was not associated with difference in OS. DHL (2 years OS 16 [CI95 :6-45] vs. 45% [CI95 : 34-59], p < 0.01) and DEL (2 years OS 33% [CI95 : 20-56], vs. 50% [CI95 : 41-60], p < 0.05) had lower OS than non-DHL and non-DEL/non-DHL counterparts, respectively. COO by IHC or GEP was not associated with OS in R/R DLBCL while DHL and DEL were adverse prognostic markers in DLBCL at first relapse.
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Linfoma de Células B Grandes Difuso , Recurrencia Local de Neoplasia , Humanos , Estudios Retrospectivos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Perfilación de la Expresión Génica , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , PronósticoRESUMEN
Post-transplant lymphoproliferative disorder (PTLD) is a complication of immunosuppressive therapy following solid organ or hematopoietic cell transplantation. Initial treatment typically includes a reduction of immunosuppression with or without rituximab. However, the optimal therapy for PTLD with plasmacytic differentiation is unclear. We present 3 cases of pediatric patients with plasmacytic PTLD. Two patients received a standard rituximab-based approach and relapsed, prompting additional chemotherapy. The third patient was treated with a novel regimen of bortezomib, dexamethasone, and daratumumab. This regimen was safe, well-tolerated, and resulted in a 2-year remission. Larger studies are needed to further explore this regimen.
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Infecciones por Virus de Epstein-Barr , Linfoma , Trastornos Linfoproliferativos , Humanos , Niño , Rituximab/uso terapéutico , Infecciones por Virus de Epstein-Barr/complicaciones , Linfoma/complicaciones , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/complicaciones , Diferenciación CelularRESUMEN
Peripheral T-cell lymphomas are a heterogeneous, and usually aggressive, group of mature T-cell neoplasms with overlapping clinical, morphologic and immunologic features. A large subset of these neoplasms remains unclassifiable with current diagnostic methods ("not otherwise specified"). Genetic profiling and other molecular tools have emerged as widely applied and transformative technologies for discerning the biology of lymphomas and other hematopoietic neoplasms. Although the application of these technologies to peripheral T-cell lymphomas has lagged behind B-cell lymphomas and other cancers, molecular profiling has provided novel prognostic and diagnostic markers as well as an opportunity to understand the biologic mechanisms involved in the pathogenesis of these neoplasms. Some biomarkers are more prevalent in specific T-cell lymphoma subsets and are being used currently in the diagnosis and/or risk stratification of patients with peripheral T-cell lymphomas. Other biomarkers, while promising, need to be validated in larger clinical studies. In this review, we present a summary of our current understanding of the molecular profiles of the major types of peripheral T-cell lymphoma. We particularly focus on the use of biomarkers, including those that can be detected by conventional immunohistochemical studies and those that contribute to the diagnosis, classification, or risk stratification of these neoplasms.
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Linfoma de Células B , Linfoma de Células T Periférico , Biomarcadores , Humanos , Linfoma de Células B/genética , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/patología , PronósticoRESUMEN
NF-κB and Notch signaling can be simultaneously activated in a variety of B-cell lymphomas. Patients with B-cell lymphoma occasionally develop clonally related myeloid tumors with poor prognosis. Whether concurrent activation of both pathways is sufficient to induce B-cell transformation and whether the signaling initiates B-myeloid conversion in a pathological context are largely unknown. Here, we provide genetic evidence that concurrent activation of NF-κB and Notch signaling in committed B cells is sufficient to induce B-cell lymphomatous transformation and primes common progenitor cells to convert to myeloid lineage through dedifferentiation, not transdifferentiation. Intriguingly, the converted myeloid cells can further transform, albeit at low frequency, into myeloid leukemia. Mechanistically, coactivation of NF-κB and Notch signaling endows committed B cells with the ability to self renew. Downregulation of BACH2, a lymphoma and myeloid gene suppressor, but not upregulation of CEBPα and/or downregulation of B-cell transcription factors, is an early event in both B-cell transformation and myeloid conversion. Interestingly, a DNA hypomethylating drug not only effectively eliminated the converted myeloid leukemia cells, but also restored the expression of green fluorescent protein, which had been lost in converted myeloid leukemia cells. Collectively, our results suggest that targeting NF-κB and Notch signaling will not only improve lymphoma treatment, but also prevent the lymphoma-to-myeloid tumor conversion. Importantly, DNA hypomethylating drugs might efficiently treat these converted myeloid neoplasms.
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Linfocitos B/patología , Transformación Celular Neoplásica/patología , Linfoma de Células B de la Zona Marginal/patología , Células Mieloides/patología , FN-kappa B/metabolismo , Receptores Notch/metabolismo , Animales , Linfocitos B/metabolismo , Transformación Celular Neoplásica/metabolismo , Femenino , Humanos , Linfoma de Células B de la Zona Marginal/genética , Linfoma de Células B de la Zona Marginal/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Células Mieloides/metabolismo , FN-kappa B/genética , Receptores Notch/genética , Transducción de SeñalRESUMEN
The transition of evapotranspiration between energy- and water-limitation regimes also denotes a nonlinear change in surface water and energy coupling strength. The regime transitions are primarily dominated by available moisture in the soil, although other micro-meteorological factors also play a role. Remotely sensed soil moisture is frequently used for detecting evapotranspiration regime transitions during inter storm dry downs. However, its sampling depth does not include the entire soil profile, over which water uptake is dominated by plant root distribution. We use flux tower, surface (θ s ; observations at 5 cm), and vertically integrated in situ soil moisture ( θ v ; 0-50 cm) observations to address the question: Can surface soil moisture robustly identify evapotranspiration regime transitions? Results demonstrate that θ s and θ v are hydraulically linked and have synchronized evapotranspiration regime transitions. As such, θ s and θ v capture comparable statistics of evapotranspiration regime prevalence, which supports the utility of remote-sensing θ s for large-scale land-atmosphere exchange analysis.
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Breast implant anaplastic large cell lymphoma (ALCL) is a T-cell neoplasm arising around textured breast implants that was recognized recently as a distinct entity by the World Health Organization. Rarely, other types of lymphoma have been reported in patients with breast implants, raising the possibility of a pathogenetic relationship between breast implants and other types of lymphoma. We report eight cases of Epstein-Barr virus (EBV)-positive large B-cell lymphoma associated with breast implants. One of these cases was invasive, and the other seven neoplasms were noninvasive and showed morphologic overlap with breast implant ALCL. All eight cases expressed B-cell markers, had a non-germinal center B-cell immunophenotype, and were EBV+ with a latency type III pattern of infection. We compared the noninvasive EBV+ large B-cell lymphoma cases with a cohort of breast implant ALCL cases matched for clinical and pathologic stage. The EBV+ large B-cell lymphoma cases more frequently showed a thicker capsule, and more often were associated with calcification and prominent lymphoid aggregates outside of the capsule. The EBV+ B-cell lymphoma cells were more often arranged within necrotic fibrinoid material in a layered pattern. We believe that this case series highlights many morphologic similarities between EBV+ large B-cell lymphoma and breast implant ALCL. The data presented suggest a pathogenetic role for breast implants (as well as EBV) in the pathogenesis of EBV+ large B-cell lymphoma. We also provide some histologic findings useful for distinguishing EBV+ large B-cell lymphoma from breast implant ALCL in this clinical setting.
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Implantación de Mama/efectos adversos , Implantes de Mama/efectos adversos , Infecciones por Virus de Epstein-Barr/virología , Linfoma de Células B Grandes Difuso/patología , Linfoma Anaplásico de Células Grandes/patología , Adulto , Anciano , Biomarcadores de Tumor/análisis , Implantación de Mama/instrumentación , Diagnóstico Diferencial , Infecciones por Virus de Epstein-Barr/diagnóstico , Femenino , Humanos , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células B Grandes Difuso/virología , Linfoma Anaplásico de Células Grandes/etiología , Linfoma Anaplásico de Células Grandes/inmunología , Persona de Mediana Edad , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Diseño de Prótesis , Factores de Riesgo , Propiedades de SuperficieRESUMEN
Variation in canopy water content (CWC) that can be detected from microwave remote sensing of vegetation optical depth (VOD) has been proposed as an important measure of vegetation water stress. However, the contribution of leaf surface water (LWs ), arising from dew formation and rainfall interception, to CWC is largely unknown, particularly in tropical forests and other high-humidity ecosystems. We compared VOD data from the Advanced Microwave Scanning Radiometer for the Earth Observing System (AMSR-E) and CWC predicted by a plant hydrodynamics model at four tropical sites in Brazil spanning a rainfall gradient. We assessed how LWs influenced the relationship between VOD and CWC. The analysis indicates that while CWC is strongly correlated with VOD (R2 = 0.62 across all sites), LWs accounts for 61-76% of the diurnal variation in CWC despite being < 10% of CWC. Ignoring LWs weakens the near-linear relationship between CWC and VOD and reduces the consistency in diurnal variation. The contribution of LWs to CWC variation, however, decreases at longer, seasonal to inter-annual, time scales. Our results demonstrate that diurnal patterns of dew formation and rainfall interception can be an important driver of diurnal variation in CWC and VOD over tropical ecosystems and therefore should be accounted for when inferring plant diurnal water stress from VOD measurements.