A Two-Gene Signature, SKI and SLAMF1, Predicts Time-to-Treatment in Previously Untreated Patients with Chronic Lymphocytic Leukemia

We developed and validated a two-gene signature that predicts prognosis in previously-untreated chronic lymphocytic leukemia (CLL) patients. Using a 65 sample training set, from a cohort of 131 patients, we identified the best clinical models to predict time-to-treatment (TTT) and overall survival (OS). To identify individual genes or combinations in the training set with expression related to prognosis, we cross-validated univariate and multivariate models to predict TTT. We identified four gene sets (5, 6, 12, or 13 genes) to construct multivariate prognostic models. By optimizing each gene set on the training set, we constructed 11 models to predict the time from diagnosis to treatment. Each model also predicted OS and added value to the best clinical models. To determine which contributed the most value when added to clinical variables, we applied the Akaike Information Criterion. Two genes were consistently retained in the models with clinical variables: SKI (v-SKI avian sarcoma viral oncogene homolog) and SLAMF1 (signaling lymphocytic activation molecule family member 1; CD150). We optimized a two-gene model and validated it on an independent test set of 66 samples. This two-gene model predicted prognosis better on the test set than any of the known predictors, including ZAP70 and serum β2-microglobulin

A Multi-telescope Campaign on FRB 121102: Implications for the FRB Population

We present results of the coordinated observing campaign that made the first subarcsecond localization of a Fast Radio Burst, FRB 121102. During this campaign, we made the first simultaneous detection of an FRB burst by multiple telescopes: the VLA at 3 GHz and the Arecibo Observatory at 1.4 GHz. Of the nine bursts detected by the Very Large Array at 3 GHz, four had simultaneous observing coverage at other observatories. We use multi-observatory constraints and modeling of bursts seen only at 3 GHz to confirm earlier results showing that burst spectra are not well modeled by a power law. We find that burst spectra are characterized by a ~500 MHz envelope and apparent radio energy as high as $10^{40}$ erg. We measure significant changes in the apparent dispersion between bursts that can be attributed to frequency-dependent profiles or some other intrinsic burst structure that adds a systematic error to the estimate of DM by up to 1%. We use FRB 121102 as a prototype of the FRB class to estimate a volumetric birth rate of FRB sources $R_{FRB} \approx 5x10^{-5}/N_r$ Mpc$^{-3}$ yr$^{-1}$, where $N_r$ is the number of bursts per source over its lifetime. This rate is broadly consistent with models of FRBs from young pulsars or magnetars born in superluminous supernovae or long gamma-ray bursts, if the typical FRB repeats on the order of thousands of times during its lifetime.Comment: 17 pages, 7 figures. Submitted to AAS Journal

Carcinoma and multiple lymphomas in one patient: establishing the diagnoses and analyzing risk factors

Multiple malignancies may occur in the same patient, and a few reports describe cases with multiple hematologic and non-hematologic neoplasms. We report the case of a patient who showed the sequential occurrence of four different lymphoid neoplasms together with a squamous cell carcinoma of the lung. A 62-year-old man with adenopathy was admitted to the hospital, and lymph node biopsy was positive for low-grade follicular lymphoma. He achieved a partial remission with chemotherapy. Two years later, a PET-CT scan showed a left hilar mass in the lung; biopsy showed a squamous cell carcinoma. Simultaneously, he was diagnosed with diffuse large B cell lymphoma in a neck lymph node; after chemo- and radiotherapy, he achieved a complete response. A restaging PET-CT scan 2 years later revealed a retroperitoneal nodule, and biopsy again showed a low-grade follicular lymphoma, while a biopsy of a cutaneous scalp lesion showed a CD30-positive peripheral T cell lymphoma. After some months, a liver biopsy and a right cervical lymph node biopsy showed a CD30-positive peripheral T cell lymphoma consistent with anaplastic lymphoma kinase-negative anaplastic large cell lymphoma. Flow cytometry and cytogenetic and molecular genetic analysis performed at diagnosis and during the patient’s follow-up confirmed the presence of two clonally distinct B cell lymphomas, while the two T cell neoplasms were confirmed to be clonally related. We discuss the relationship between multiple neoplasms occurring in the same patient and the various possible risk factors involved in their development

Rapid generation of human B-cell lymphomas via combined expression of Myc and Bcl2 and their use as a preclinical model for biological therapies

Although numerous mouse models of B-cell malignancy have been developed via the enforced expression of defined oncogenic lesions, the feasibility of generating lineage-defined human B-cell malignancies using mice reconstituted with modified human hematopoietic stem cells (HSCs) remains unclear. In fact, whether human cells can be transformed as readily as murine cells by simple oncogene combinations is a subject of considerable debate. Here, we describe the development of humanized mouse model of MYC/BCL2-driven ‘double-hit’ lymphoma. By engrafting human HSCs transduced with the oncogene combination into immunodeficient mice, we generate a fatal B malignancy with complete penetrance. This humanized-MYC/BCL2-model (hMB) accurately recapitulates the histopathological and clinical aspects of steroid-, chemotherapy- and rituximab-resistant human ‘double-hit’ lymphomas that involve the MYC and BCL2 loci. Notably, this model can serve as a platform for the evaluation of antibody-based therapeutics. As a proof of principle, we used this model to show that the anti-CD52 antibody alemtuzumab effectively eliminates lymphoma cells from the spleen, liver and peripheral blood, but not from the brain. The hMB humanized mouse model underscores the synergy of MYC and BCL2 in ‘double-hit’ lymphomas in human patients. Additionally, our findings highlight the utility of humanized mouse models in interrogating therapeutic approaches, particularly human-specific monoclonal antibodies.Kathy and Curt Marble Cancer Research FundSingapore-MIT Alliance for Research and TechnologyNational Institutes of Health (U.S.) (Grant R01-CA128803)Virginia and Daniel K. Ludwig Graduate FellowshipNational Institute of General Medical Sciences (U.S.) (Medical Scientist Training Program Grant T32GM007753)MIT School of Science (Cancer Research Fellowship

High-rate quantum cryptography in untrusted networks

We extend the field of continuous-variable quantum cryptography to a network formulation where two honest parties connect to an untrusted relay by insecure quantum links. To generate secret correlations, they transmit coherent states to the relay where a continuous-variable Bell detection is performed and the outcome broadcast. Even though the detection could be fully corrupted and the links subject to optimal coherent attacks, the honest parties can still extract a secret key, achieving high rates when the relay is proximal to one party, as typical in public networks with access points or proxy servers. Our theory is confirmed by an experiment generating key-rates which are orders of magnitude higher than those achievable with discrete-variable protocols. Thus, using the cheapest possible quantum resources, we experimentally show the possibility of high-rate quantum key distribution in network topologies where direct links are missing between end-users and intermediate relays cannot be trusted.Comment: Theory and Experiment. Main article (6 pages) plus Supplementary Information (additional 13 pages

Gray zones around diffuse large B cell lymphoma. Conclusions based on the workshop of the XIV meeting of the European Association for Hematopathology and the Society of Hematopathology in Bordeaux, France

The term “gray-zone” lymphoma has been used to denote a group of lymphomas with overlapping histological, biological, and clinical features between various types of lymphomas. It has been used in the context of Hodgkin lymphomas (HL) and non-Hodgkin lymphomas (NHL), including classical HL (CHL), and primary mediastinal large B cell lymphoma, cases with overlapping features between nodular lymphocyte predominant Hodgkin lymphoma and T-cell/histiocyte-rich large B cell lymphoma, CHL, and Epstein–Barr-virus-positive lymphoproliferative disorders, and peripheral T cell lymphomas simulating CHL. A second group of gray-zone lymphomas includes B cell NHL with intermediate features between diffuse large B cell lymphoma and classical Burkitt lymphoma. In order to review controversial issues in gray-zone lymphomas, a joint Workshop of the European Association for Hematopathology and the Society for Hematopathology was held in Bordeaux, France, in September 2008. The panel members reviewed and discussed 145 submitted cases and reached consensus diagnoses. This Workshop summary is focused on the most controversial aspects of gray-zone lymphomas and describes the panel’s proposals regarding diagnostic criteria, terminology, and new prognostic and diagnostic parameters

A direct localization of a fast radio burst and its host

Fast radio bursts are astronomical radio flashes of unknown physical nature with durations of milliseconds. Their dispersive arrival times suggest an extragalactic origin and imply radio luminosities orders of magnitude larger than any other kind of known short-duration radio transient. Thus far, all FRBs have been detected with large single-dish telescopes with arcminute localizations, and attempts to identify their counterparts (source or host galaxy) have relied on contemporaneous variability of field sources or the presence of peculiar field stars or galaxies. These attempts have not resulted in an unambiguous association with a host or multi-wavelength counterpart. Here we report the sub-arcsecond localization of FRB 121102, the only known repeating burst source, using high-time-resolution radio interferometric observations that directly image the bursts themselves. Our precise localization reveals that FRB 121102 originates within 100 mas of a faint 180 uJy persistent radio source with a continuum spectrum that is consistent with non-thermal emission, and a faint (25th magnitude) optical counterpart. The flux density of the persistent radio source varies by tens of percent on day timescales, and very long baseline radio interferometry yields an angular size less than 1.7 mas. Our observations are inconsistent with the fast radio burst having a Galactic origin or its source being located within a prominent star-forming galaxy. Instead, the source appears to be co-located with a low-luminosity active galactic nucleus or a previously unknown type of extragalactic source. [Truncated] If other fast radio bursts have similarly faint radio and optical counterparts, our findings imply that direct sub-arcsecond localizations of FRBs may be the only way to provide reliable associations.Comment: Nature, published online on 4 Jan 2017, DOI: 10.1038/nature2079