Background: Histological transformation (HT) is a well-known event in patients with follicular lymphoma (FL) conferring an unfavorable prognosis. The aim of the study was to analyze incidence and ...risk factors for HT in a large series of FL patients. Patients and methods: 276 patients (median age: 54 years; M139/F137) diagnosed with FL (42% grade 1, 51% 2, 7% 3) in a single institution were studied. Initial treatment consisted of combined chemotherapy in most cases. Median survival was 11.3 years. Main clinic and biological variables were assessed for HT and survival. Results: 30 of 276 patients (11%) presented HT after a median follow-up of 6.5 years, with a risk of 15% and 22% at 10 and at 15 years, respectively. All HT corresponded to diffuse large B-cell lymphoma (DLBCL). Grade 3 histology, nodal areas >4, increased LDH and β2-microglobulin, and high-risk IPI and FLIPI were associated with HT. In multivariate analysis, grade 3 histology and FLIPI retained prognostic significance. Only FLIPI predicted HT in grade 1–2 patients. 28 patients received salvage treatment for HT, with a CR rate of 52%. Median survival from transformation was 1.2 years, with 6/13 CR patients being alive >5 years after HT. Conclusion: FLIPI and histology were the most important variables predicting HT. Upon HT, only patients achieving CR reached prolonged survival, thus emphasizing the need for effective therapies once this event occurs.
The giant HII region NGC 604 constitutes a complex and rich population to studying detail many aspects of massive star formation, such as their environments and physical conditions, the evolutionary ...processes involved, the initial mass function for massive stars and star-formation rates, among many others. Here, we present our first results of a near-infrared study of NGC 604 performed with NIRI images obtained with Gemini North. Based on deep JHK photometry, 164 sources showing infrared excess were detected, pointing to the places where we should look for star-formation processes currently taking place. In addition, the color-color diagram reveals a great number of objects that could be giant/supergiant stars or unresolved, small, tight clusters. A extinction map obtained based on narrow-band images is also shown.
We describe the Sloan Digital Sky Survey IV (SDSS-IV), a project encompassing three major spectroscopic programs. The Apache Point Observatory Galactic Evolution Experiment 2 (APOGEE-2) is observing ...hundreds of thousands of Milky Way stars at high resolution and high signal-to-noise ratios in the near-infrared. The Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey is obtaining spatially resolved spectroscopy for thousands of nearby galaxies (median ). The extended Baryon Oscillation Spectroscopic Survey (eBOSS) is mapping the galaxy, quasar, and neutral gas distributions between and 3.5 to constrain cosmology using baryon acoustic oscillations, redshift space distortions, and the shape of the power spectrum. Within eBOSS, we are conducting two major subprograms: the SPectroscopic IDentification of eROSITA Sources (SPIDERS), investigating X-ray AGNs and galaxies in X-ray clusters, and the Time Domain Spectroscopic Survey (TDSS), obtaining spectra of variable sources. All programs use the 2.5 m Sloan Foundation Telescope at the Apache Point Observatory; observations there began in Summer 2014. APOGEE-2 also operates a second near-infrared spectrograph at the 2.5 m du Pont Telescope at Las Campanas Observatory, with observations beginning in early 2017. Observations at both facilities are scheduled to continue through 2020. In keeping with previous SDSS policy, SDSS-IV provides regularly scheduled public data releases; the first one, Data Release 13, was made available in 2016 July.
ObjectiveThe transcription factor Kruppel-like factor 2 (KLF2) modulates the expression of multiple endothelial vasoprotective genes. In the absence of KLF2, the endothelial phenotype becomes ...dysfunctional. To date, blood-derived shear stress is the main physiological stimulus identified to trigger and sustain endothelial KLF2 expression. Portal hypertension is a common complication of cirrhosis. Sinusoidal distortion and endothelial dysfunction play a significant role in its pathogenesis. This study aimed to assess whether abnormal intrahepatic haemodynamics in cirrhosis could modify KLF2 expression and consequently its downstream transcriptional programmes.DesignRats received carbon tetrachloride or vehicle for two (acute injury), six (early cirrhosis) and twelve weeks (advanced cirrhosis). Systemic and hepatic haemodynamic parameters were measured in vivo. Hepatic expression of KLF2 and its vasoprotective targets were determined. Additionally, KLF2 expression was determined in liver sections, in freshly-isolated hepatic endothelial cells, and in livers from simvastatin-treated cirrhotic animals.ResultsCirrhotic livers have increased endothelial KLF2 expression compared with controls. KLF2 elevation, observed at six weeks of cirrhosis induction, was accompanied by a parallel increase in portal pressure and an increase in the expression of its target genes eNOS, thrombomodulin and CNP. Simvastatin administration further increased hepatic KLF2 and target genes expression.ConclusionsThis study shows an increase in the expression of the vasoprotective transcription factor KLF2 in the cirrhotic liver, accompanied by an activation of its downstream transcriptional programmes. These data suggest that the marked increase in KLF2 expression may represent an endothelial compensatory mechanism to improve the ongoing vascular dysfunction in the cirrhotic liver.
To study the main clinicobiologic features, response, and outcome of patients with diffuse large B-cell lymphoma (DLBCL) according to the primary site, lymph node, or different extranodal organs of ...the disease.
We included 382 patients consecutively diagnosed with DLBCL in a single institution during a 13-year period. Morphology, immunophenotyping, proliferation index, differentiation profile, bcl-2/JH rearrangement, and clinical characteristics were analyzed according to the primary site of the lymphoma.
Sites of the disease were: lymph node, 222 cases (58%); Waldeyer's ring (WR), 42 (11%); and extranodal sites, 118 (31%), including GI tract in 45 cases. Primary extranodal cases, particularly GI, showed a bcl-6 expression more frequently than nodal cases. Patients with primary WR or GI lymphomas presented with early-stage disease, no marrow infiltration, normal serum lactate dehydrogenase, and low- to low/intermediate-risk international prognostic index (IPI) more frequently than the remainder. Complete response (CR) rate was 63%, with WR and GI lymphomas having a higher CR rate (85% and 80%, respectively) than the other groups. In the whole series, 5-year overall survival (OS) was 52%. Patients with WR or GI lymphomas showed better OS (5-year OS: 77% and 68%, respectively) than patients with nodal or other extranodal sites. In the multivariate analysis, IPI, bulky disease, and beta2-microglobulin were the main variables to predict OS; no nodal or extranodal site maintained their prognostic value.
In the present series, the primary site of disease was associated with particular clinicopathologic features and outcome, though the latter largely depended on other factors.
ABTL0812 is a first-in-class small molecule with anti-cancer activity, which is currently in clinical evaluation in a phase 2 trial in patients with advanced endometrial and squamous non-small cell ...lung carcinoma (NCT03366480). Previously, we showed that ABTL0812 induces TRIB3 pseudokinase expression, resulting in the inhibition of the AKT-MTORC1 axis and macroautophagy/autophagy-mediated cancer cell death. However, the precise molecular determinants involved in the cytotoxic autophagy caused by ABTL0812 remained unclear. Using a wide range of biochemical and lipidomic analyses, we demonstrated that ABTL0812 increases cellular long-chain dihydroceramides by impairing DEGS1 (delta 4-desaturase, sphingolipid 1) activity, which resulted in sustained ER stress and activated unfolded protein response (UPR) via ATF4-DDIT3-TRIB3 that ultimately promotes cytotoxic autophagy in cancer cells. Accordingly, pharmacological manipulation to increase cellular dihydroceramides or incubation with exogenous dihydroceramides resulted in ER stress, UPR and autophagy-mediated cancer cell death. Importantly, we have optimized a method to quantify mRNAs in blood samples from patients enrolled in the ongoing clinical trial, who showed significant increased DDIT3 and TRIB3 mRNAs. This is the first time that UPR markers are reported to change in human blood in response to any drug treatment, supporting their use as pharmacodynamic biomarkers for compounds that activate ER stress in humans. Finally, we found that MTORC1 inhibition and dihydroceramide accumulation synergized to induce autophagy and cytotoxicity, phenocopying the effect of ABTL0812. Given the fact that ABTL0812 is under clinical development, our findings support the hypothesis that manipulation of dihydroceramide levels might represents a new therapeutic strategy to target cancer.
Abbreviations: 4-PBA: 4-phenylbutyrate; AKT: AKT serine/threonine kinase; ATG: autophagy related; ATF4: activating transcription factor 4; Cer: ceramide; DDIT3: DNA damage inducible transcript 3; DEGS1: delta 4-desaturase, sphingolipid 1; dhCer: dihydroceramide; EIF2A: eukaryotic translation initiation factor 2 alpha; EIF2AK3: eukaryotic translation initiation factor 2 alpha kinase 3; ER: endoplasmic reticulum; HSPA5: heat shock protein family A (Hsp70) member 5; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MEF: mouse embryonic fibroblast; MTORC1: mechanistic target of rapamycin kinase complex 1; NSCLC: non-small cell lung cancer; THC: Δ
9
-tetrahydrocannabinol; TRIB3: tribbles pseudokinase 3; XBP1: X-box binding protein 1; UPR: unfolded protein response.
The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since 2014 July. This paper describes the second data release from this phase, and the 14th from SDSS overall ...(making this Data Release Fourteen or DR14). This release makes the data taken by SDSS-IV in its first two years of operation (2014-2016 July) public. Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey; the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data-driven machine-learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from the SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS web site (www.sdss.org) has been updated for this release and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020 and will be followed by SDSS-V.
Abstract Introduction Hemophagocytic syndromes (hemophagocytic lymphohistiocytosis, HLH) are characterized by a wide range of etiologies, symptoms, and outcomes, but have a common etiopathogenic ...pathway leading to organ damage: an excessive inflammatory response. Biological therapies have been proposed as a therapeutic option for refractory HLH, but have also been related to the development of HLH in severe immunosuppressed patients. Objectives and methods The purpose of this study was to analyze the clinical characteristics and outcomes of adult patients who developed HLH after receiving biological therapies. Results We identified 30 patients (29 from the PubMed search and one unpublished case), including 19 women and 11 men, with a mean age of 46.5 years. Underlying diseases consisted of rheumatologic/autoimmune diseases in 24 patients and hematological neoplasia in the remaining 6. Biological agents received before the development of HLH were mainly anti-TNF agents ( n = 19). Search for microorganisms confirmed systemic infection in 20 (67%) patients, including Mycobacterium tuberculosis ( n = 5), cytomegalovirus (CMV) ( n = 4), Epstein–Barr virus (EBV) ( n = 3), Histoplasma capsulatum ( n = 3), Escherichia coli ( n = 2), Staphylococcus aureus , Leishmania amastigotes and Brucella melitensis ( n = 1, respectively); viral infections were mainly reported in inflammatory bowel disease (IBD) patients. Patients with infections had more frequently received previous immunosuppressive therapies ( p = 0.036) and had lower leukocyte counts ( p = 0.020) in comparison with patients without associated infections. The outcome was described in 29 patients. After a mean follow-up of 6.3 months, 8 patients died (28%) and 6 had received anti-TNF agents. There was a high mortality rate in patients aged >65 years and those with tuberculosis (62% and 60%, respectively). Conclusions In patients receiving biological therapies who develop HLH, searching for a concomitant infectious process is mandatory, and specific surveillance for EBV/CMV infections (in patients with IBD) and for bacteria, including mycobacteria (in elderly patients receiving anti-TNF therapy), is recommended.
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