Description: We utilize carbonate clumped isotope thermometry to explore the diagenetic and thermal histories of exhumed brachiopods, crinoids, cements, and host rock in the Permian Palmarito Formation, Venezuela, and the Carboniferous Bird Spring Formation, Nevada, USA. Carbonate components in the Palmarito Formation, buried to ~4 km depth, yield statistically indistinguishable clumped isotope temperatures [ T ( 47 )] ranging from 86 to 122 °C. Clumped isotope temperatures of components in the more deeply buried Bird Spring Formation (〉5 km) range from ~100 to 165 °C and differ by component type, with brachiopods and pore-filling cements yielding the highest T ( 47 ) (mean = 153 and 141 °C, respectively) and crinoids and host rock yielding significantly cooler T ( 47 ) (mean = 103 and 114 °C). New high-resolution thermal histories are coupled with kinetic models to predict the extent of solid-state C-O bond reordering during burial and exhumation for both sites. Application of these models, termed "THRMs" (thermal history reordering models), suggests that brachiopods in the Palmarito Formation experienced partial bond reordering without complete equilibration of clumped isotopes at maximum burial temperature. In contrast, clumped isotope bonds of brachiopods from the Bird Spring Formation completely equilibrated at maximum burial temperature, and now reflect blocking temperatures achieved during cooling. The 40–50-°C-cooler clumped isotope temperatures measured in Bird Spring Formation crinoids and host rock can be explained by recrystallization and cementation during shallow burial combined with a greater inherent resistance to solid-state reordering than brachiopods.

Description: Purpose: The prognostic impact of total metabolic tumor volume (TMTV) measured on pretreatment 18 F-FDG PET/CT and its added value to molecular characteristics was investigated in patients with diffuse large B-cell lymphoma (DLBCL). Experimental Design: For 81 newly diagnosed patients with DLBCL treated with rituximab and CHOP/CHOP-like regimen, TMTV was computed using the 41% SUV max thresholding method. According to the gene expression profile, determined using DASL (cDNA-mediated Annealing, Selection, Ligation and extension) technology, a subset of 57 patients was classified in germinal center B (GCB) or activated B-cell (ABC) subtypes and MYC or BCL2 overexpressed. Results: Median follow-up was 64 months. Five-year progression-free survival (PFS) and overall survival (OS) were 60% and 63% in the whole population. Median pretherapy TMTV was 320 cm 3 (25th–75th percentiles 106–668 cm 3 ). With a 300 cm 3 cutoff, patients with high TMTV ( n = 43) had a 5-year PFS and OS of 43% and 46% compared with 76% and 78% for patients with a low TMTV ( P = 0.0023, P = 0.0047). ABC status, MYC , or BCL2 overexpression and both overexpression ("dual expressor," DE) were significantly associated with a worse PFS and OS. TMTV combined with molecular data allowed a significant better risk substratification of ABC/GCB patients, on PFS and OS. High TMTV individualized in molecular-low-risk patients a group with a poor outcome ( MYC , PFS=51%, OS=55% BCL2 , PFS=49%, OS=49% or DE PFS=50%, OS=50%) and a group with a good outcome ( MYC , PFS=93%, OS=93% BCL2 , PFS=86%, OS=86%, or DE PFS=81%, OS=81%). Conclusions: The combination of molecular and imaging characteristics at diagnosis could lead to a more accurate selection of patients, to increase tailor therapy. Clin Cancer Res; 22(15); 3801–9. ©2016 AACR .

Description: Background First-line maintenance strategies are a current matter of debate in the management of mCRC. Their impact on patient's health-related quality of life (HRQOL) has not yet been evaluated. The objective of this study was to assess whether differences in HRQOL during any active maintenance treatment compared with no maintenance treatment exist. Patient and methods Eight hundred and thirty-seven patients were enrolled in the AIO KRK 0207 trial. Four hundred and seventy-two underwent randomization (after 24 weeks of induction treatment) into one of the maintenance arms: FP plus Bev (arm A), Bev alone (arm B), or no active treatment (arm C). HRQOL were assessed every 6 weeks during induction and maintenance treatment independent from treatment stop, delay, or modification, and also continued after progression, using the EORTC QLQ-C30, QLQ-CR29. The mean value of the global quality of life dimension (GHS/QoL) of the EORTC QLQ-C30, calculated as the average of all available time points after randomization was considered as pre-specified main endpoint. Additionally, EORTC QLQ-C30 response scores were analyzed. Results For HRQOL analysis, 413 patients were eligible (arm A: 136 ; arm B: 142 , arm C: 135 ). Compliance rate with the HRQOL questionnaires was 95% at time of randomization and remained high during maintenance (98%, 99%, 97% and 97% at week 6, 12, 18 and 24). No significant differences between treatment arms in the mean GHS/QoL scores were observed at any time point. Also, rates of GHS/QoL score deterioration were similar (20.5%; 17.2% and 20.7% of patients), whereas a score improvement occurred in 36.1%; 43.8% and 42.1% (arms A, B and C). Conclusion Continuation of an active maintenance treatment with FP/Bev after induction treatment was neither associated with a detrimental effect on GHS/QoL scores when compared with both, less active treatment with Bev alone or no active treatment. Clinical trials number NCT00973609 (ClinicalTrials.gov).

Description: The human cytomegalovirus (HCMV) tegument protein pUL71 is required for efficient secondary envelopment and accumulates at the Golgi compartment-derived viral assembly complex (vAC) during infection. Analysis of various C-terminally truncated pUL71 proteins fused to enhanced green fluorescent protein (eGFP) identified amino acids 23 to 34 as important determinants for its Golgi complex localization. Sequence analysis and mutational verification revealed the presence of an N-terminal tyrosine-based trafficking motif (YXX) in pUL71. This led us to hypothesize a requirement of the YXX motif for the function of pUL71 in infection. Mutation of both the tyrosine residue and the entire YXX motif resulted in an altered distribution of mutant pUL71 at the plasma membrane and in the cytoplasm during infection. Both YXX mutant viruses exhibited similarly decreased focal growth and reduced virus yields in supernatants. Ultrastructurally, mutant-virus-infected cells exhibited impaired secondary envelopment manifested by accumulations of capsids undergoing an envelopment process. Additionally, clusters of capsid accumulations surrounding the vAC were observed, similar to the ultrastructural phenotype of a UL71-deficient mutant. The importance of endocytosis and thus the YXX motif for targeting pUL71 to the Golgi complex was further demonstrated when clathrin-mediated endocytosis was inhibited either by coexpression of the C-terminal part of cellular AP180 (AP180-C) or by treatment with methyl-β-cyclodextrin. Both conditions resulted in a plasma membrane accumulation of pUL71. Altogether, these data reveal the presence of a functional N-terminal endocytosis motif that is an important determinant for intracellular localization of pUL71 and that is furthermore required for the function of pUL71 during secondary envelopment of HCMV capsids at the vAC. IMPORTANCE Human cytomegalovirus (HCMV) is the leading cause of birth defects among congenital virus infections and can lead to life-threatening infections in immunocompromised hosts. Current antiviral treatments target viral genome replication and are increasingly overcome by viral mutations. Therefore, identifying new targets for antiviral therapy is important for future development of novel treatment options. A detailed molecular understanding of the complex virus morphogenesis will identify potential viral as well as cellular targets for antiviral intervention. Secondary envelopment is an important viral process through which infectious virus particles are generated and which involves the action of several viral proteins, such as tegument protein pUL71. Targeting of pUL71 to the site of secondary envelopment appears to be crucial for its function during this process and is regulated by utilizing host trafficking mechanisms that are commonly exploited by viral glycoproteins. Thus, intracellular trafficking, if targeted, might present a novel target for antiviral therapy.

Description: Cathepsin G is broadly expressed in acute myeloid leukemia and is an effective immunotherapeutic target Leukemia 31, 234 (January 2017). doi:10.1038/leu.2016.249 Authors: G Alatrash, H R Garber, M Zhang, P Sukhumalchandra, Y Qiu, H Jakher, A A Perakis, L Becker, S Y Yoo, K C Dwyer, K Coombes, A H Talukder, L S St John, V Senyukov, D A Lee, A Sergeeva, H He, Q Ma, P M Armistead, J Roszik, E A Mittendorf, J J Molldrem, D Hawke, G Lizee & S M Kornblau

Description: The purpose of this study was to compare in a large series of peripheral T cell lymphoma, as a model of diffuse disease, the prognostic value of baseline total metabolic tumor volume (TMTV) measured on 18 F-FDG PET/CT with adaptive thresholding methods with TMTV measured with a fixed 41% SUV max threshold method. Methods: One hundred six patients with peripheral T cell lymphoma, staged with PET/CT, were enrolled from 5 Lymphoma Study Association centers. In this series, TMTV computed with the 41% SUV max threshold is a strong predictor of outcome. On a dedicated workstation, we measured the TMTV with 4 adaptive thresholding methods based on characteristic image parameters: Daisne (Da) modified, based on signal-to-background ratio; Nestle (Ns), based on tumor and background intensities; Fit, including a 3-dimensional geometric model based on spatial resolution (Fit); and Black (Bl), based on mean SUV max . The TMTV values obtained with each adaptive method were compared with those obtained with the 41% SUV max method. Their respective prognostic impacts on outcome prediction were compared using receiver-operating-characteristic (ROC) curve analysis and Kaplan–Meier survival curves. Results: The median value of TMTV 41% , TMTV Da , TMTV Ns , TMTV Fit , and TMTV Bl were, respectively, 231 cm 3 (range, 5–3,824), 175 cm 3 (range, 8–3,510), 198 cm 3 (range, 3–3,934), 175 cm 3 (range, 8–3,512), and 333 cm 3 (range, 3–5,113). The intraclass correlation coefficients were excellent, from 0.972 to 0.988, for TMTV Da , TMTV Fit , and TMTV Ns , and less good for TMTV Bl (0.856). The mean differences obtained from the Bland–Altman plots were 48.5, 47.2, 19.5, and –253.3 cm 3 , respectively. Except for Black, there was no significant difference within the methods between the ROC curves ( P 〉 0.4) for progression-free survival and overall survival. Survival curves with the ROC optimal cutoff for each method separated the same groups of low-risk (volume ≤ cutoff) from high-risk patients (volume 〉 cutoff), with similar 2-y progression-free survival (range, 66%–72% vs. 26%–29%; hazard ratio, 3.7–4.1) and 2-y overall survival (79%–83% vs. 50%–53%; hazard ratio, 3.0–3.5). Conclusion: The prognostic value of TMTV remained quite similar whatever the methods, adaptive or 41% SUV max , supporting its use as a strong prognosticator in lymphoma. However, for implementation of TMTV in clinical trials 1 single method easily applicable in a multicentric PET review must be selected and kept all along the trial.

Description: The contribution of subsidence to relative sea-level rise in the Ganges-Brahmaputra delta (GBD) is largely unknown and may considerably enhance exposure of the Bengal basin populations to sea level rise and storm surges. This paper focuses on estimating the present-day subsidence induced by Holocene sediment in the Bengal basin and by oceanic loading due to eustatic sea level rise over the past 18 kyr. Using a viscoelastic Earth model and sediment deposition history based on in-situ measurements, results suggest that massive sediment influx initiated in the early Holocene under a strengthened South Asian monsoon may have contributed significantly to the present-day subsidence of the GBD. We estimate that the Holocene loading generates up to 1.6 mm/yr of the present-day subsidence along the GBD coast, depending on the rheological model of the Earth. This rate is close to the 20 th century global mean sea level rise (1.1-1.7 mm/yr). Thus, past climate change, by way of enhanced sedimentation, is impacting vulnerability of the GBD populations.

Description: The Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in 2012 as the causative agent of a severe respiratory disease with a fatality rate of approximately 30%. The high virulence and mortality rate prompted us to analyze aspects of MERS-CoV pathogenesis, especially its interaction with innate immune cells such as antigen-presenting cells (APCs). Particularly, we analyzed secretion of type I and type III interferons (IFNs) by APCs, i.e., B cells, macrophages, monocyte-derived/myeloid dendritic cells (MDDCs/mDCs), and by plasmacytoid dendritic cells (pDCs) of human and murine origin after inoculation with MERS-CoV. Production of large amounts of type I and III IFNs was induced exclusively in human pDCs, which were significantly higher than IFN induction by severe acute respiratory syndrome (SARS)-CoV. Of note, IFNs were secreted in the absence of productive replication. However, receptor binding, endosomal uptake, and probably signaling via Toll-like receptor 7 (TLR7) were critical for sensing of MERS-CoV by pDCs. Furthermore, active transcription of MERS-CoV N RNA and subsequent N protein expression were evident in infected pDCs, indicating abortive infection. Taken together, our results point toward dipeptidyl peptidase 4 (DPP4)-dependent endosomal uptake and subsequent infection of human pDCs by MERS-CoV. However, the replication cycle is stopped after early gene expression. In parallel, human pDCs are potent IFN-producing cells upon MERS-CoV infection. Knowledge of such IFN responses supports our understanding of MERS-CoV pathogenesis and is critical for the choice of treatment options. IMPORTANCE MERS-CoV causes a severe respiratory disease with high fatality rates in human patients. Recently, confirmed human cases have increased dramatically in both number and geographic distribution. Understanding the pathogenesis of this highly pathogenic CoV is crucial for developing successful treatment strategies. This study elucidates the interaction of MERS-CoV with APCs and pDCs, particularly the induction of type I and III IFN secretion. Human pDCs are the immune cell population sensing MERS-CoV but secrete significantly larger amounts of IFNs, especially IFN-α, than in response to SARS-CoV. A model for molecular virus-host interactions is presented outlining IFN induction in pDCs. The massive IFN secretion upon contact suggests a critical role of this mechanism for the high degree of immune activation observed during MERS-CoV infection.

Description: Hypoxia-induced p38 MAPK activation reduces Mcl-1 expression and facilitates sensitivity towards BH3 mimetics in chronic lymphocytic leukemia Leukemia 29, 981 (April 2015). doi:10.1038/leu.2014.320 Authors: M F Huelsemann, M Patz, L Beckmann, K Brinkmann, T Otto, J Fandrey, H J Becker, S Theurich, M von Bergwelt-Baildon, C P Pallasch, R P Zahedi, H Kashkar, H C Reinhardt, M Hallek, C M Wendtner & L P Frenzel