Sorafenib for Advanced and Refractory Desmoid Tumors Gounder, Mrinal M; Mahoney, Michelle R; Van Tine, Brian A ...
New England journal of medicine/The New England journal of medicine,
12/2018, Letnik:
379, Številka:
25
Journal Article
Recenzirano
Odprti dostop
Desmoid tumors are rare and difficult to treat. This trial of daily sorafenib versus placebo documented an objective response rate of 33% with sorafenib and 20% with placebo. The 2-year ...progression-free survival rate was 81% with sorafenib and 36% with placebo.
Protein acetylation is an important contributor to cancer initiation. Histone deacetylase 6 (HDAC6) controls JAK2 translation and protein stability and has been implicated in JAK2-driven diseases ...best exemplified by myeloproliferative neoplasms (MPNs). By using novel classes of highly selective HDAC inhibitors and genetically deficient mouse models, we discovered that HDAC11 rather than HDAC6 is necessary for the proliferation and survival of oncogenic JAK2-driven MPN cells and patient samples. Notably, HDAC11 is variably expressed in primitive stem cells and is expressed largely upon lineage commitment. Although Hdac11is dispensable for normal homeostatic hematopoietic stem and progenitor cell differentiation based on chimeric bone marrow reconstitution, Hdac11 deficiency significantly reduced the abnormal megakaryocyte population, improved splenic architecture, reduced fibrosis, and increased survival in the MPLW515L-MPN mouse model during primary and secondary transplantation. Therefore, inhibitors of HDAC11 are an attractive therapy for treating patients with MPN. Although JAK2 inhibitor therapy provides substantial clinical benefit in MPN patients, the identification of alternative therapeutic targets is needed to reverse MPN pathogenesis and control malignant hematopoiesis. This study establishes HDAC11 as a unique type of target molecule that has therapeutic potential in MPN.
•HDAC11, the sole class IV HDAC, not HDAC6, is a therapeutic vulnerability for MPNs.•Hdac11 plays a key role in oncogene-induced, but not homeostatic, hematopoiesis.
Display omitted
The kidney is the most common transplanted organ, accounting for almost all living donor transplantations and most deceased donor organ transplantations. The organ shortage has caused policymakers in ...many nations to debate the merits of adopting presumed consent legislation as a way to increase donor organ donation from deceased donors.
To compare characteristics and kidney transplantation rates for countries with presumed consent for deceased organ donation with countries with explicit consent.
A longitudinal study of international kidney transplantation from 1997 to 2007.
44 nations performing kidney transplantation.
Recipients of deceased and living kidney donor transplants.
Rates of transplantation of kidneys from deceased and living donors.
National characteristics, such as population size, proportion of the population self-identified as Catholic, per capita gross domestic product, health expenditures, and physician density, varied widely for the 22 nations with presumed consent and the 22 nations with explicit consent. Deceased donor kidney transplantation rates were higher in nations with presumed consent (median, 22.6 transplantations per million population pmp; interquartile range IQR, 9.3 to 33.8) versus nations with explicit consent (median, 13.9 transplantations pmp; IQR, 3.6 to 23.1). Living donor kidney transplantation rates were lower in nations with presumed consent (median, 2.4 transplantations pmp; IQR, 1.7 to 4.3) versus nations with explicit consent (median, 5.9 transplantations pmp; IQR, 2.3 to 12.2). The findings were consistent when nations were classified according to per capita gross domestic product, health expenditures, and physician density.
As with any observational study, associations may not be causal.
Nations with presumed consent have higher rates of deceased donor kidney transplantation than nations with explicit consent. Any nation deciding to adopt presumed consent should carefully consider and reduce any negative effect on rates of living donation.
Canadian Institutes of Health Research and Lawson Health Research Institute.
In the town of Idrija, Slovenia, the world's second largest mercury mine was active for 500 years and about 37,000 tons of mercury has been lost in the environment. Mercury is still drained from ...soil, riverbed and floodplains and transported with the Idrijca and Soča Rivers to the Gulf of Trieste. A part of inorganic mercury is methylated either in the river system, or later in the coastal area, and, due to its bioaccumulation and biomagnification represents potential danger to human health. A 1-D aquatic model MeRiMod was used to simulate hydrodynamics and sediment transport in the river system from Idrija to the Soča River mouth. Transport of particle bound and dissolved mercury as well as potential net methylation of mercury in the river system was simulated. The simulation of an observed flood wave with 20-year recurrence period was performed in order to validate the model. Methylation was simulated at lower discharges, as higher methylation rates occur in such conditions. The measurement data and the MeRiMod model were also used to establish a historical mercury mass balance of the Idrijca and Soča Rivers catchment. Sediment core data from the Gulf of Trieste and the measured concentrations from floodplains were used to verify and calibrate the model. Simulations of different high discharges were performed as most of the transport of particulate mercury occurs within flood wave conditions. Compared to the measurements, the results of the model showed an agreement within an order of magnitude, for the transport of total mercury mostly within a factor of 4, and for the methylation within a factor of 5. However, proper trends of the phenomena were obtained by simulations. The combination of modelling and measurements has resulted in some interesting conclusions about the phenomenon of the transport and transformations of mercury in the observed river system.
The Idrija Mine is the second largest Hg mine in the world which operated for 500 years. Mercury (Hg)-laden tailings still line the banks, and the system is a threat to the Idrija River and water ...bodies downstream including the Soca/Isonzo River and the Gulf of Trieste in the northern Adriatic Sea. A multidisciplinary study was conducted in June 1998 on water samples collected throughout the Idrija and Soca River systems and waters and sediments in the Gulf. Total Hg in the Idrija River increased >20-fold downstream of the mine from <3 to >60 ng liter−1 with methyl mercury (MeHg) accounting for ∼0.5%. Concentrations increased again downstream and into the estuary with MeHg accounting for nearly 1.5% of the total. While bacteria upstream of the mine did not contain mercury detoxification genes (mer), such genes were detected in bacteria collected downstream. Benthic macroinvertebrate diversity decreased downstream of the mine. Gulf waters near the river mouth contained up to 65 ng liter−1 total Hg with ∼0.05 ng liter−1 MeHg. Gulf sediments near the river mouth contained 40 μg g−1 total Hg with MeHg concentrations of about 3 ng g−1. Hg in sediment pore waters varied between 1 and 8 ng liter−1, with MeHg accounting for up to 85%. Hg methylation and MeHg demethylation were active in Gulf sediments with highest activities near the surface. MeHg was degraded by an oxidative pathway with >97% C released from MeHg as CO2. Hg methylation depth profiles resembled profiles of dissolved MeHg. Hg-laden waters still strongly impact the riverine, estuarine, and marine systems. Macroinvertebrates and bacteria in the Idrija River responded to Hg stress, and high Hg levels persist into the Gulf. Increases in total Hg and MeHg in the estuary demonstrate the remobilization of Hg, presumably as HgS dissolution and recycling. Gulf sediments actively produce MeHg, which enters bottom waters and presumably the marine food chain.
Introduction: Acetylated histone and non-histone proteins are pharmacologic targets for both solid and hematological cancers including myeloproliferative neoplasms (MPNs), a group of clonal ...hematological malignancies driven by aberrant JAK2/STAT signaling. MPNs are characterized by epigenetic alterations, including aberrant acetylation, which makes this disease particularly interesting for targeting with HDAC inhibitors. Four classes of histone deacetylases (Class I-IV HDACs) regulate gene transcription and modulate cellular processes that drive the initiation and progression of cancer. Pan-HDAC and class I-selective HDAC inhibitors have gained traction in clinical settings, yet we reasoned that specific targeting of the 18 distinct HDAC proteins may establish roles for select HDACs as therapeutic vulnerabilities in MPNs.
Methods: To explore the roles of individual HDACs in MPN, we first conducted an inhibitor screen of compounds having distinct HDAC selectivity based on electrophoretic mobility shift assays with full-length human HDAC proteins expressed in baculovirus and unique peptide substrates. Ultra-specific HDAC6 compounds were initially targeted for analysis based on its previously defined role in HSP90-mediated JAK2 stabilization and translation. Survival of MPN cell line models, MPN patient samples, leukemia cell lines, and MPN disease progression in mice transplanted with Hdac6-/-, and Hdac11-/- hematopoietic stem cells (HSCs) transduced with the MPLW515L oncogene, as well as Tg-Hdac11-eGfp mice were used to show the role of HDAC6 and HDAC11 in oncogene-driven and homeostatic hematopoiesis. As further proof of specificity, HDAC6 and HDAC11 were genetically ablated in MPN model cell lines using either RNA interference or inducible shRNA. For HDAC11 substrate identification, a combination of RNA-seq, acetylated proteome (SILAC), global metabolomics (LC-MS), Seahorse metabolic assays (Agilent Technologies), enzymatic assays, and acetylation-specific immunoblotting and mutation profiling were performed (Fig. 1).
Results: Despite the established interplay between HDAC6, HSP90 and JAK2, neither a highly selective HDAC6 inhibitor, HDAC6 silencing, nor the Hdac6 deficiency suppressed MPN pathogenesis, although there were clear effects on the acetylation of α-tubulin, a well characterized HDAC6-selective substrate. Intriguingly, both inhibition of HDAC11 activity with highly-specific HDAC11 inhibitors and silencing HDAC11 using an inducible validated shRNA, identified HDAC11 as a therapeutic vulnerability for multiple human MPN cell lines. The Tg-Hdac11-eGFP reporter mice showed that HDAC11 is expressed in several hematopoietic cell types, including myeloid cells, erythroblasts, and megakaryocytes. Thus, Hdac11-/- and Hdac11+/+ MPLWT bone marrow were examined for steady-state hematopoiesis and transplantation chimerism. These studies demonstrated that HDAC11 does not contribute to homeostatic or transplantated bone marrow reconstitution. However, in the oncogenic MPL model, recipient mice transplanted withoncogenic MPLW515L-expressing Hdac11-deficient HSCs displayed markedly impaired cytokine-independent colony-formation, had less fibrosis, and displayed improved survival in primary and secondary MPN hematopoietic stem cell transplantation; thus HDAC11 contributes to MPN pathogenesis (Fig. 1). Studies in additional leukemia cell lines, including THP-1, HL-60, and mantle lymphoma cell lines, but not in Ramos or K562 cells, established that HDAC11 contributes to oncogene-driven events in other cell types. Mechanistically, RNA-seq, SILAC proteomics, and metabolic profiling revealed that HDAC11 controls aerobic glycolysis by deacetylating Lys343 of the glycolytic enzyme enolase-1 (ENO1), functionally inactivating ENO1. Finally, the effects of targeting HDAC11 on metabolism were augmented by blocking compensatory pathways of oxidative phosphorylation that are induced via JAK2V617Fand MPLW515L oncogenic signaling.
Conclusions: Our comprehensive screens of HDAC inhibitors, coupled with our biological, in vivo and molecular studies, indicate that HDAC11 is an attractive and potent target for disabling MPN metabolism and pathogenesis. These finding support the rationale for further development of clinical HDAC11 inhibitors for the treatment of metabolically-active cancers such as MPNs.
Display omitted
Pinilla Ibarz:Teva: Consultancy; TG Therapeutics: Consultancy; Sanofi: Speakers Bureau; Bayer: Speakers Bureau; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Abbvie: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Reuther:Incyte Corporation: Research Funding. Levine:Loxo: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Research Funding; Lilly: Honoraria; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Imago Biosciences: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Gilead: Consultancy; Celgene: Consultancy, Research Funding; Qiagen: Membership on an entity's Board of Directors or advisory committees; Prelude Therapeutics: Research Funding; Amgen: Honoraria. Verma:BMS: Research Funding; Janssen: Research Funding; Stelexis: Equity Ownership, Honoraria; Acceleron: Honoraria; Celgene: Honoraria. Epling-Burnette:Incyte Corporation: Research Funding; Celgene Corporation: Patents & Royalties, Research Funding; Forma Therapeutics: Research Funding.
The innate immune system senses pathogens through pattern-recognition receptors (PRRs) that signal to induce effector cytokines, such as type I interferons (IFNs). We characterized IFN-ε as a type I ...IFN because it signaled via the Ifnar1 and Ifnar2 receptors to induce IFN-regulated genes. In contrast to other type I IFNs, IFN-ε was not induced by known PRR pathways; instead, IFN-ε was constitutively expressed by epithelial cells of the female reproductive tract (FRT) and was hormonally regulated. Ifn-ε-deficient mice had increased susceptibility to infection of the FRT by the common sexually transmitted infections (STIs) herpes simplex virus 2 and Chlamydia muridarum. Thus, IFN-ε is a potent antipathogen and immunoregulatory cytokine that may be important in combating STIs that represent a major global health and socioeconomic burden.
Reconstructing the locomotion of extinct vertebrates offers insights into their palaeobiology and helps to conceptualize major transitions in vertebrate evolution
. However, estimating the locomotor ...behaviour of a fossil species remains a challenge because of the limited information preserved and the lack of a direct correspondence between form and function
. The evolution of advanced locomotion on land-that is, locomotion that is more erect, balanced and mechanically power-saving than is assumed of anamniote early tetrapods-has previously been linked to the terrestrialization and diversification of amniote lineages
. To our knowledge, no reconstructions of the locomotor characteristics of stem amniotes based on multiple quantitative methods have previously been attempted: previous methods have relied on anatomical features alone, ambiguous locomotor information preserved in ichnofossils or unspecific modelling of locomotor dynamics. Here we quantitatively examine plausible gaits of the stem amniote Orobates pabsti, a species that is known from a complete body fossil preserved in association with trackways
. We reconstruct likely gaits that match the footprints, and investigate whether Orobates exhibited locomotor characteristics that have previously been linked to the diversification of crown amniotes. Our integrative methodology uses constraints derived from biomechanically relevant metrics, which also apply to extant tetrapods. The framework uses in vivo assessment of locomotor mechanics in four extant species to guide an anatomically informed kinematic simulation of Orobates, as well as dynamic simulations and robotics to filter the parameter space for plausible gaits. The approach was validated using two extant species that have different morphologies, gaits and footprints. Our metrics indicate that Orobates exhibited more advanced locomotion than has previously been assumed for earlier tetrapods
, which suggests that advanced terrestrial locomotion preceded the diversification of crown amniotes. We provide an accompanying website for the exploration of the filters that constrain our simulations, which will allow revision of our approach using new data, assumptions or methods.
CT colonography (CTC) has been recognized as a complementary approach to evaluating the entire colon after incomplete colonoscopy (IC) in patients with occlusive colorectal cancer (CRC). The ...objective of this study is to evaluate changes in preoperative surgical planning after CTC is performed for patients with occlusive CRC and IC in an oncologic hospital.
This retrospective study included 65 consecutive patients with occlusive CRC who underwent CTC after IC at our institution from February 2000 to April 2016. CTC examinations and radiology reports were reviewed by an abdominal radiologist. Clinical information was obtained from a review of the electronic medical record.
CTC contributed to a change in the initial surgical plan of the surgeon for 14 of 65 patients (21.5%). In these 14 patients, CTC detected five synchronous proximal colon polyps (35.7%), five synchronous proximal cancers (35.7%), two imprecise CRC locations (14.3%), one case of proximal colon ischemia (7.1%), and one instance of tumor infiltration of the urinary bladder (7.1%). All CTC findings were confirmed at surgery, and all proximal colon polyps were subsequently confirmed to be advanced adenomas.
The preoperative CTC findings optimized the surgical management plan for 21.5% of patients with occlusive CRC and IC.
PDF
