Indolent non-Hodgkin lymphoma (iNHL) remains largely incurable and often requires multiple lines of treatment after becoming refractory to standard therapies. Duvelisib was approved by the Food and ...Drug Administration for relapsed or refractory (RR) chronic lymphocytic leukemia or small lymphocytic lymphoma (SLL) and RR follicular lymphoma (FL) after two or more prior systemic therapies. On the basis of the activity of duvelisib, a first-in-class oral dual inhibitor of phosphoinositide 3-kinase-δ,-γ, in RR iNHL in a phase I study, the safety and efficacy of duvelisib monotherapy was evaluated in iNHL refractory to rituximab and either chemotherapy or radioimmunotherapy.
Eligible patients had measurable iNHL (FL, SLL, or marginal zone B-cell lymphoma) double refractory to rituximab (monotherapy or in combination) and to either chemotherapy or radioimmunotherapy. All were treated with duvelisib 25 mg orally twice daily in 28-day cycles until progression, unacceptable toxicity, or death. The primary end point was overall response rate (ORR) using the revised International Working Group criteria for malignant lymphoma.
This open-label, global phase II trial enrolled 129 patients (median age, 65 years; median of three prior lines of therapy) with an ORR of 47.3% (SLL, 67.9%; FL, 42.2%; MZL, 38.9%). The estimated median duration of response was 10 months, and the estimated median progression-free survival was 9.5 months. The most frequent any-grade treatment-emergent adverse events (TEAEs) were diarrhea (48.8%), nausea (29.5%), neutropenia (28.7%), fatigue (27.9%), and cough (27.1%). Among the 88.4% of patients with at least one grade 3 or greater TEAE, the most common TEAEs were neutropenia (24.8%), diarrhea (14.7%), anemia (14.7%), and thrombocytopenia (11.6%).
In the DYNAMO study, oral duvelisib monotherapy demonstrated clinically meaningful activity and a manageable safety profile in heavily pretreated, double-refractory iNHL, consistent with previous observations. Duvelisib may provide a new oral treatment option for this patient population of which many are elderly and in need of additional therapies.
The 2023 terahertz science and technology roadmap Leitenstorfer, Alfred; Moskalenko, Andrey S; Kampfrath, Tobias ...
Journal of physics. D, Applied physics,
04/2023, Letnik:
56, Številka:
22
Journal Article
Recenzirano
Odprti dostop
Abstract
Terahertz (THz) radiation encompasses a wide spectral range within the electromagnetic spectrum that extends from microwaves to the far infrared (100 GHz–∼30 THz). Within its frequency ...boundaries exist a broad variety of scientific disciplines that have presented, and continue to present, technical challenges to researchers. During the past 50 years, for instance, the demands of the scientific community have substantially evolved and with a need for advanced instrumentation to support radio astronomy, Earth observation, weather forecasting, security imaging, telecommunications, non-destructive device testing and much more. Furthermore, applications have required an emergence of technology from the laboratory environment to production-scale supply and in-the-field deployments ranging from harsh ground-based locations to deep space. In addressing these requirements, the research and development community has advanced related technology and bridged the transition between electronics and photonics that high frequency operation demands. The multidisciplinary nature of THz work was our stimulus for creating the 2017 THz Science and Technology Roadmap (Dhillon
et al
2017
J. Phys. D: Appl. Phys.
50
043001). As one might envisage, though, there remains much to explore both scientifically and technically and the field has continued to develop and expand rapidly. It is timely, therefore, to revise our previous roadmap and in this 2023 version we both provide an update on key developments in established technical areas that have important scientific and public benefit, and highlight new and emerging areas that show particular promise. The developments that we describe thus span from fundamental scientific research, such as THz astronomy and the emergent area of THz quantum optics, to highly applied and commercially and societally impactful subjects that include 6G THz communications, medical imaging, and climate monitoring and prediction. Our Roadmap vision draws upon the expertise and perspective of multiple international specialists that together provide an overview of past developments and the likely challenges facing the field of THz science and technology in future decades. The document is written in a form that is accessible to policy makers who wish to gain an overview of the current state of the THz art, and for the non-specialist and curious who wish to understand available technology and challenges. A such, our experts deliver a ‘snapshot’ introduction to the current status of the field and provide suggestions for exciting future technical development directions. Ultimately, we intend the Roadmap to portray the advantages and benefits of the THz domain and to stimulate further exploration of the field in support of scientific research and commercial realisation.
The reconstruction of modern and paleo-sulfur cycling relies on understanding the long-term relative contribution of its main actors; these include microbial sulfate reduction (MSR) and microbial ...sulfur disproportionation (MSD). However, a unifying theory is lacking for how MSR and MSD, with the same enzyme machinery and intimately linked evolutionary histories, perform two drastically different metabolisms. Here, we aim at shedding some light on the distribution, diversity, and evolutionary histories of MSR and MSD, with a focus on the
as a test case. The
is a diverse and widespread order of bacteria in the
(formerly
) phylum primarily composed of sulfate reducing bacteria. Recent culture- and sequence-based approaches have revealed an expanded diversity of organisms and metabolisms within this clade, including the presence of obligate and facultative sulfur disproportionators. Here, we present draft genomes of previously unsequenced species of
, substantially expanding the available genomic diversity of this clade. We leverage this expanded genomic sampling to perform phylogenetic analyses, revealing an evolutionary history defined by vertical inheritance of sulfur metabolism genes with numerous convergent instances of transition from sulfate reduction to sulfur disproportionation.
Sulfur isotopes in ancient sediments provide a record of past environmental conditions. The long–time-scale variability and apparent asymmetry in the magnitude of minor sulfur isotope fractionation ...in Archean sediments remain unexplained. Using an integrated biogeochemical model of the Archean sulfur cycle, we find that the preservation of mass-independent sulfur is influenced by a variety of extra-atmospheric mechanisms, including biological activity and continental crust formation. Preservation of atmospherically produced mass-independent sulfur implies limited metabolic sulfur cycling before ~2500 million years ago; the asymmetry in the record indicates that bacterial sulfate reduction was geochemically unimportant at this time. Our results suggest that the large-scale structure of the record reflects variability in the oxidation state of volcanic sulfur volatiles.
The Paleocene-Eocene Thermal Maximum (PETM) was an abrupt global warming event associated with a large injection of carbon into the ocean-atmosphere system, as evidenced by a diagnostic carbon ...isotope excursion (CIE). Evidence also suggests substantial hydrologic perturbations, but details have been hampered by a lack of appropriate proxies. To address this shortcoming, here we isolate and measure the isotopic composition of hydroxyl groups (OH
) in clay minerals from a highly expanded PETM section in the North Sea Basin, together with their bulk oxygen isotope composition. At this location, we show that hydroxyl O- and H-isotopes are less influenced than bulk values by clay compositional changes due to mixing and/or inherited signals and thus better track hydrologic variability. We find that clay OH
hydrogen-isotope values (δ
H
) decrease slowly prior to the PETM and then abruptly by ∼8‰ at the CIE onset. Coincident with an increase in relative kaolinite content, this indicates increased rainfall and weathering and implies an enhanced hydrologic cycle response to global warming, particularly during the early stages of the PETM. Subsequently, δ
H
returns to pre-PETM values well before the end of the CIE, suggesting hydrologic changes in the North Sea were short-lived relative to carbon-cycle perturbations.
A mechanistic understanding of relationships between global glaciation, a putative second rise in atmospheric oxygen, the Shuram carbon isotope excursion, and the appearance of Ediacaran-type fossil ...impressions and bioturbation is dependent on the construction of accurate geological records through regional stratigraphic correlations. Here we integrate chemo-, litho-, and sequence-stratigraphy of fossiliferous Ediacaran strata in northwestern Canada. These data demonstrate that the FAD of Ediacara-type fossil impressions in northwestern Canada occur within a lowstand systems tract and above a major sequence boundary in the informally named June beds, not in the early Ediacaran Sheepbed Formation from which they were previously reported. This distinction is substantiated by δ13Ccarb chemostratigraphy of the Sheepbed carbonate, which overlies the Sheepbed Formation, and the Gametrail Formation, which overlies the June beds. The Sheepbed carbonate hosts heavy δ13Ccarb values whereas the Gametrail Formation contains a large δ13Ccarb excursion, which we correlate with the globally recognized Shuram excursion. Stratigraphically above the Gametrail excursion, the first bilaterian burrows are present in the basal Blueflower Formation. Together, these data allow us to construct an age model for Ediacaran strata in northwestern Canada and conclude that a purported shift in Fe speciation in the Sheepbed Formation significantly predates the shift recorded above the ca. 582Ma Gaskiers glaciation in Newfoundland and the first appearance of Ediacaran biota.
The Gametrail excursion shares many characteristics with Shuram negative δ13Ccarb excursion: 1) δ13Ccarb and δ18Ocarb covary; 2) δ13Ccarb and δ13Corg do not covary; 3) the excursion is developed during a transgressive systems tract and recovers in an highstand systems tract; and 4) values in some sections are well below mantle δ13C input values but are variable between sections. We relate regional lateral variability in the magnitude and character of this excursion to condensation and diachronous deposition during the transgression and local authigenic carbonate production. In light of these observations, we explore a variety of models for the genesis of the Shuram excursion and suggest that the location and amount of authigenic carbonate production played a role in the excursion.
•The first appearance of Ediacaran fossils in NW Canada occurs above the Sheepbed Formation.•Fe-speciation shifts are not correlative with first appearance of Ediacaran fossils.•A Shuram-like carbon isotope excursion occurs above the first appearance of Ediacaran fossils.•The first bilaterian burrows are present directly above the Shuram-like excursion.•We suggest that Shuram-like excursions form in global authigenic events.
Mercury (Hg) stable isotope signatures are widely used to understand Hg cycling in the environment. Sample preparation methods for determining Hg isotope ratios by CV-MC-ICP-MS vary widely among ...laboratory facilities and sample types. Here, we present a novel and rapid method for preparing solid samples prior to determining Hg isotope composition. We use a direct Hg analyzer (that measures total Hg) for sample combustion, amalgamation and analysis. During the thermal release of Hg from the amalgamator and following detection, the analyte gas enters a trapping solution consisting of 10% HCl/BrCl (5:1, vol/vol). We find Hg blank values are less than 1% of the Hg introduced during sample analysis, Hg detection is not altered by modifying the system, and more than 90% of the introduced Hg is recovered in the trapping solution. Hg isotope results are statistically indistinguishable from accepted values for previously published certified reference materials and uncertainty of 2σ (0.05–0.12‰) is similar to the solution standard RM8610 (2σ = 0.09‰). This new method allows for solid sample preparation for Hg isotope analysis in under 15 min. It has the additional advantage of minimizing use of sample mass during simultaneous detection and preparation.
Display omitted
•Preconcentration of Hg during total Hg analysis reduces preparation time and sample mass required.•Sample preparation for Hg isotope analysis only takes ∼8 min.•Hg isotope analysis of SRMs matches literature data with good reproducibility.
Canadian boreal woodlands and forests cover approximately 3.09 × 106km2, located within a larger boreal zone characterized by cool summers and long cold winters. Warming since the 1850s, increases in ...annual mean temperature of at least 2 °C between 2000 and 2050 are highly probable. Annual mean temperatures across the Canadian boreal zone could be 4–5 °C warmer than today's by 2100. All aspects of boreal forest ecosystem function are likely to be affected. Further, several potential “tipping elements” — where exposure to increasing changes in climate may trigger distinct shifts in ecosystem state — can be identified across the Canadian boreal zone. Approximately 40% of the forested area is underlain by permafrost, some of which is already degrading irreversibly, triggering a process of forest decline and re-establishment lasting several decades, while also releasing significant quantities of greenhouse gases that will amplify the future global warming trend. Warmer temperatures coupled with significant changes in the distribution and timing of annual precipitation are likely to cause serious tree-killing droughts in the west; east of the Great Lakes, however, where precipitation is generally nonlimiting, warming coupled with increasing atmospheric carbon dioxide may stimulate higher forest productivity. Large wildfires, which can cause serious economic losses, are expected to become more frequent, but increases in mean annual area burned will be relatively gradual. The most immediate threats could come from endemic forest insect pests that have the potential for population outbreaks in response to relatively small temperature increases. Quantifying the multiple effects of climate change will be challenging, particularly because there are great uncertainties attached to possible interactions among them, as well as with other land-use pressures. Considerable ingenuity will be needed from forest managers and scientists to address the formidable challenges posed by climate change to boreal ecosystems and develop effective strategies to adapt sustainable forest management practices to the impending changes.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Antimony (Sb) and arsenic (As) are priority environmental contaminants that often co-occur at mining-impacted sites. Despite their chemical similarities, Sb mobility in waterlogged sediments is ...poorly understood in comparison to As, particularly across the sediment–water interface (SWI) where changes can occur at the millimeter scale. Combined diffusive gradients in thin films (DGT) and diffusive equilibration in thin films (DET) techniques provided a high resolution, in situ comparison between Sb, As, and iron (Fe) speciation and mobility across the SWI in contaminated freshwater wetland sediment mesocosms under an oxic–anoxic–oxic transition. The shift to anoxic conditions released Fe(II), As(III), and As(V) from the sediment to the water column, consistent with As release being coupled to the reductive dissolution of iron(III) (hydr)oxides. Conversely, Sb(III) and Sb(V) effluxed to the water column under oxic conditions and fluxed into the sediment under anoxic conditions. Porewater DGT–DET depth profiles showed apparent decoupling between Fe(II) and Sb release, as Sb was primarily mobilized across the SWI under oxic conditions. Solid-phase X-ray absorption spectroscopy (XAS) revealed the presence of an Sb(III)-S phase in the sediment that increased in proportion with depth and the transition from oxic to anoxic conditions. The results of this study showed that Sb mobilization was decoupled from the Fe cycle and was, therefore, more likely linked to sulfur and/or organic carbon (e.g., most likely authigenic antimony sulfide formation or Sb(III) complexation by reduced organic sulfur functional groups).
Although recent data suggests that osteoblasts play a key role within the hematopoietic stem cell (HSC) niche, the mechanisms underpinning this remain to be fully defined. The studies described ...herein examine the role in hematopoiesis of Osteopontin (Opn), a multidomain, phosphorylated glycoprotein, synthesized by osteoblasts, with well-described roles in cell adhesion, inflammatory responses, angiogenesis, and tumor metastasis. We demonstrate a previously unrecognized critical role for Opn in regulation of the physical location and proliferation of HSCs. Within marrow, Opn expression is restricted to the endosteal bone surface and contributes to HSC transmarrow migration toward the endosteal region, as demonstrated by the markedly aberrant distribution of HSCs in Opn–/– mice after transplantation. Primitive hematopoietic cells demonstrate specific adhesion to Opn in vitro via β1 integrin. Furthermore, exogenous Opn potently suppresses the proliferation of primitive HPCs in vitro, the physiologic relevance of which is demonstrated by the markedly enhanced cycling of HSC in Opn–/– mice. These data therefore provide strong evidence that Opn is an important component of the HSC niche which participates in HSC location and as a physiologic-negative regulator of HSC proliferation.
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