The development of immunotherapies for lymphoma has undergone a revolutionary evolution over the past decades. Since the advent of rituximab as the first successful immunotherapy for B-cell ...non-Hodgkin lymphoma over two decades ago, a plethora of new immunotherapeutic approaches to treat lymphoma has ensued. Four of the most exciting classes of immunotherapies include: chimeric antigen receptor T-cells, bispecific antibodies, immune checkpoint inhibitors, and vaccines. However, with addition of these novel therapies the appropriate timing of treatment, optimal patient population, duration of therapy, toxicity, and cost must be considered. In this review, we describe the most-promising immunotherapeutic approaches for the treatment of lymphoma in clinical development, specifically focusing on clinical trials performed to date and strategies for improvement.
Vaccinia virus (VV) is the most studied member of the poxvirus family, is responsible for the successful elimination of smallpox worldwide, and has been developed as a vaccine vehicle for infectious ...diseases and cancer immunotherapy. We have previously shown that the unique potency of VV in the activation of CD8
T cell response is dependent on efficient activation of the innate immune system through Toll-like receptor (TLR)-dependent and -independent pathways. However, it remains incompletely defined what regulate CD8
T cell response to VV infection. In this study, we showed that γδT cells play an important role in promoting CD8
T cell response to VV infection. We found that γδT cells can directly present viral antigens in the context of MHC-I for CD8
T cell activation to VV
, and we further demonstrated that cell-intrinsic MyD88 signaling in γδT cells is required for activation of γδT cells and CD8
T cells. These results illustrate a critical role for γδT cells in the regulation of adaptive T cell response to viral infection and may shed light on the design of more effective vaccine strategies based on manipulation of γδT cells.
The evolution of oxygenic photosynthesis is a pivotal event in Earth's history because the O
released fundamentally changed the planet's redox state and facilitated the emergence of multicellular ...life. An intriguing hypothesis proposes that hydrogen peroxide (H
O
) once acted as the electron donor prior to the evolution of oxygenic photosynthesis, but its abundance during the Archean would have been limited. Here, we report a previously unrecognized abiotic pathway for Archean H
O
production that involves the abrasion of quartz surfaces and the subsequent generation of surface-bound radicals that can efficiently oxidize H
O to H
O
and O
. We propose that in turbulent subaqueous environments, such as rivers, estuaries and deltas, this process could have provided a sufficient H
O
source that led to the generation of biogenic O
, creating an evolutionary impetus for the origin of oxygenic photosynthesis.
In part composed of Mg calcite and dolomite with a nearly continuous spectrum of MgCO3 contents, carbonates forming at marine methane seeps are ideal candidates to study the formation of early ...diagenetic dolomite at surface conditions. Laboratory experiments, modelling and the co‐variation of mineralogical and geochemical attributes of seep carbonates suggest that sulphide – locally released from sulphate‐driven anaerobic oxidation of methane – drives catalytic dolomite formation at seeps. Direct comparison of the concentration of dissolved sulphide with the MgCO3 content of seep carbonate could test this hypothesis. Although the concentration of sulphide during precipitation of carbonate cannot be determined, sedimentary fabrics probably had an effect on local sulphide concentration. Carbonates from the seabed of the Shenhu seepage area of the South China Sea reveal longitudinal, winding and branched fabrics with a width of 400 to 700 μm, interpreted to represent burrows piercing semi‐consolidated sediment. The abandoned burrows were infilled with fine‐grained sediment, which was subsequently cemented by microcrystalline dolomite and Mg calcite. The degree of cation ordering of dolomite in burrow infills and host sediment is similar, indicating virtually coeval dolomite formation. The Mg/Ca mole ratios of carbonate minerals are lower in burrow infills than in the surrounding sedimentary matrix. Similarly, δ13Ccarbonate values tend to be higher for burrow infills (from −41 to −33‰) than for the matrix (from −43 to −38‰), suggesting stronger seawater influence on pore waters in the burrows. More reducing microenvironments of the sedimentary matrix supposedly came along with higher concentrations of dissolved sulphide, which allowed more Mg2+ ions to enter the crystal lattice and led to more catalytic dolomite formation in the host sediment. The distribution of MgCO3 contents and δ13C values in the authigenic Shenhu carbonates reinforces the hypothesis that sulphide release by sulphate‐driven anaerobic oxidation of methane is a key factor in the formation of dolomite at seeps.
Abstract Kumdykolite is a polymorph of albite that has been predominantly identified within crystallized melt inclusions in high-temperature metamorphic rocks. This study reports a new occurrence of ...kumdykolite that formed during internal mineral carbonation within amphibole-hosted fluid inclusions in postcollisional hornblendite from the Dabie orogen, central China. Amphibole in the hornblendite trapped CO2-rich fluid inclusions at magmatic stage, and mineral carbonation, referring to the reaction of mineral rich in divalent cations and CO2 into carbonate, occurred in situ within the fluid inclusions due to interaction between trapped CO2-rich fluids and host amphibole during cooling of the hornblendite. Kumdykolite was produced along with calcite, dolomite, chlorite, talc, a SiO2 phase (quartz or cristobalite), a TiO2 phase (rutile or anatase), and mica during internal mineral carbonation within the fluid inclusions. It is estimated that kumdykolite in the fluid inclusions crystallized under near-surface conditions, which are significantly different from the conditions of crystallization proposed in previous studies. It is further inferred that kumdykolite may crystallize metastably across the stability field of albite, and presence of kumdykolite is not indicative of extreme thermobaric and fluid-absent conditions.
Background Previous studies have investigated the association of ambient air pollution with blood pressure (BP) in children and adolescents, however, the results are not consistent. We conducted a ...systematic review and meta-analysis to assess the relationship between short-term and long-term ambient air pollutant exposure with BP values among children and adolescents. Methods and Results We searched PubMed, Web of Science, and Embase before September 6, 2020. Two reviewers independently searched and selected studies, extracted data, and assessed study quality. The studies were divided into groups by composition of air pollutants (NO
, particulate matter (PM) with diameter ≤10 μm or ≤2.5 μm) and length of exposure. The beta regression coefficients (β) and their 95% CIs were calculated to evaluate the strength of the effect with each 10 μg/m
increase in air pollutants. Out of 36 650 articles, 14 articles were included in this meta-analysis. The meta-analysis showed short-term exposure to PM with diameter ≤10 μm (β=0.267; 95% CI, 0.033‒0.501) was significantly associated with elevated systolic BP values. In addition, long-term exposure to PM with diameter ≤2.5 μm (β=1.809; 95% CI, 0.962‒2.655), PM with diameter ≤10 μm (β=0.526; 95% CI, 0.095‒0.958), and NO
(β=0.754; 95% CI, 0.541‒0.968) were associated with systolic BP values and long-term exposure to PM with diameter ≤2.5 μm (β=0.931; 95% CI, 0.157‒1.705), and PM with diameter ≤10 μm (β=0.378; 95% CI, 0.022‒0.735) was associated with diastolic BP. Conclusions Our study indicates that both short-term and long-term exposure to some ambient air pollutants may increase BP values among children and adolescents.
The integrated effects of the Western Pacific Warm Pool (WPWP) and the Kuroshio Current (KC) on the thermal evolution of the subtropical northwestern Pacific during the Holocene have remained ...elusive. This study presents new δ18O and Mg/Ca ratio records of subsurface-dwelling planktonic foraminifera Pulleniatina obliquiloculata at Site A7 in the Okinawa Trough to reconstruct thermocline-water evolution since the last deglaciation (∼18 ka) and further explore the effects of the WPWP and the KC dynamics throughout the Holocene. The Mg/Ca-based thermocline-water temperature (TWT) record displays a long-term cooling trend of ∼3 °C since the middle Holocene (∼7 ka), with a similar trend with that in the WPWP. Furthermore, two major thermocline warming events occurred with an amplitude of ∼2–3 °C in the early (∼11.8–9.5 ka) and middle (∼8–6.5 ka) Holocene, respectively. Both events are comparable with those in the WPWP. Besides, our TWT record had nine Holocene rapid cooling events with amplitudes of ∼1–2 °C around 1.7, 3.2, 4.4, 6.0, 7.2, 7.5, 8.2, 8.9, and 10 ka, respectively. The cooling events were also identified in the temperature records of the thermocline and/or intermediate waters in the WPWP within the chronological uncertainties. The comparability of these temperature records between both regions reveals that the dynamic KC transmitted thermal signals of the WPWP thermocline/intermediate waters into the Okinawa Trough on centennial to multi-millennial timescales, highlighting a crucial role of the WPWP in influencing subtropical ocean thermodynamics and climate in the Holocene.
•Thermocline temperature record was reconstructed in the Okinawa Trough since 18 ka.•A mid- to late Holocene thermocline cooling trend and two major EH & MH thermocline warming events in the Okinawa Trough.•Thermal signals of the WPWP were transmitted by the KC on centennial to multi-millennial timescales in the Holocene.
NK cells are critical for the innate immune control of poxviral infections. Previous studies have shown that NK cells are efficiently activated in response to infection with vaccinia virus (VV), the ...most studied member of the poxvirus family. However, it remains unknown whether the activation of NK cells in response to VV infection is tightly regulated. In this study, we showed that myeloid-derived suppressor cells (MDSCs) rapidly accumulated at the site of VV infection. In vivo depletion of MDSCs led to enhanced NK cell proliferation, activation, and function in response to VV infection. This was accompanied by an increase in mortality and systemic IFN-γ production. We further demonstrated that the granulocytic-MDSC (G-MDSC) subset was responsible for the suppression on NK cells and that this suppression was mediated by reactive oxygen species. These results indicate that G-MDSCs can negatively regulate NK cell activation and function in response to VV infection and suggest that manipulation of G-MDSCs could represent an attractive strategy for regulating NK cell activities for potential therapeutic benefits.
The Holocene evolution of the Indian Ocean Monsoon (IOM), especially the spatiotemporal nature of its maximum precipitation period, remains controversial. Here we reconstruct high-resolution local ...δ18Osw and sea surface temperature (SST) values by pairing Mg/Ca values and the δ18O data from planktonic foraminifera Globigerinoides ruber (white) in the southern Andaman Sea in order to understand IOM rainfall variability during the Holocene. Local δ18Osw values show that local maximum rainfall occurred between 10.6 ka and 8.6 ka in the southern Andaman Sea, before declining markedly during the 8.6–5.0 ka period, and then decreasing slightly after 5.0 ka. The Mg/Ca-SST was relatively low during the 10.3–8.6 ka period, before increasing slightly between 8.6 ka and 4.0 ka; it declined thereafter. But the sedimentation rate at the site of Core ADM-C1 relating to monsoonal precipitation of the source region of sediments exhibited its highest value during the 8.6–5.5 ka period. After making further comparisons with other published records for this region, we would propose that maximum IOM precipitation during the early Holocene has exhibited a clearly meridional migration: it was located in the tropics around 7°N during the 10.6–8.6 ka period, migrated northward to the subtropics during the 8.6–5.5 ka period, before migrating southward again after 5.0 ka. We would suggest that the northward shift of maximum precipitation during the Early Holocene in the IOM region was in response to the progressively northward migration of the Intertropical Convergence Zone (ITCZ) and the change of El Niño Southern Oscillation (ENSO) and Indian Ocean Dipole (IOD) activities.
•Local precipitation is estimated by paired Mg/Ca and oxygen isotope of G. ruber.•Holocene high-resolution monsoon rainfall is reconstructed in the southern Andaman Sea.•Peak IOM precipitation show a meridional south-to-north migration during the Early Holocene.
A palynological investigation of a 514cm long continuous core section from Qinghai Crater Lake, western Yunnan Province, southwestern China, was performed in order to reconstruct regional vegetation ...and climate from 15.8cal kyr BP to the present. The results show that the area was covered with deciduous broadleaved forest dominated by deciduous Quercus between 15.8 and 12.8cal kyr BP, suggesting slightly cold and dry conditions. From 12.8 to 8.3cal kyr BP, the vegetation continued to be dominated by deciduous broadleaved forest, but there was also a sudden increase in Castanopsis/Lithocarpus and a slight drop in deciduous Quercus and Alnus, reflecting a gradual increase in both temperature and humidity. During the period 8.3–4.6cal kyr BP, the mixed deciduous forests became more diverse and dense, with thermophilous and hygrophilous species expanding to their maximum extents, implying a warm and rather humid climate. From 4.6 to 0.5cal kyr BP, the vegetation was succeeded by open mixed deciduous forest dominated by Alnus, with a retreating evergreen broadleaved forest, indicating a cool and slightly dry climate. After 0.5cal kyr BP, the vegetation became less diverse and more open, but evergreen broadleaved trees increased their spread markedly, suggesting that the climate had become warmer and drier. In recent decades, human activity resulted in a large increase in Alnus and Pinus around this lake basin. Specifically, we concluded that the warm and moist climate detected between 8.3 and 4.6cal kyr BP may have occurred in response to the high sea surface temperatures and high sea levels in the Bay of Bengal existent at that time.
•A pollen record for the last 15.8 kyr from Qinghai Crater Lake in western Yunnan Province, southwestern China shows five major stages of vegetation development.•The reconstruction indicate the climatic was slightly cold and dry from 15.8 to 12.8cal kyr BP, and a warm and rather humid climate occurred at the period of 8.3–4.6cal kyr BP.•The warm and moist climate between 8.3 and 4.6cal kyr BP may response to the high sea surface temperatures and high sea levels in the Bay of Bengal at that time.
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