Carbon is one of the key elements in organisms and non-living compounds on Earth. Carbon dioxide and methane are important greenhouse gases in the atmosphere, dissolved inorganic (DIC) and organic ...carbon (DOC) determine water biogeochemistry, and carbonates are major constituents of marine sediments. Stable carbon isotope ratios (13C/12C), expressed as δ13C values, are widely used in modern Earth sciences. δ13CCO2 values of atmospheric carbon dioxide reflect global climate evolution and change. Marine δ13CDIC is used as water-mass tracer and helps quantifying the anthropogenic CO2 uptake of the ocean. The δ13C values of fossil planktic and benthic carbonates indicate changes in circulation pattern and deep-water ventilation of ancient oceans, as well as paleoproductivity at the sea surface and methane release at the sea floor. The δ13COM values of sedimentary organic matter (OM) and compound-specific δ13C values of molecular organic biomarkers indicate whether the organic carbon is of marine or terrestrial provenience. Secular δ13C variations and excursions in carbonates are important stratigraphic marker and tie points.
Here we review the application of stable carbon isotope ratios in ocean water and biogenic carbonates as proxies in paleoceanography, including the atmospheric and sedimentary reservoirs oceanic carbon is in exchange with. Due to the wide use of δ13C values in Earth sciences, this overview necessarily does not claim to be complete; rather we focus on field-based stable carbon isotope research and its significance in paleoceanography. This may assist in evaluating general circulation model results and foster development of new innovative proxies.
Alterations of cellular metabolism represent a hallmark of cancer. Numerous metabolic changes are required for malignant transformation, and they render malignant cells more prone to disturbances in ...the metabolic framework. Despite the high incidence of chronic lymphocytic leukemia (CLL), metabolism of CLL cells remains a relatively unexplored area. The examined untreated CLL patients displayed a metabolic condition known as oxidative stress, which was linked to alterations in their lymphoid compartment. Our studies identified mitochondrial metabolism as the key source for abundant reactive oxygen species (ROS). Unlike in other malignant cells, we found increased oxidative phosphorylation in CLL cells but not increased aerobic glycolysis. Furthermore, CLL cells adapted to intrinsic oxidative stress by upregulating the stress-responsive heme-oxygenase-1 (HO-1). Our data implicate that HO-1 was, beyond its function as an antioxidant, involved in promoting mitochondrial biogenesis. Thus ROS, adaptation to ROS, and mitochondrial biogenesis appear to form a self-amplifying feedback loop in CLL cells. Taking advantage of the altered metabolic profile, we were able to selectively target CLL cells by PK11195. This benzodiazepine derivate blocks the mitochondrial F1F0-ATPase, leads to a surplus production of mitochondrial superoxide, and thereby induces cell death in CLL cells. Taken together, our findings depict how bioenergetics and redox characteristics could be therapeutically exploited in CLL.
•Increased mitochondrial ROS production, adaptation to intrinsic oxidative stress, and mitochondrial biogenesis are interconnected in CLL.•Targeting the respiratory chain and promoting mitochondrial ROS lead to selective cytotoxicity in CLL cells.
Abstract About a century ago Otto Warburg observed that tumor cells exhibited increased glycolysis despite the presence of oxygen and stated this metabolic shift to glycolysis as the origin of cancer ...cell. In the meantime it has become clear, that the altered glucose metabolism is only one piece of the tumor metabolome puzzle. In addition, amino acid, lipid and adenosine metabolism are adapted to fulfill the tumors needs for energy and generation of building blocks such as lipids and nucleotides for new cell structures. The altered tumor metabolism leads to accumulation of specific metabolites in the tumor environment and creates a favorable milieu for tumor growth, progression and metastasis. These tumor-derived metabolites are important players in immune escape mechanisms beside other known factors such as cytokines, chemokines and growth factors. A variety of metabolites re-educate immune cells and prevent an effective immune response against tumor cells. Furthermore, tumor infiltrating immune cells support tumor growth by the secretion of cytokines, growth factors and other metabolic determinants. Hence, a complex interplay of tumor metabolites, cytokines and stromal factors is active in tumors and facilitates their establishment and growth. Pharmacological blockade of tumor metabolites could overcome some limitations of cancer treatment and rescue the endogenous immune response against tumor cells.
High resolution climate records of the ice age terminations from monsoon-dominated regions reveal the interplay of regional and global driving forces. Speleothem records from Chinese caves indicate ...that glacial terminations were interrupted by prominent weak monsoon intervals (WMI), lasting a few thousand years. Deglacial WMIs are interpreted as the result of cold temperature anomalies generated by sea ice feedbacks in the North Atlantic, most prominently during Heinrich Events. Recent modeling results suggest, however, that WMIs reflect changes in the intensity of the Indian rather than the East Asian monsoon. Here we use foraminiferal trace element (Mg/Ca and Ba/Ca) and stable isotope records from a sediment core off the Malabar coast in the southeastern Arabian Sea with centennial-scale resolution to test this hypothesis and to constrain the nature and timing of deglacial climate change in the tropical Indian Ocean. The Malabar deglacial SST record is unique in character and different from other tropical climate records. SST at the Last Glacial Maximum was 2.7±0.5°C colder than pre-industrial SST. Deglacial warming started at 18.6 (95% CI range 18.8−18.1)kyrBP, within error of the onset of warming at other tropical sites as well as in Antarctica and the Southern Ocean and either coeval with or up to 1kyr before the atmospheric CO2 rise. Warming took place in two steps separated by an interval of stable SST between 15.7 (16.2−14.9) and 13.2 (13.9−12.0)kyrBP. The δ18O-water record and the Ba/Ca record, which is a measure of Indian sub-continent riverine runoff, indicate that the last ice age termination was marked by a prominent weak Indian Monsoon interval interrupted by an intense monsoon phase, as seen in speleothem records and predicted by modeling. A strong correspondence between the timing of the Malabar δ18Osw record and the Hulu Cave monsoon record suggests that deglacial δ18O changes in both localities dominantly reflect compositional changes in precipitation, likely driven by changes in the North Atlantic.
•First ever centennial scale deglacial SST record from the northern Indian Ocean.•SST at the Last Glacial Maximum was 2.7±0.5°C colder than pre-industrial SST.•Warming began at 18.6kyrBP either coeval with or up to 1kyr before the CO2 rise.•Deglaciation marked by weak monsoon interval interrupted by intense monsoon phase.•δ18O reflect compositional change in precipitation, likely driven by N Atlantic.
Paleonutrient proxies are widely used to reconstruct the geometry of deep-water masses during the Last Glacial Maximum (LGM). Epibenthic δ13C provides best spatial coverage, and artifacts are well ...investigated. Discrepancies between reconstructed LGM-circulation patterns derived from models or different benthic nutrient proxies can partly be resolved by varying air–sea signatures of δ13C, i.e. δ13Cas. However, there are very few data available to calculate a δ13Cas of modern bottom water dissolved inorganic carbon (DIC) δ13C, and to document how this signal is recorded in benthic foraminiferal δ13C. Here I show that today bottom water in the Atlantic sector of the Southern Ocean is 13C enriched with δ13CDIC values between 0.4 and 1.0‰ and δ13Cas values >0.4‰, and that this signal is recorded in live and dead epibenthic δ13C. This is in contrast to a uniform modern Antarctic circumpolar δ13CDIC of rather 0.4‰, which hitherto is used as modern framework to compare to low LGM δ13CDIC of southern sourced bottom-water and glacial inter basin differences. I conclude that a potential reduction of the strong Recent thermodynamic imprint during bottom-water generation in glacial times could explain depleted circum Antarctic 13CDIC without associated CO2 enrichment and anoxia in Antarctic bottom waters. The present synoptic compilation of δ13CDIC and live benthic foraminifera δ13C is in support of hypotheses that explain low LGM δ13C by a depletion of southern end-member 13CDIC due to extensive sea-ice formation with low δ13Cas-brine rejection and diminished air–sea gas exchange.
► Modern Antarctic circumpolar δ13CDIC is more variable than previously considered. ► Low δ13Cas may have caused low δ13CDIC of the glacial Southern Ocean. ► Extended sea ice and low-δ13Cas brine rejection during glacials suggested.
As substantial constituents of the multiple myeloma (MM) microenvironment, pro-inflammatory macrophages have emerged as key promoters of disease progression, bone destruction, and immune impairment. ...We identify beta-2-microglobulin (β2m) as a driver in initiating inflammation in myeloma-associated macrophages (MAMs). Lysosomal accumulation of phagocytosed β2m promotes β2m amyloid aggregation in MAMs, resulting in lysosomal rupture and ultimately production of active interleukin-1β (IL-1β) and IL-18. This process depends on activation of the NLRP3 inflammasome after β2m accumulation, as macrophages from NLRP3-deficient mice lack efficient β2m-induced IL-1β production. Moreover, depletion or silencing of β2m in MM cells abrogates inflammasome activation in a murine MM model. Finally, we demonstrate that disruption of NLRP3 or IL-18 diminishes tumor growth and osteolytic bone destruction normally promoted by β2m-induced inflammasome signaling. Our results provide mechanistic evidence for β2m’s role as an NLRP3 inflammasome activator during MM pathogenesis. Moreover, inhibition of NLRP3 represents a potential therapeutic approach in MM.
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•β2m that accumulates in multiple myeloma (MM) is ingested by MM-associated macrophages•β2m uptake leads to β-fibril aggregation, lysosomal rupture, and inflammasome activation•β2m contributes to inflammation in MM via IL-1β and IL-18 secretion•Inhibition of NLRP3 delays onset and reduces severity of MM in preclinical models
MM is characterized by β2m abundance. The role of β2m remains unknown. Hofbauer et al. show that MM-associated macrophages take up β2m. Phagocytosed β2m forms β-fibrils and leads to lysosomal rupture and inflammasome activation. They reveal β2m as a promoter of inflammation, which plays a role in MM initiation and progression.
The adoptive transfer of in vitro generated tumor antigen-specific cytotoxic T lymphocytes (CTL) provides a promising approach to the immunotherapy of cancer. A phase I study was conducted to test ...the feasibility, safety, and survival of adoptively transferred Melan-A-specific CTL lines in melanoma patients.
Eleven HLA-A2+ patients with metastatic melanoma received at least three intravenous infusions of Melan-A-specific CTL at 2-week intervals. CTL were generated by four rounds of in vitro stimulation of purified CD8+ peripheral blood lymphocytes with autologous dendritic cells pulsed with an HLA-A2 binding Melan-A peptide. Each T-cell infusion was accompanied by a 6-day course of low-dose interleukin-2.
A total of 52 T-cell infusions were administered, averaging 2.1 x 10(8) Melan-A-specific CTL per infusion. Clinical adverse effects were mild and consisted of chills and low-grade fever in seven of 11 patients. Clinical and immunologic responses revealed an antitumor response in three of 11 patients (one complete regression, one partial regression, one mixed response), an elevated frequency of circulating Melan-A tetramer+ T cells up to 2 weeks in all the patients with a maximal frequency of 2% of total CD8+ T cells, an increase in eosinophils to up to 50% in seven of 11 patients, and a selective loss of Melan-A expression in lymph node metastases in two evaluated patients after T-cell transfer.
Our data indicate that the adoptive transfer of antigen-specific T cells in melanoma patients can induce clinical tumor-specific immune responses without major adverse effects.
The tumor milieu can influence dendritic cell (DC) differentiation. We analyzed DC differentiation in a 3-dimensional tumor model and propose a new mechanism of DC modulation by the tumor ...environment. Monocytes were cultured in the presence of IL-4 and GM-CSF within multicellular tumor spheroids (MCTSs) generated from different tumor cell lines. Monocytes invaded the MCTSs and differentiated into tumor-associated dendritic cells (TADCs). The antigen expression was altered on TADCs independent of the culture conditions (immature/mature DCs, Langerhans cells) and IL-12 secretion was reduced. Supernatants of MCTSs could partially transfer the suppressive effect. Conditioned media from urothelial carcinoma cell lines contained high levels of M-CSF and IL-6, both cytokines known to modulate DC differentiation. In contrast, melanoma and prostate carcinoma MCTS cocultures produced little M-CSF and IL-6, but high levels of lactic acid. Indeed, addition of lactic acid during DC differentiation in vitro induced a phenotype comparable with TADCs generated within melanoma and prostate carcinoma MCTSs. Blocking of lactic acid production in melanoma MCTS cocultures reverted the TADC phenotype to normal. We therefore conclude that tumor-derived lactic acid is an important factor modulating the DC phenotype in the tumor environment, which may critically contribute to tumor escape mechanisms.
D-2-hydroxyglutarate (D-2HG) is released by various types of malignant cells including acute myeloid leukemia (AML) blasts carrying isocitrate dehydrogenase (IDH) gain-of-function mutations. D-2HG ...acting as an oncometabolite promotes proliferation, anoikis, and differentiation block of hematopoietic cells in an autocrine fashion. However, prognostic impact of IDH mutations and high D-2HG levels remains controversial and might depend on the overall mutational context. An increasing number of studies focus on the permissive environment created by AML blasts to promote immune evasion. Impact of D-2HG on immune cells remains incompletely understood. Here, we sought out to investigate the effects of D-2HG on T-cells as key mediators of anti-AML immunity. D-2HG was efficiently taken up by T-cells in vitro, which is in line with high 2-HG levels measured in T-cells isolated from AML patients carrying IDH mutations. T-cell activation was slightly impacted by D-2HG. However, D-2HG triggered HIF-1a protein destabilization resulting in metabolic skewing towards oxidative phosphorylation, increased regulatory T-cell (Treg) frequency, and reduced T helper 17 (Th17) polarization. Our data suggest for the first time that D-2HG might contribute to fine tuning of immune responses.
To compare disease-free survival (DFS) after maintenance therapy with the selective protein kinase C β (PKCβ) inhibitor, enzastaurin, versus placebo in patients with diffuse large B-cell lymphoma ...(DLBCL) in complete remission and with a high risk of relapse after first-line therapy.
This multicenter, phase III, randomized, double-blind, placebo-controlled trial enrolled patients who were at high risk of recurrence after rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Patients (N = 758) with stage II bulky or stage III to IV DLBCL, three or more International Prognostic Index risk factors at diagnosis, and a complete response or unconfirmed complete response after 6 to 8 cycles of R-CHOP were assigned 2:1 to receive oral enzastaurin 500 mg daily or placebo for 3 years or until disease progression or unacceptable toxicity. Primary end point was DFS 3 years after the last patient entered treatment. Correlative analyses of biomarkers, including cell of origin by immunohistochemistry and PKCβ expression, with efficacy outcomes were exploratory objectives.
After a median follow-up of 48 months, DFS hazard ratio for enzastaurin versus placebo was 0.92 (95% CI, 0.689 to 1.216; two-sided log-rank P = .541; 4-year DFS, 70% v 71%, respectively). Independent of treatment, no significant associations were observed between PKCβ protein expression or cell of origin and DFS or overall survival.
Enzastaurin did not significantly improve DFS in patients with high-risk DLBCL after achieving complete response to R-CHOP. Achievement of a complete response may have abrogated the prognostic significance of cell of origin by immunohistochemistry.
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