NK cell adoptive therapy is a promising cancer therapeutic approach, but there are significant challenges that limiting its feasibility and clinical efficacy. One difficulty is the paucity of ...clinical grade manufacturing platforms to support the large scale expansion of highly active NK cells. We created an NK cell feeder cell line termed 'NKF' through overexpressing membrane bound IL-21 that is capable of inducing robust and sustained proliferation (>10,000-fold expansion at 5 weeks) of highly cytotoxic NK cells. The expanded NK cells exhibit increased cytotoxic function against a panel of blood cancer and solid tumor cells as compared to IL-2-activated non-expanded NK cells. The NKF-expanded NK cells also demonstrate efficacy in mouse models of human sarcoma and T cell leukemia. Mechanistic studies revealed that membrane-bound IL-21 leads to an activation of a STAT3/c-Myc pathway and increased NK cell metabolism with a shift towards aerobic glycolysis. The NKF feeder cell line is a promising new platform that enables the large scale proliferation of highly active NK cells in support of large scale third party NK cell clinical studies that have been recently intiatied. These results also provide mechanistic insights into how membrane-bound IL-21 regulates NK cell expansion.
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Autoimmune thyroid disease (AITD) pathogenesis may result from a loss of immune tolerance to thyroid antigens. Regulatory T cells (Tregs) control immune responses, prevent excessive inflammation, and ...may be dysfunctional in AITD. We investigated the role of Tregs in Hashimoto's thyroiditis (HT) and Graves' disease (GD), complicated by Down syndrome (DS). Our goal was to identify differences in CD4(+)CD25(high) Treg function or number in patients with GD and HT, compared to healthy controls (HC).
Treg number was assessed by flow cytometric analysis in samples from 20 AITD patients (seven GD, 13 HT), nine HC, and seven individuals with DS, a genetic disorder associated with multiple autoimmune disorders including AITD. Treg function was assessed by the inhibition of proliferation (radioactive thymidine incorporation into DNA) of blood-derived T effector (Teff) cells by Tregs in a coculture. Various methods of stimulation were contrasted. Cytokine levels were determined in conditioned media from the co-cultures.
No differences were found in the frequency of Tregs as a percentage of CD4(+) cells between AITD and HC. AITD Tregs were less capable of inhibiting the proliferation of Teff cells when compared to HC; however, the impairment was dependent on the type of stimulation used. DS patients without AITD exhibited normal Treg function. We observed few differences in cytokine production between HC and AITD patients.
Tregs from AITD patients are partly dysfunctional, possibly explaining their autoimmunity. Future work will elucidate the diagnostic potential and pathophysiology of Tregs in AITD.
Most importantly, no evidence of increased mortality at low blood pressures has been shown in population cohort studies (people without clinical coronary artery disease at entry).2 The 2·30 ...(unadjusted) hazard ratio (HR) of cardiovascular death in patients with systolic blood pressure of less than 120 mm Hg versus those with...
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Manufactured and out-of-home foods contribute to excessive calories and have a critical role in fueling the obesity epidemic. We propose a 20% fat reduction in these foods.
To evaluate the potential ...impact of the proposed strategy on energy intake, obesity and related health outcomes in the population.
We used the National Diet and Nutrition Survey rolling program (NDNS RP) data to calculate fat and energy contributions from 46 manufactured and out-of-home food categories. We considered a gradual fat reduction—focusing on SFA—in these categories to achieve a 20% reduction in 5 years. We estimated the reduction in energy intake in the NDNS RP population and predicted the body weight reduction using a weight loss model. We scaled up the body weight reduction to the UK adult population. We estimated reductions in overweight/obesity and type 2 diabetes cases. We calculated the reductions of LDL, ischemic heart disease (IHD), and stroke deaths that could be prevented from the SFA reduction.
The selected categories contributed to 38.6% of the population’s energy intake. By the end of the fifth year, our proposed strategy would reduce the mean energy intake by 67.6 kcal/d/person (95% CI: 66.1–68.8). The energy reduction would reduce the mean body weight by 2.7 kg (95% CI: 2.6–2.8). The obesity prevalence would be reduced by 5.3% and the overweight prevalence by 1.5%, corresponding to 3.5 and 1 million cases of obesity and overweight, respectively, being reduced in the United Kingdom. The body weight reduction could prevent 183,000 (95% CI: 171,000–194,000) cases of type 2 diabetes over 2 decades. Energy from SFA would fall by 2.6%, lowering LDL by 0.13 mmol/L and preventing 87,560 IHD deaths (95% CI: 82,260–112,760) and 9520 stroke deaths (95% CI: 4400–14,660) over 20 years.
A modest fat reduction (particularly in SFA) in widely consumed foods would prevent obesity, type 2 diabetes, and cardiovascular disease.
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CMK, GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Background Prospective cohort studies have not been consistent in showing an association between serum homocysteine and dementia. Objective To conduct a meta-analysis of cohort studies that ...examined the relationship between serum homocysteine and dementia, and to estimate the change in risk of dementia for a unit change in serum homocysteine. Methods The data from eight cohort studies (involving 8669 participants; range of mean ages, 47–81 years; median duration of study, 5 years) of serum homocysteine on the incidence of dementia were combined and the odds ratio of dementia per 5 μmol/L increase in serum homocysteine was determined. Results There was a statistically significant association between serum homocysteine and the incidence of dementia: the odds ratio for a 5 μmol/L increase in serum homocysteine was 1.35 (95% confidence interval, 1.02–1.79) or 1.50 (1.13–2.00) adjusted for regression dilution bias. The odds ratio for a 3 μmol/L decrease in serum homocysteine (the average reduction expected using folic acid and B12) was 0.78 (0.66–0.93). Conclusion The meta-analysis of epidemiological cohort studies shows a positive association between serum homocysteine and dementia. Although the results do not provide evidence of cause and effect, they do provide an estimate of the expected effect if the relationship were causal; an approximate 20% reduction in risk of dementia from treatment with folic acid and B12.
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FZAB, GEOZS, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBJE, SBMB, UL, UM, UPUK
Earthquake early warning (EEW) systems are relatively new technologies having first emerged as regional systems in the 1990s. Japan was the first nation to develop and implement a nationwide system ...in October 2007, and in the United States, ShakeAlert became available on the entire length of the US West Coast in May 2021. Assessing how EEW is perceived and utilized by alert recipients is considered essential. Such assessments are necessary to evaluate whether alert recipients are taking advantage of alert messages to initiate protective actions upon receipt of an alert, how they regard the usefulness of alerts, desirable thresholds for issuing alerts, and other aspects of these systems. Having information from users will also facilitate assessments of the success of earthquake preparedness educational programs such as the ShakeOut and whether annual drills which include information on EEW systems are resulting in behavioral response consistent with the content of these programs. Finally, information on EEW utilization will provide data useful to social scientists who study hazards to advance our understanding of behavioral response to warnings. Survey research in the aftermath of a significant earthquake in which an EEW has been issued is one obvious method of achieving these objectives and there already exist a number of survey instruments for this purpose. A related strategy and the goal of the present research is to develop a brief questionnaire, consistent with those already developed, as a supplement to the United States Geological Survey's "Did You Feel It?" questionnaire that has provided earthquake intensities and information on behavioral response in earthquakes, both domestic and international, since 2004. Having the intensity level at each respondent's location is essential for relating their perspectives and actions to the shaking they experienced.
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Building collapse is the dominant cause of casualties during earthquakes. In order to better predict human fatalities, the U.S. Geological Survey's Prompt Assessment of Global Earthquakes for ...Response (PAGER) program requires collapse fragility functions for global building types. The collapse fragility is expressed as the probability of collapse at discrete levels of the input hazard defined in terms of macroseismic intensity. This article provides a simple procedure for quantifying collapse fragility using vulnerability criteria based on the European Macroseismic Scale (1998) for selected European building types. In addition, the collapse fragility functions are developed for global building types by fitting the beta distribution to the multiple experts' estimates for the same building type (obtained from EERI's World Housing Encyclopedia (WHE)-PAGER survey). Finally, using the collapse probability distributions at each shaking intensity level as a prior and field-based collapse-rate observations as likelihood, it is possible to update the collapse fragility functions for global building types using the Bayesian procedure.
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As the defining feature of Acute Myeloid Leukemia (AML) is a maturation arrest, a highly desirable therapeutic strategy is to induce leukemic cell maturation. This therapeutic strategy has the ...potential of avoiding the significant side effects that occur with the traditional AML therapeutics. We identified a natural compound securinine, as a leukemia differentiation-inducing agent. Securinine is a plant-derived alkaloid that has previously been used clinically as a therapeutic for primarily neurological related diseases. Securinine induces monocytic differentiation of a wide range of myeloid leukemia cell lines as well as primary leukemic patient samples. Securinine's clinical potential for AML can be seen from its ability to induce significant growth arrest in cell lines and patient samples as well as its activity in significantly impairing the growth of AML tumors in nude mice. In addition, securinine can synergize with currently employed agents such as ATRA and decitabine to induce differentiation. This study has revealed securinine induces differentiation through the activation of DNA damage signaling. Securinine is a promising new monocytic differentiation inducing agent for AML that has seen previous clinical use for non-related disorders.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A shot in the arm for damaged tissue
Tissue damage can be caused by injury, disease, and even certain medical treatments. There is great interest in identifying drugs that accelerate tissue ...regeneration and recovery, especially drugs that might benefit multiple organ systems. Zhang
et al.
describe a compound with this desired activity, at least in mice (see the Perspective by FitzGerald). SW033291 promotes recovery of the hematopoietic system after bone marrow transplantation, prevents the development of ulcerative colitis in the intestine, and accelerates liver regeneration after hepatic surgery. It acts by inhibiting an enzyme that degrades prostaglandins, lipid signaling molecules that have been implicated in tissue stem cell maintenance.
Science
, this issue
10.1126/science.aaa2340
; see also p.
1208
A compound that inhibits prostaglandin degradation enhances tissue regeneration in multiple organs in mice.
Also see Perspective by
FitzGerald
INTRODUCTION
Agents that promote tissue regeneration could be beneficial in a variety of clinical settings, such as stimulating recovery of the hematopoietic system after bone marrow transplantation. Prostaglandin PGE2, a lipid signaling molecule that supports expansion of several types of tissue stem cells, is a candidate therapeutic target for promoting tissue regeneration in vivo. To date, therapeutic interventions have largely focused on targeting two PGE2 biosynthetic enzymes, cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2), with the aim of reducing PGE2 production. In this study, we take the converse approach: We examine the role of a prostaglandin-degrading enzyme, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), as a negative regulator of tissue repair, and we explore whether inhibition of this enzyme can potentiate tissue regeneration in mouse models.
RATIONALE
We used 15-PGDH knockout mice to elucidate the role of 15-PGDH in regulating tissue levels of PGE2 and tissue repair capacity in multiple organs. We then developed SW033291, a potent small-molecule inhibitor of 15-PGDH with activity in vivo. We used SW033291 to investigate the therapeutic potential of 15-PGDH inhibitors in tissue regeneration and to identify a 15-PGDH–regulated hematopoietic pathway within the bone marrow niche.
RESULTS
We found that in comparison with wild-type mice, 15-PGDH–deficient mice display a twofold increase in PGE2 levels across multiple tissues—including bone marrow, colon, and liver—and that they show increased fitness of these tissues in response to damage. The mutant mice also show enhanced hematopoietic capacity, with increased neutrophils, increased bone marrow SKL (Sca-1
+
C-kit
+
Lin
−
) cells (enriched for stem cells), and greater capacity to generate erythroid and myeloid colonies in cell culture. The 15-PGDH–deficient mice respond to colon injury from dextran sulfate sodium (DSS) with a twofold increase in cell proliferation in colon crypts, which confers resistance to DSS-induced colitis. The mutant mice also respond to partial hepatectomy with a greater than twofold increase in hepatocyte proliferation, which leads to accelerated and more extensive liver regeneration. SW033291, a potent small-molecule inhibitor of 15-PGDH (inhibitor dissociation constant
K
i
~0.1 nM), recapitulates in mice the phenotypes of 15-PGDH gene knockout, inducing increased hematopoiesis, resistance to DSS colitis, and more rapid liver regeneration after partial hepatectomy. Moreover, SW033291-treated mice show a 6-day-faster reconstitution of hematopoiesis after bone marrow transplantation, with accelerated recovery of neutrophils, platelets, and erythrocytes, and greater recovery of bone marrow SKL cells. This effect is mediated by bone marrow CD45
–
cells, which respond to increased PGE2 with a fourfold increase in production of CXCL12 and SCF, two cytokines that play key roles in hematopoietic stem cell homing and maintenance.
CONCLUSIONS
Studying mouse models, we have shown that 15-PGDH negatively regulates tissue regeneration and repair in the bone marrow, colon, and liver. Of most direct utility, our observations identify 15-PGDH as a therapeutic target and provide a chemical formulation, SW033291, that is an active 15-PGDH inhibitor in vivo and that potentiates repair in multiple tissues. SW033291 or related compounds may merit clinical investigation as a strategy to accelerate recovery after bone marrow transplantation and other tissue injuries.
Inhibiting 15-PGDH accelerates tissue repair.
(
A
) The enzyme 15-PGDH degrades and negatively regulates PGE2. (
B
) SW033291 inhibits 15-PGDH, increases tissue levels of PGE2, and induces CXCL12 and SCF expression from CD45
–
bone marrow cells. This in turn accelerates homing of transplanted hematopoietic stem cells (HSC), generation of mature blood elements, and post-transplant recovery of normal blood counts. Inhibiting 15-PGDH similarly stimulates cell proliferation after injury to colon or liver, accelerating repair of these tissues.
Agents that promote tissue regeneration could be beneficial in a variety of clinical settings, such as stimulating recovery of the hematopoietic system after bone marrow transplantation. Prostaglandin PGE2, a lipid signaling molecule that supports expansion of several types of tissue stem cells, is a candidate therapeutic target for promoting tissue regeneration in vivo. Here, we show that inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme, potentiates tissue regeneration in multiple organs in mice. In a chemical screen, we identify a small-molecule inhibitor of 15-PGDH (SW033291) that increases prostaglandin PGE2 levels in bone marrow and other tissues. SW033291 accelerates hematopoietic recovery in mice receiving a bone marrow transplant. The same compound also promotes tissue regeneration in mouse models of colon and liver injury. Tissues from 15-PGDH knockout mice demonstrate similar increased regenerative capacity. Thus, 15-PGDH inhibition may be a valuable therapeutic strategy for tissue regeneration in diverse clinical contexts.
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We extended the U.S. Geological Survey's Prompt Assessment of Global Earthquakes for Response (PAGER) empirical fatality estimation methodology proposed by Jaiswal et al. (2009) to rapidly estimate ...economic losses after significant earthquakes worldwide. The requisite model inputs are shaking intensity estimates made by the ShakeMap system, the spatial distribution of population available from the LandScan database, modern and historic country or sub-country population and Gross Domestic Product (GDP) data, and economic loss data from Munich Re's historical earthquakes catalog. We developed a strategy to approximately scale GDP-based economic exposure for historical and recent earthquakes in order to estimate economic losses. The process consists of using a country-specific multiplicative factor to accommodate the disparity between economic exposure and the annual per capita GDP, and it has proven successful in hindcasting past losses. Although loss, population, shaking estimates, and economic data used in the calibration process are uncertain, approximate ranges of losses can be estimated for the primary purpose of gauging the overall scope of the disaster and coordinating response. The proposed methodology is both indirect and approximate and is thus best suited as a rapid loss estimation model for applications like the PAGER system.
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