Abstract Metastatic breast cancer is an intractable disease that responds poorly to immunotherapy. We show that p38MAPKα inhibition (p38i) limits tumor growth by reprogramming the metastatic tumor microenvironment in a CD4+ T cell-, IFNγ-, and macrophage-dependent manner. To identify targets that further increased p38i efficacy, we utilized a stromal labeling approach and single-cell RNA sequencing. Thus, we combined p38i and an OX40 agonist that synergistically reduced metastatic growth and increased overall survival. Intriguingly, patients with a p38i metastatic stromal signature had better overall survival that was further improved by the presence of an increased mutational load, leading us to ask if our approach would be effective in antigenic breast cancer. The combination of p38i, anti-OX40, and cytotoxic T-cell engagement cured mice of metastatic disease and produced long-term immunologic memory. Our findings demonstrate that a detailed understanding of the stromal compartment can be used to design effective antimetastatic therapies. Significance: Immunotherapy is rarely effective in breast cancer. We dissected the metastatic tumor stroma, which revealed a novel therapeutic approach that targets the stromal p38MAPK pathway and creates an opportunity to unleash an immunologic response. Our work underscores the importance of understanding the tumor stromal compartment in therapeutic design. This article is highlighted in the In This Issue feature, p. 1275

Aim Mangrove wetlands span broad geographical gradients, resulting in functionally diverse tree communities. We asked whether latitudinal variation, allometric scaling relationships and species composition influence mangrove forest structure and biomass allocation across biogeographical regions and distinct coastal morphologies. Location Global. Time period Present. Major taxa studied Mangrove ecosystems. Methods We built the largest field-based dataset on mangrove forest structure and biomass to date (c. 2,800 plots from 67 countries) to address macroecological questions pertaining to structural and functional diversity of mangroves spanning biogeographical and coastal morphology gradients. We used frequentist inference statistics and machine learning models to determine environmental drivers that control biomass allocation within and across mangrove communities globally. Results Allometric scaling relationships and forest structural complexity were consistent across biogeographical and coastal morphology gradients, suggesting that mangrove biomass is controlled by regional forcings rather than by latitude or species composition. For instance, nearly 40% of the global variation in biomass was explained by regional climate and hydroperiod, revealing nonlinear thresholds that control biomass accumulation across broad geographical gradients. Furthermore, we found that ecosystem-level carbon stocks (average 401 +/- 48 MgC/ha, covering biomass and the top 1 m of soil) varied little across diverse coastal morphologies, reflecting regional bottom-up geomorphic controls that shape global patterns in mangrove biomass apportioning. Main conclusions Our findings reconcile views of wetland and terrestrial forest macroecology. Similarities in stand structural complexity and cross-site size-density relationships across multiscale environmental gradients show that resource allocation in mangrove ecosystems is independent of tree size and invariant to species composition or latitude. Mangroves follow a universal fractal-based scaling relationship that describes biomass allocation for several other terrestrial tree-dominated communities. Understanding how mangroves adhere to these universal allometric rules can improve our ability to account for biomass apportioning and carbon stocks in response to broad geographical gradients.

Mangrove forests play an important role in climate change adaptation and mitigation by maintaining coastline elevations relative to sea level rise, protecting coastal infrastructure from storm damage, and storing substantial quantities of carbon (C) in live and detrital pools. Determining the efficacy of mangroves in achieving climate goals can be complicated by difficulty in quantifying C inputs (i.e., differentiating newer inputs from younger trees from older residual C pools), and mitigation assessments rarely consider potential offsets to CO2 storage by methane (CH4) production in mangrove sediments. The establishment of non‐native Rhizophora mangle along Hawaiian coastlines over the last century offers an opportunity to examine the role mangroves play in climate mitigation and adaptation both globally and locally as novel ecosystems. We quantified total ecosystem C storage, sedimentation, accretion, sediment organic C burial and CH4 emissions from ~70 year old R. mangle stands and adjacent uninvaded mudflats. Ecosystem C stocks of mangrove stands exceeded mudflats by 434 ± 33 Mg C/ha, and mangrove establishment increased average coastal accretion by 460%. Sediment organic C burial increased 10‐fold (to 4.5 Mg C ha−1 year−1), double the global mean for old growth mangrove forests, suggesting that C accumulation from younger trees may occur faster than previously thought, with implications for mangrove restoration. Simulations indicate that increased CH4 emissions from sediments offset ecosystem CO2 storage by only 2%–4%, equivalent to 30–60 Mg CO2‐eq/ha over mangrove lifetime (100 year sustained global warming potential). Results highlight the importance of mangroves as novel systems that can rapidly accumulate C, have a net positive atmospheric greenhouse gas removal effect, and support shoreline accretion rates that outpace current sea level rise. Sequestration potential of novel mangrove forests should be taken into account when considering their removal or management, especially in the context of climate mitigation goals.

To the Editor:In the recent special report on the assessment of apolipoprotein B (apoB)1 and nuclear magnetic resonance particle number (1), the authors recommended that measurement of particle number be incorporated into the guidelines for the assessment of cardiovascular disease (CVD) risk.However, the literature reviewed provides no basis for this recommendation. Searching the literature using the key terms apo B and LDL-P (LDL particle number) and the name …

BACKGROUNDThe number of circulating LDL particles is a strong indicator of future cardiovascular disease (CVD) events, even superior to the concentration of LDL cholesterol. Atherogenic (primarily LDL) particle number is typically determined either directly by the serum concentration of apolipoprotein B (apo B) or indirectly by nuclear magnetic resonance (NMR) spectroscopy of serum to obtain NMR-derived LDL particle number (LDL-P).CONTENTTo assess the comparability of apo B and LDL-P, we reviewed 25 clinical studies containing 85 outcomes for which both biomarkers were determined. In 21 of 25 (84.0%) studies, both apo B and LDL-P were significant for at least 1 outcome. Neither was significant for any outcome in only 1 study (4.0%). In 50 of 85 comparisons (58.8%), both apo B and LDL-P had statistically significant associations with the clinical outcome, whereas in 17 comparisons (20.0%) neither was significantly associated with the outcome. In 18 comparisons (21.1%) there was discordance between apo B and LDL-P.CONCLUSIONSIn most studies, both apo B and LDL-P were comparable in association with clinical outcomes. The biomarkers were nearly equivalent in their ability to assess risk for CVD and both have consistently been shown to be stronger risk factors than LDL-C. We support the adoption of apo B and/or LDL-P as indicators of atherogenic particle numbers into CVD risk screening and treatment guidelines. Currently, in the opinion of this Working Group on Best Practices, apo B appears to be the preferable biomarker for guideline adoption because of its availability, scalability, standardization, and relatively low cost.

Among the least studied ecosystem services of mangroves is their value as global carbon (C) stocks. This is significant as mangroves are subject to rapid rates of deforestation and therefore could be significant sources of atmospheric emissions. Mangroves could be key ecosystems in strategies addressing the mitigation of climate change though reduced deforestation. We quantified ecosystem C stocks at the seaward, interior, and upland edges of mangroves in the Republic of Palau and Yap, Federated States of Micronesia. The relatively high aboveground biomass coupled with carbon-rich soils resulted in the presence of large ecosystem carbon stocks compared to other tropical forests. Ecosystem C storage at the Palau site ranged from 479 Mg/ha in the seaward zone to 1,068 Mg/ha in the landward zone; in the Yap site C storage ranged from 853 to 1,385 Mg/ha along this gradient. Soils contained ~70% of the ecosystem C stocks. The elevation range of mangroves was <146 cm, suggesting that projected sea-level rise can influence a large portion of existing stands. Declines in ecosystem carbon stocks will be pronounced if mangroves are replaced by communities adapted to greater inundation such as seagrass communities, where C pools were ≤7% of that of mangroves (48 Mg C/ha).

As no doubt we all know, no single instant, no atom of our life (of our relation to the world and to being) is not marked today, directly or indirectly, by that [atomic] speed race.--Jacques Derrida, No Apocalypse, Not Now, Diacritics [ILLUSTRATION OMITTED] The history of (the) Bikini [1] An important psychic moment occurred during the post-war 1940s. Hitler's holocaust, as well as the war, drastically altered humanity's conception of its own demise, recognizably clear from the thousands of soldiers and civilians' bodies. The dreadfully efficient methods in the concentration camps permanently recast notions of the possibility of human eradication, realizing a nightmare more comparable to natural disasters, like the Black Death or the China Floods of 1931, than to conventional human warfare. Before the full force and significance of V-E Day could reach a place of propitious understanding within the human psyche, less than three months subsequent, Hiroshima and Nagasaki became ever etched into the cognizance of humanity worldwide as remnants of a newly weaponized horror. The two lessons created an important juncture vis-a-vis the fragile history of human existence, yet both theaters of war, in Europe and the Pacific, instilled a similar fear of annihilation. The violence that the belligerents perpetrated exposed bodies in demonstrably new fashions: the entire Wannsee-inspired apparatus quickly unclothed bodies for death chambers, and the nuclear bombs mangled Japanese bodies into wrecked torsos and limbs--once persons but now corpses. During World War II, the naked body became a central image and rem(a)inder of the scientific and meticulous dynamos of death. [2] Another naked yet presumably benign cultural image that emerged in the '40s, but which came to prominence nearly a decade later, was called Bikini. Four days after the first American nuclear test in the Bikini Atoll, Louis Reard, a French fashion designer, revealed his newly christened two-piece bathing suit at a Paris pool on July 5,1946. He named it the bikini, purloining the name from the newspaper headlines about the Americans' test. However, the bikini would not be in vogue until the late 1950s in the United States due to austere taste and convention. The skimpiness the bikini required of its wearer was un peu immodest, for this swimsuit exposed the body in a fashion that had not been customary in quite some time. [3] A year before the tests in the Bikini Atoll, the bombs fell on Hiroshima and Nagasaki, and another less notable event occurred. The Swiss psychiatrist Ludwig Binswanger chronicled the first recorded case of anorexia nervosa in Ellen West (Bordo 140). Though the illness had most assuredly existed before his 1945 record, that Binswanger was unawares arguably suggests that the disorder had less prominence previous to the mid-forties (319). This illness dealt with patients, notably women, who expressed traits of body dysmorphia that extended to habits harmful to her body and her well-being. That the atomic bomb exploded into the public sphere, that Binswanger recorded West's case of anorexia nervosa, and that the bikini bathing suit appeared all within the span of the same year indicate an important connection that links bodies and the bikini bathing suit with atomic weaponry. [4] In this essay, I propose that the fears of the atomic bomb get displaced onto the bikini-clad woman's body. To be sure, this displacement does, at least figuratively, weaken the primary fear--that of nuclear weapons. The metaphorical action of bomb-to-bikini domesticates the threat of the nuclear, which appears as a threat to the increasingly vulnerable, naked bodies--in that women's bodies, while also dangerous, could display a controlled and managed nudity. However, the bikini has its own problems. In some ways, the dangers of or drawbacks to the bikini parallel the effects of the bomb. The dietary and exercise regimens, for example, that a woman must follow in order to wear a bikini appropriately is not only a result of the displaced and domesticated threat; they are also causes that could lead the bikini wearer to dangers similar to those of the bomb's. …

The use of biomarkers during clinical drug-development programs may expedite pipeline decision making by adding critical information about the pharmacological mechanism and efficacy of a potential therapeutic agent. Currently, advice for laboratorians conducting method development and analytical validation of biomarker methods is provided by published White Paper recommendations from industry thought leaders. The adaptation of commercial test kits to generate biomarker data to support regulated studies offers unique challenges and limitations. In this perspective, we address these issues, including factors to consider when identifying a kit manufacturer and adapting commercial test kits for use in regulated studies. We offer a logical and systematic approach for defining the extent of analytical validation needed for application of commercial kits based upon the intended use of the biomarker data.

Tropical cyclones are common disturbances that have strong effects on mangrove composition and structure. Because there are numerous ecosystem services provided by mangroves, it is important to understand their adaptations and responses to these climatic events. In April 2004, Typhoon Sudal, a category 3–4 cyclone, passed over the state of Yap, Federated States of Micronesia. For four months following the typhoon we measured forest structure, above-ground biomass, tree mortality and response in six mangroves. The sites were dominated by species common in mangroves throughout the Indo-Pacific—Sonneratia alba, Brugueira gymnorrhiza, and Rhizophora apiculata. Total above-ground biomass (TAGB) of mangrove forests ranged from 211–573 Mg ha-1. Tree mortality ranged from 6% to 32% among stands. Adaptations and responses to the typhoon varied by species, as well as by geographic location. Sonneratia alba had a higher frequency of mainstems broken (26%), but was the only species that vigorously sprouted from dormant basal or epicormic tissues. Standing live trees accounted for 80–95% of TAGB, suggesting that adaptations of mangrove trees can facilitate the persistence of an intact forest structure following typhoons of this intensity. Climatic changes such as sea level rise and increased severity of cyclonic events could alter this relationship.

Introduction: A1C can be measured by portable point-of-care methods that might offer advantages compared with conventional sampling of venous blood for eventual laboratory testing. Methods: In a 2-part study, we compared the performance and ease of use of A1C measurement with a single-use, disposable A1C test (A1cNow) and a venous sample measured by a reference laboratory. Part 1: At 3 sites, 297 untrained subjects self-tested with an A1cNow. Trained medical professionals performed a second A1cNow test on each subject. Venous blood was sent to a National Glycohemoglobin Standardization Program Secondary Reference Laboratory for A1C testing. Untrained and professional A1cNow test results were compared with the reference results and with each other. A quiz and questionnaire evaluated, respectively, subject comprehension of A1cNow's product labeling and opinions on ease of use. Part 2: At a fourth site, trained medical professionals performed an A1cNow test on 30 subjects. Venous blood was sent to the same reference laboratory. Professional A1cNow test results were compared with reference results. The professionals recorded the amounts of time needed for A1cNow testing and reference laboratory testing. Results: Part 1: For untrained A1cNow versus reference, the slope and y intercept were 0.988 and 0.168, respectively, with r = 0.93 (paired Student t test, P = 0.50). For professional A1cNow versus reference, the slope and y intercept were 0.965 and 0.400, respectively, with r = 0.94 (paired Student t test, P = 0.21). For untrained versus professional A1cNow, with Deming regression, the slope and y intercept were 0.972 and 0.269, respectively, with r = 0.88 (paired Student t test, P = 0.58). Overwhelmingly, subjects responded correctly to quiz questions and favorably to opinion questions about the product's ease of use. Part 2: For professional A1cNow versus reference, the slope and intercept were 0.9504 and +0.28, respectively, with r = 0.95 (paired Student t test, P = 0.85). Conclusions: Untrained users can operate the A1cNow test with good performance equivalent to that obtained by trained medical professional users.

Four tree species were harvested periodically over a 13-year period from plantations in the humid lowlands of Costa Rica: Cedrela odorata, Cordia alliodora, Hyeronima alchorneoides, and Euterpe oleracea. The soil was a well-drained, volcanic alluvium, and high fertility coupled with 4m of annual rainfall and high temperatures led to rapid growth rates; at age 13 many individual were >30cm dbh and >30m tall. Harvested trees were dissected into their component parts: leaves, rachises (for Cedrela and Euterpe), branches, boles, and coarse roots (i.e., >0.5cm diameter). Roots of small trees were excavated in their entirety; those of large trees were harvested from a cylinder 1.0m in diameter, immediately beneath the trunk. Large numbers of trees were sampled: 258–379 per species. Size classes sampled ranged from seedlings too small to have a dbh to trees of ∼30cm dbh. Two separate allometric equations (one for trees having only a basal diameter and another for trees having a dbh), with diameter-squared times height as the metrics, were developed for each component of each species. Based on breaks in linear trends of ln–ln plots and deviations of predicted from actual values, we developed separate allometric equations, by component, for trees of different sizes. The resulting 40 equations (with one exception, involving very small trees) fit the data well and enable the user to predict biomass, by component, for each of the four species. A single (non-allometric) linear equation, combining all plant parts of all three dicot species, also fit the data well, but it would not provide either the detail or the accuracy provided by the species-specific, plant-part-specific equations. Large sample sizes, a 13-year run of data collection, and the economic and ecological importance of the species studied make this data set uniquely useful for biomass estimations and for understanding the inherent heterogeneity of tree structure in dynamic tropical environments.

Unbelievable! A book written by biostatisticians about clinical trials that is actually easy to read and chock-full of useful information for the nonstatistician. Authors Chow and Liu have truly met their aim of producing a book that not only fills the gap between clinical and statistical disciplines but also provides a comprehensive and unified presentation of clinical and scientific issues, statistical concepts, and methodology. Perhaps the greatest value of this book will be as a reference source for almost anything one would want to know about planning, performing, or analyzing data from a clinical trial. The book is well organized, and each subject is covered in great detail with numerous appropriate examples that clarify or …

OBJECTIVE:1,5-Anhydroglucitol (1,5AG) is a major circulating polyol arising primarily from ingestion and excreted competitively with glucose. Japanese studies have demonstrated reduced concentrations of 1,5AG in serum in hyperglycemic patients in comparison with euglycemic subjects and a gradual normalization of 1,5AG values for patients responding to antihyperglycemic therapies. In this first U.S. study, we assessed the ability of 1,5AG measurements to monitor glycemic control in a cohort of 77 patients with diabetes (22 with type 1 diabetes, 55 with type 2 diabetes) who presented with suboptimal glycemic control at baseline (defined as HbA(1c) >or=7%).RESEARCH DESIGN AND METHODS:Each patient received therapies consisting of combinations of diabetes education, nutritional counseling, and addition or dose adjustment of various insulins or oral antihyperglycemic medications. Therapy was targeted to reduce mean HbA(1c) by >or=1.0% over the monitoring period. 1,5AG, HbA(1c), fructosamine, and random glucose measurements were performed at baseline and at 2, 4, and 8 weeks after the initiation of therapy.RESULTS:1,5AG, fructosamine, and glucose values progressed significantly toward euglycemia by week 2 of monitoring (Wilcoxon's signed-rank test, P < 0.05), with median changes of 93, -7, and -13% for 1,5AG, fructosamine, and glucose, respectively. In contrast, HbA(1c) values did not respond significantly to therapy until week 4. On an individual patient basis, 89.6% of patients displayed longitudinal changes of 1,5AG from baseline to week 8 in concordance with HbA(1c). 1,5AG was also highly correlated with HbA(1c) and fructosamine (Spearman rho = -0.6459 and -0.6751, respectively; both P < 0.0001).CONCLUSIONS:We conclude that 1,5AG responds sensitively and rapidly to changes in glycemia and monitors glycemic control in accordance with established markers.

BACKGROUND:Beta-thalassemia minor (BTM) is a common benign condition that can be present in patients with diabetes mellitus. There are conflicting reports about the effect of BTM on glycated hemoglobin (gHb) measurements. We evaluated 6 gHb methods using samples from non-diabetic subjects with BTM. METHODS:Samples submitted for hemoglobin phenotype analysis were evaluated. A total of 57 samples (30 controls and 27 with BTM) from non-diabetic subjects were selected. GHb analysis was performed by Tosoh A1c 2.2+, Primus CLC 330, Bayer DCA 2000, Beckman Coulter, Synchron CX7 and LX20, and Roche Tina-quant II assays. RESULTS:The A1c 2.2+, CLC 330, DCA 2000 and Tina-quant II assays showed no statistically significant difference between the control and BTM groups. In contrast, BTM results were significantly higher than controls on the Synchron CX7 analyzer and borderline significant on the Synchron LX20 (p=0.051). Further investigation demonstrated an increase in Synchron %HbA(1c) results with decreasing hemoglobin concentrations. CONCLUSIONS:In this study using samples from subjects with normal or near-normal gHb, BTM does not affect gHb measurements per se. However, the Synchron methods yielded higher results for samples with lower hemoglobin concentrations, like those that can be seen in BTM. The Synchron method was improved at the end of 2003, which minimized this problem.

BACKGROUND:1,5-Anhydroglucitol (1,5-AG) is a glucose analogue, which is decreased in hyperglycemic individuals. We report the technical performance of an assay (GlycoMark) on a chemistry analyzer, evaluation of analyte stability and determination of reference intervals for 1,5-AG in a non-diabetic US population. METHODS:NCCLS protocols were followed to evaluate the reagent on a Hitachi 917 chemistry analyzer. RESULTS:Intra- and interassay imprecision ranged from 1.3% to 3.8% and 0.79% to 3.7%, respectively. The assay was linear to 110 microg/ml. Interference from triglyceride, hemoglobin and bilirubin was <10% to concentrations of 12.6 mmol/l, 12.1 and 911.4 micromol/l, respectively. Correlation coefficients between lot numbers on the Hitachi 917 and between analyses on the Hitachi 917 and the Hitachi 7170 analyzers were >0.99. The lowest limit of detection was 0.49 microg/ml (mean+/-2 S.D.). 1,5-AG was stable at 4 degrees C for 7 days, at 22 degrees C for 5 days, at -80 degrees C for 14 days and for three freeze-thaw cycles at -80 degrees C. The US reference intervals (nonparametric 2.5th-97.5th percentiles) were 10.2-33.8 microg/ml (males) and 5.9-31.8 microg/ml (females). CONCLUSIONS:The performance of the GlycoMark assay for the measurement of 1,5-AG was acceptable on the Hitachi 917 analyzer.

The Centers for Disease Control and Prevention (CDC) in collaboration with the American Heart Association (AHA) convened a workshop in Atlanta, Ga, on March 14 and 15, 2002, titled, “CDC/AHA Workshop on Inflammatory Markers and Cardiovascular Disease: Applications to Clinical and Public Health Practice,” which was intended to address issues about the appropriate selection and use of inflammatory markers to predict cardiovascular disease (CVD) risk.1 Three concurrent discussion groups on issues related to laboratory, clinical, and population science were held. This report details the discussions and findings of the laboratory science group.

This relatively short book is crammed with useful tips and pointers for users of this powerful spectroscopic technique.The book is organized into seven chapters, with an extensive list of literature references at the end.Organization of the text is logical, moving from a general overview, theory, and background to method development (chapter 4), routine analysis (chapter 5), and the very valuable "Trouble-Shooting and Maintenance" (chapter 6).Numerous specific applications are described in some detail, and original research manuscripts or government protocols (e.g., USEPA) are referenced.To this reviewer, the most useful and unique feature of the book was the inclusion of complementary information, listed with identifying symbols as "practical tips", addi-

Cardiac natriuretic peptides are of interest for their potential role in assisting in the diagnosis, prognosis, and monitoring of left ventricular dysfunction and congestive heart failure (1). An electrochemiluminescence immunoassay for the measurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) on the Elecsys® immunoassay analyzer platform (Roche Diagnostics Corporation) has recently received Food and Drug Administration clearance to aid in the diagnosis of congestive heart failure (2). We report here on the stability of the NT-proBNP analyte when measured with the Roche Diagnostic NT-proBNP assay after specimen storage at −80 °C for longer than 1 year and after five freeze-thaw (−80 and 22 °C) cycles. Twenty-five samples were collected from healthy and heart failure clinic adult volunteers under informed consent according to the policies of the Washington University School of Medicine’s Institutional Review Board. All glass collection tubes were from Becton Dickinson. Lithium-heparin plasma (prod. no. 367686) was collected from …