A condensed global photochemical mechanism for two-dimensional atmospheric models

A condensed chemical mechanism that represents the reactions of organic compounds in the atmosphere is developed and tested using a one-dimensional model. Due to the differences between the full and condensed mechanisms, the reduced version cannot be considered an accurate predictor of globally important trace species concentrations. The condensed mechanism must be improved before it can be used with confidence in two-dimensional models. Appendix contains both full and reduced mechanisms of photolysis and thermal reactions as well as species profile comparisons. 3 refs., 8 figs

Quantified estimates of total GWPs for greenhouse gases taking into account tropospheric chemistry

The purpose of this report is to give interim account of the progress being made at Lawrence Livermore National Laboratory (LLNL) in developing an improved capability for assessing the direct and indirect effects on Global Warming Potentials. Much of our current efforts are being devoted to improving the capability for modeling of global tropospheric processes in our state-of-the-art zonally-averaged chemical-radiative-transport model of the troposphere and stratosphere. These efforts are in preparation for an improved evaluation and better quantification of the indirect GWPs resulting from effects on tropospheric ozone from ethane and other gases with significant human-related emissions. There are three major findings that should result from this project that should have significant impacts on EPA and its programs. First, the current and ongoing studies of the direct and indirect GWPs should have a significant influence on the continuing national and international assessments of climate change. Second, the improved capability for modeling of chemical and physical processes should lead to enhanced understanding of the controlling factors influencing ozone, hydroxyl and other key tropospheric constituents. Third, the enhanced modeling capability should be important to future studies of human-related influences on tropospheric and stratospheric chemical processes

O{sub 3} and stratospheric H{sub 2}O radiative forcing resulting from a supersonic jet transport emission scenario

The tropospheric radiative forcing has been calculated for ozone and water vapor perturbations caused by a realistic High Speed Civil Transport (HSCT) aircraft emission scenario. Atmospheric profiles of water vapor and ozone were obtained using the LLNL 2-D chemical-radiative-transport model (CRT) of the global troposphere and stratosphere. IR radiative forcing calculations were made with the LLNL correlated k-distribution radiative transfer model. UV-Visible-Near IR radiative forcing calculations were made with the LLNL two stream solar radiation model. For the case of water vapor the IR and Near IR radiative forcing was determined at five different latitudes and then averaged using an appropriate latitudinal average to obtain the global average value. Global average values of radiative forcing were approximately 1.2--2.6 10{sup {minus}3} W/m{sup 2}, depending on the background atmospheric water vapor profile. This result is consistent with prior published values for a similar aircraft scenario and supports the conclusion that the water vapor climate forcing effect is very small. The radiative forcing in the IR and UV-Visible spectral ranges, due to the ozone perturbation, was calculated for the globally averaged atmosphere. Global average values of the radiative forcing were 0.034 W/m{sup 2} for the UV-Visible spectral range and 0.006 W/m{sup 2} for the IR spectral range (0.04 W/m{sup 2} total). This result is also consistent with the range of published values obtained for a similar HSCT scenario. As was the case for water vapor, the ozone forcing is too small to be of major consequence

Local estrogen axis in the human bone microenvironment regulates estrogen receptor-positive breast cancer cells.

BACKGROUND:Approximately 70% of all breast cancers express the estrogen receptor, and are regulated by estrogen. While the ovaries are the primary source of estrogen in premenopausal women, most breast cancer is diagnosed following menopause, when systemic levels of this hormone decline. Estrogen production from androgen precursors is catalyzed by the aromatase enzyme. Although aromatase expression and local estrogen production in breast adipose tissue have been implicated in the development of primary breast cancer, the source of estrogen involved in the regulation of estrogen receptor-positive (ER+) metastatic breast cancer progression is less clear. METHODS:Bone is the most common distant site of breast cancer metastasis, particularly for ER+ breast cancers. We employed a co-culture model using trabecular  bone tissues obtained from total hip replacement (THR) surgery specimens to study ER+ and estrogen receptor-negative (ER-) breast cancer cells within the human bone microenvironment. Luciferase-expressing ER+ (MCF-7, T-47D, ZR-75) and ER- (SK-BR-3, MDA-MB-231, MCF-10A) breast cancer cells were cultured directly on bone tissue fragments or in bone tissue-conditioned media, and monitored over time with bioluminescence imaging (BLI). Bone tissue-conditioned media were generated in the presence vs. absence of aromatase inhibitors, and testosterone. Bone tissue fragments were analyzed for aromatase expression by immunohistochemistry. RESULTS:ER+ breast cancer cells were preferentially sustained in co-cultures with bone tissues and bone tissue-conditioned media relative to ER- cells. Bone fragments analyzed by immunohistochemistry revealed expression of the aromatase enzyme. Bone tissue-conditioned media generated in the presence of testosterone had increased estrogen levels and heightened capacity to stimulate ER+ breast cancer cell proliferation. Pretreatment of cultured bone tissues with aromatase inhibitors, which inhibited estrogen production, reduced the capacity of conditioned media to stimulate ER+ cell proliferation. CONCLUSIONS:These results suggest that a local estrogen signaling axis regulates ER+ breast cancer cell viability and proliferation within the bone metastatic niche, and that aromatase inhibitors modulate this axis. Although endocrine therapies are highly effective in the treatment of ER+ breast cancer, resistance to these treatments reduces their efficacy. Characterization of estrogen signaling networks within the bone microenvironment will identify new strategies for combating metastatic progression and endocrine resistance

Breast Cancer Cell Colonization of the Human Bone Marrow Adipose Tissue Niche

BACKGROUND/OBJECTIVES: Bone is a preferred site of breast cancer metastasis, suggesting the presence of tissue-specific features that attract and promote the outgrowth of breast cancer cells. We sought to identify parameters of human bone tissue associated with breast cancer cell osteotropism and colonization in the metastatic niche. METHODS: Migration and colonization patterns of MDA-MB-231-fLuc-EGFP (luciferase-enhanced green fluorescence protein) and MCF-7-fLuc-EGFP breast cancer cells were studied in co-culture with cancellous bone tissue fragments isolated from 14 hip arthroplasties. Breast cancer cell migration into tissues and toward tissue-conditioned medium was measured in Transwell migration chambers using bioluminescence imaging and analyzed as a function of secreted factors measured by multiplex immunoassay. Patterns of breast cancer cell colonization were evaluated with fluorescence microscopy and immunohistochemistry. RESULTS: Enhanced MDA-MB-231-fLuc-EGFP breast cancer cell migration to bone-conditioned versus control medium was observed in 12/14 specimens (P = .0014) and correlated significantly with increasing levels of the adipokines/cytokines leptin (P = .006) and IL-1β (P = .001) in univariate and multivariate regression analyses. Fluorescence microscopy and immunohistochemistry of fragments underscored the extreme adiposity of adult human bone tissues and revealed extensive breast cancer cell colonization within the marrow adipose tissue compartment. CONCLUSIONS: Our results show that breast cancer cells migrate to human bone tissue-conditioned medium in association with increasing levels of leptin and IL-1β, and colonize the bone marrow adipose tissue compartment of cultured fragments. Bone marrow adipose tissue and its molecular signals may be important but understudied components of the breast cancer metastatic niche

Immune reconstitution and infectious complications following axicabtagene ciloleucel therapy for large B-cell lymphoma

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 has significantly improved outcomes in the treatment of refractory or relapsed large B-cell lymphoma (LBCL). We evaluated the long-term course of hematologic recovery, immune reconstitution, and infectious complications in 41 patients with LBCL treated with axicabtagene ciloleucel (axi-cel) at a single center. Grade 3+ cytopenias occurred in 97.6% of patients within the first 28 days postinfusion, with most resolved by 6 months. Overall, 63.4% of patients received a red blood cell transfusion, 34.1% of patients received a platelet transfusion, 36.6% of patients received IV immunoglobulin, and 51.2% of patients received growth factor (granulocyte colony-stimulating factor) injections beyond the first 28 days postinfusion. Only 40% of patients had recovered detectable CD19+ B cells by 1 year, and 50% of patients had a CD4+ T-cell count <200 cells per μL by 18 months postinfusion. Patients with durable responses to axi-cel had significantly longer durations of B-cell aplasia, and this duration correlated strongly with the recovery of CD4+ T-cell counts. There were significantly more infections within the first 28 days compared with any other period of follow-up, with the majority being mild-moderate in severity. Receipt of corticosteroids was the only factor that predicted risk of infection in a multivariate analysis (hazard ratio, 3.69; 95% confidence interval, 1.18-16.5). Opportunistic infections due to Pneumocystis jirovecii and varicella-zoster virus occurred up to 18 months postinfusion in patients who prematurely discontinued prophylaxis. These results support the use of comprehensive supportive care, including long-term monitoring and antimicrobial prophylaxis, beyond 12 months after axi-cel treatment