Toward High Precision XCO2 Retrievals From TanSat Observations: Retrieval Improvement and Validation Against TCCON Measurements.

TanSat is the 1st Chinese carbon dioxide (CO2) measurement satellite, launched in 2016. In this study, the University of Leicester Full Physics (UoL-FP) algorithm is implemented for TanSat nadir mode XCO2 retrievals. We develop a spectrum correction method to reduce the retrieval errors by the online fitting of an 8th order Fourier series. The spectrum-correction model and its a priori parameters are developed by analyzing the solar calibration measurement. This correction provides a significant improvement to the O2 A band retrieval. Accordingly, we extend the previous TanSat single CO2 weak band retrieval to a combined O2 A and CO2 weak band retrieval. A Genetic Algorithm (GA) has been applied to determine the threshold values of post-screening filters. In total, 18.3% of the retrieved data is identified as high quality compared to the original measurements. The same quality control parameters have been used in a footprint independent multiple linear regression bias correction due to the strong correlation with the XCO2 retrieval error. Twenty sites of the Total Column Carbon Observing Network (TCCON) have been selected to validate our new approach for the TanSat XCO2 retrieval. We show that our new approach produces a significant improvement on the XCO2 retrieval accuracy and precision when compared to TCCON with an average bias and RMSE of -0.08 ppm and 1.47 ppm, respectively. The methods used in this study can help to improve the XCO2 retrieval from TanSat and subsequently the Level-2 data production, and hence will be applied in the TanSat operational XCO2 processing.

Monoclonal anitbodies in the lymphatics: toward the diagnosis and therapy of tumor metastases.

Monoclonal antibodies subcutaneously injected into mice track to regional lymph nodes and specifically label target cells there. The lymphatic route of administration can be expected to provide much higher sensitivity, higher target-to-background ratio, faster localization, and lower toxicity than the intravenous route when the aim is to diagnose or treat tumor metastases or lymphoma in the lymph nodes.

Monoclonal antibodies in the lymphatics: selective delivery to lymph node metastases of a solid tumor.

After subcutaneous injection, monoclonal antibodies directed against a tumor can enter local lymphatic vessels, pass to the draining lymph nodes, and bind to metastases there. Lymphatic delivery of antibody to early metastases is more efficient than intravenous administration, and the lymphatic route can be used to image smaller metastatic deposits. Perhaps more important, the lymphatic route minimizes binding of antibodies to circulating tumor antigens and to cross-reactive antigens present on normal tissues. Antibodies inappropriate for intravenous use because of binding to normal tissues may therefore be useful against lymph node metastases when injected subcutaneously or directly into lymphatic vessels.

Assessment of heavy metal enrichment factors and the degree of contamination in marine sediments from Tamaki Estuary, Auckland, New Zealand.

Eight sediment cores recovered from Tamaki Estuary were analysed for Cu, Pb, Zn, and Cd using downward cored sub-samples. The results indicate a significant upward enrichment in heavy metals with the highest concentrations found in the uppermost 0-10 cm layer. Assessment of heavy metal pollution in marine sediments requires knowledge of pre-anthropogenic metal concentrations to act as a reference against which measured values can be compared. Pristine values for the cored sediments were determined from flat "base-line" metal trends evident in lower core samples. Various methods for calculating metal enrichment and contamination factors are reviewed in detail and a modified and more robust version of the procedure for calculating the degree of contamination is proposed. The revised procedure allows the incorporation of a flexible range of pollutants, including various organic species, and the degree of contamination is expressed as an average ratio rather than an absolute summation number. Comparative data for normalized enrichment factors and the modified degree of contamination show that Tamaki Estuary sediments have suffered significant systematic heavy metal contamination following catchment urbanization. Compared to baseline values the uppermost sediment layers show four-fold enrichment averaged across eight cores and four analysed metals.

Acquired cisplatin resistance in human ovarian cancer cells is associated with enhanced repair of cisplatin-DNA lesions and reduced drug accumulation.

Studies were undertaken to investigate acquired resistance to cisplatin in human ovarian cancer cells. The cell lines A2780 and A2780/CP70 were studied to assess their respective characteristics of drug accumulation and efflux, cytosolic inactivation of drug, and DNA repair. All experiments were performed using 1-h drug exposures. The A2780/CP70 cell line was 13-fold more resistant to cisplatin than A2780 cells. When studied at their respective IC50 doses, drug accumulation rates were similar for the two cell lines. However, the resistant cell line was twofold more efficient at effluxing drug, which was associated with reduced total drug accumulation for equivalent micromolar drug exposures. At equivalent levels of total cellular drug accumulation, the two cell lines formed the same levels of cisplatin-DNA damage, suggesting that cytosolic inactivation of drug does not contribute to the differential in resistance between these cell lines. Resistant cells were also twofold more efficient at repairing cisplatin-DNA lesions in cellular DNA and in transfected plasmid DNA. We conclude that in these paired cell lines, alterations in drug uptake/efflux and in DNA repair are the major contributing factors to acquired resistance to cisplatin.

Lymphatic absorption and tissue disposition of liposome-entrapped [14C]adriamycin following intraperitoneal administration to rats.

The lymphatic absorption and tissue distribution of free [14C]Adriamycin, "empty" [3H]liposomes, free [14C]Adriamycin plus empty [3H]liposomes, and [14C]Adriamycin entrapped into [3H]liposomes have been examined at intervals after i.p. injection into rats. Following treatment with empty [3H]liposomes, almost 30% of the liposomal lipid marker was recovered in 24-hr thoracic duct lymph, but when [14C]Adriamycin was added to or encapsulated in liposomes, this value was reduced to 10%. Conversely, only 1% of free [14C]Adriamycin was recovered in 24-hr lymph, but liposomal encapsulation produced a six-fold increase in this value. Studies on the tissue distribution of the liposomal lipid marker after dosing with empty liposomes revealed uptake by diaphragm, liver and spleen, but the highest tissue concentrations were noted in lymph nodes. Liposomal encapsulation of Adriamycin altered its tissue disposition, chiefly by increasing the concentration of drug equivalents in diaphragm, liver and spleen. Although free Adriamycin was accumulated by lymph nodes to some extent, this lymph node accumulation was markedly enhanced by liposomal encapsulation and was present only in those nodes through which lymph draining the peritoneal cavity passes. This finding, together with the observation that diaphragm and thoracic duct lymph contain relatively high levels of liposomal lipid and Adriamycin equivalents, indicates that liposomes are selectively absorbed from the peritoneal cavity by lymphatics and are retained by certain lymph nodes. The results of this study suggest that i.p. administration of liposome-encapsulated drugs may provide a means of selectively concentrating anti-tumor agents in lymphatic channels and lymph nodes.

Ormaplatin sensitivity/resistance in human ovarian cancer cells made resistant to cisplatin.

The human ovarian cancer cell lines A2780 and A2780/CP70 were studied to investigate the cellular basis for their relative sensitivities to tetrachloro(DL-trans)-1,2-diamminecyclohexaneplatinum(IV) (ormaplatin). Cells were exposed to ormaplatin for 1 h in all experiments. As assessed by colony formation assays, the A2780/CP70 cell line [50% inhibitory dose (IC50) = 3.6 microM] was 9.5-fold more resistant to ormaplatin than the A2780 cell line [IC50 = 0.38 microM]. For cisplatin, the IC50 doses were 40 and 3 microM, respectively. Both cell lines were treated with ormaplatin at doses ranging from 0.10 to 40 microM, for the purpose of studying drug accumulation and efflux, and DNA adduct formation and repair. When these cell lines were treated at their respective IC50 doses, drug accumulation was greater in the resistant cells. When treated at equal microM doses, the sensitive cells formed 8-fold more DNA adduct than the resistant cells. When cells were treated with ormaplatin so as to achieve equivalent levels of platinum-DNA modification, sensitive cells removed 53% of the platinum-DNA damage in the first 6 h after drug exposure, compared to 68% in the resistant cells. We conclude that in human ovarian cancer cells made resistant to cisplatin, there is moderate cross-resistance to ormaplatin. This cross-resistance is not explained by differences in drug accumulation but is associated with reduced platinum-DNA adduct formation, which may be attributable in part to cytosolic inactivation of drug.

Pharmacokinetics of monoclonal immunoglobulin G1, F(ab')2, and Fab' in mice.

The pharmacokinetics of an immunoglobulin G1 (IgG1) and its F(ab')2 and Fab' fragments following i.v. administration in mice has been studied by constructing a physiologically based, organ-specific model to describe antibody biodistribution, catabolism, and excretion. The antibody selected for study (MOPC-21) has no known binding sites in the body and therefore is useful for defining antibody metabolism by nontumor tissues. Whole IgG remains in the body for 8.3 days, the majority of time in the carcass (53.0% of the total residence time); has a distribution volume exceeding that of plasma plus interstitial fluid; distributes into these volumes rapidly for most enteral organs (equilibration time less than 2.6 min for liver, spleen, kidney, and lung), slower for the gut (less than 20 min), and slowest for the carcass (less than 260 min); produces interstitial:plasma concentration ratios of greater than 0.5 for enteral organs and 0.18 for carcass; has the greatest percentage of its catabolism due to the gut (72.8%), followed by the liver (20.5%), then the spleen (3.6%); has the highest extraction on a single pass by the gut (0.14%) and cycles through the interstitial spaces of the body at least 2.8 times/g of organ weight before being metabolized or excreted. When compared with whole IgG, the Fab' fragment is cleared from the body 35 times faster; has a larger total distribution volume; distributes more rapidly into this volume; produces higher interstitial:plasma concentration ratios; is catabolized principally by the kidney (73.4% of total catabolism), followed by the gut (22.9%), then the spleen (3.1%); is extracted from the circulation to the extent of 3.4% on each pass through the kidney, and less by gut (1.0%) and spleen (0.14%) and cycles through non-kidney interstitial spaces at least 0.4 cycles/g of tissue weight before metabolism or excretion. The F(ab')2 fragment has pharmacokinetic characteristics that fall between those of whole IgG and Fab'. These results provide pharmacokinetic criteria for selecting whole IgG, F(ab')2, or Fab' for various in vivo applications; provide a framework for predicting cumulative tissue exposure to antibody labeled with different isotopes; and provide a reference metabolic state for the analysis of more complex systems that do include antibody binding.

Targeting of murine radiolabeled monoclonal antibodies in the lymphatics.

The tissue localization of a radiolabeled monoclonal antibody directed against a mouse Class I major histocompatibility antigen has been determined in mice following i.v. and s.c. administration. When labeled antibody was given s.c., radioactivity rapidly accumulated in regional lymph nodes draining the injection site, allowing visualization of the nodes by gamma camera imaging within minutes of injection. At 2 h after s.c. injection, radioactivity in regional nodes was present largely as intact antibody, but considerable degradation of antibody present in nodes was noted by 12 h after injection. Since little of the radioactivity reached the blood stream, visualization of regional nodes was possible for long periods after dosing. In contrast, antibody given i.v. showed no significant accumulation in lymph nodes at any time after dosing.

Optimization of monoclonal antibody delivery via the lymphatics: the dose dependence.

After interstitial injection in mice, antibody molecules enter local lymphatic vessels, flow with the lymph to regional lymph nodes, and bind to target antigens there. Compared with i.v. administration, delivery via the lymphatics provides a more efficient means for localizing antibody in lymph nodes. An IgG2a (36-7-5) directed against the murine class I major histocompatibility antigen H-2Kk has proved useful for studying the pharmacology of lymphatic delivery. The antibody specifically binds to most cells in Kk-positive strains of mice and to none in Kk-negative mice. At very low doses, most of the antibody remains at the injection site in Kk-positive animals. As the dose is progressively increased, most effective labeling occurs first in nodes proximal to the injection site and then in the next group of nodes along the lymphatic chain. At higher doses, antibody overflows the lymphatic system and enters the blood-stream via the thoracic duct and other lymphatic-venous connections. Once in the blood, antibody is rapidly cleared, apparently by binding to Kk-bearing cells. These findings indicate that the single-pass distribution of monoclonal antibodies in the lymphatics can be strongly dose dependent, a principle which may be of clinical significance in the improvement of immunolymphoscintigraphic imaging, especially with antibodies directed against normal and malignant lymphoid cells. Monoclonal antibodies directed against normal cell types in the lymph node may be useful for assessing the integrity of lymphatic chains by immunolymphoscintigraphy or, more speculatively, for altering the status of regional immune function. The results presented here indicate that a low or intermediate antibody dose may optimize the signal:noise ratio for imaging. In Kk-negative animals, the percentage of dose taken up in the major organs was essentially independent of the dose administered; there was no evidence for saturable sites of nonspecific binding. These findings provide background for attempts to use antitumor antibodies via the lymphatic route. Specific binding to target cells (and any cross-reaction with normal tissues) would presumably be superimposed on the nonspecific pharmacology of the antibody in vivo.

Platinum-DNA adduct in leukocyte DNA of a cohort of 49 patients with 24 different types of malignancies.

Using atomic absorbance spectrometry with Zeeman background correction, we measured platinum-DNA adduct levels in leukocyte DNA of 49 patients receiving therapy consisting of only carboplatin and cisplatin. Twenty-four histological types of malignancy were included in the cohort. Peripheral blood leukocytes were collected at defined times during the first two cycles of treatment. The relationship between adduct level and disease response was highly statistically significant during cycle 1 of therapy (two-sided P = 0.007 at day 2), but statistical significance was lost during cycle 2. On all days studied, median and mean adduct levels were consistently higher in responders as compared to nonresponders (summary two-sided P = 0.0004). These data suggest that the processes which protect cellular DNA may be common to malignant and nonmalignant rapidly dividing tissues of the same individual, regardless of the type of tumor that individual may harbor.

Levels of multidrug resistance (MDR1) P-glycoprotein expression by human breast cancer correlate with in vitro resistance to taxol and doxorubicin.

To determine whether multidrug resistance (MDR1) P-glycoprotein (Pgp) expression correlated with clinical MDR1-related drug resistance, we established a protocol for quantitative measurement of Pgp expression and in vitro drug resistance in doxorubicin resistant MCF7 breast cancer cell lines and 359 freshly resected specimens of breast carcinoma. Pgp expression was detected with 4E3, UIC2, and JSB-1 monoclonal antibodies using flow cytometry and immunohistochemistry (IHC). Pgp function was determined using PSC833 in a drug resistance-reversal assay and with a three-dimensional agarose-based extreme drug resistance assay. MCF7 calibrator cell lines expressed Pgp, which was functional and in proportion to the degree of drug resistance. Flow cytometry, UIC2 shift assays, IHC scores, and determination of absorbance products by image analysis were all highly correlated (r > 0.9). Overall Pgp expression increased from 11% in untreated patients to 30% in patients who had previously received chemotherapy. Compared with Pgp-negative tumors, a significant increase in doxorubicin and Taxol resistance was seen for breast cancers that expressed Pgp, regardless of prior treatment. A strong correlation between the degree of Pgp expression and in vitro resistance to Taxol and doxorubicin (but not to 5-fluorouracil) was found when either IHC scores or image analysis-based methods were used to quantify Pgp expression (n = 185, P < 0.0001). The degree of Pgp expression strongly correlated with the degree of drug resistance in the clinical specimens studied. These data suggest that (a) Pgp contributes to clinical MDR1-related drug resistance, and (b) both intrinsic and acquired expression of Pgp in breast cancer may contribute in part to therapeutic failure and relapse.

Pneumothorax following central venous catheterisation?

A chest radiograph performed to check the position of a central venous catheter in a patient appeared to show a pneumothorax. Intercostal drain insertion was prepared. Reassessment of the patient and a further radiograph confirmed that the "pneumothorax" was an artefact from a prominent skin fold due to the patient's body habitus.

Hypothyroidism--an unexpected diagnosis following emergency treatment for heatstroke.

Heat illness is a common presentation to emergency departments during periods of high ambient temperatures. The thyroid axis is involved in thermoregulation, and its dysfunction dysfunction leads to loss of thermal homeostasis. Hyperthyroidism predisposes an individual to heat illness and hypothyroidism to hypothermia. For heat illness to be the presenting feature of hypothyroidism is very rare. In this report, a case is presented and a discussion of the thyroid axis, thermoregulation, its failure and possible mechanisms follows on.

Taxol effect on cisplatin sensitivity and cisplatin cellular accumulation in human ovarian cancer cells.

Taxol and cisplatin are the two most effective agents discovered to date for treating advanced-stage cancer of the ovary. Learning how best to combine these agents is the focus of preclinical and clinical studies conducted at a number of institutions. Taxol's effect on cellular sensitivity to cisplatin was studied in paired cisplatin-sensitive A2780 and cisplatin-resistant A2780/CP70 human ovarian cancer cell lines. Cisplatin growth curves were generated under conditions of specific sequencing with Taxol, and IC50s (concentrations at which growth is inhibited to 50% of control) for cisplatin were obtained and compared. Taxol was used at an IC10 dose in all experiments. Taxol treatments were for 24 hours and cisplatin treatments were for 1 hour in all experiments. Dimethyl sulfoxide (DMSO) was the diluent for all Taxol stock solutions. Separately, the effects of Taxol and DMSO on cisplatin cellular accumulation were measured. End points reported include measures of cytotoxicity and Taxol effects on cisplatin cellular accumulation. Using a microculture tetrazolium assay, cisplatin growth curves were obtained under the influence of Taxol, at a Taxol dose of 3 nM for both cell lines. DMSO alone had no effect on tumor cell growth. In A2780 cells, the influence of Taxol on cisplatin cytotoxicity was modest, whereas cisplatin-induced cell kill was augmented 1.5-fold when cisplatin was given immediately after Taxol. In A2780/CP70 cells, Taxol augmented cisplatin-induced cell kill by 30-fold when cisplatin was given immediately after Taxol; 75-fold when cisplatin was given 24 hours after completion of Taxol; and 19-fold when cisplatin was given 48 hours after completion of Taxol.(ABSTRACT TRUNCATED AT 250 WORDS)

Vascular relaxation, aging and thyroid hormones.

Previous work indicates vascular can be studied in vitro and that there is a marked age-associated decrease in the ability of rat aortic strips to relax in response to beta-adrenergic agonists. The present studies were aimed at better understanding the role of thyroid hormones in vascular relaxation and aging. Removal of the thyroid gland from young rats resulted in a decrease in the ability of isoproterenol to relax the aorta. Relaxation caused by nitroglycerin, a non-specific relaxant, was not impaired by thyroidectomy. In 22-month-old rats, isoproterenol caused no relaxation unless exogenous thyroid hormones were administered. Hypophysectomy seven months prior to testing improved the ability of thyroid hormones to restore isoproterenol relaxation of the aorta. The loss of relaxation with age could be due in part to a pituitary mediated loss of responsiveness of aortic tissue to thyroid hormones. The data provide new evidence for the importance of thyroid hormones in beta-adrenergic receptor mediated vascular relaxation and demonstrate that the loss of aortic relaxation with aging can be reversed.

Effect of cadmium on human ovarian cancer cells with acquired cisplatin resistance.

Cadmium (Cd) dichloride is a compound that has teratogenic, mutagenic, and carcinogenic properties. Recent reports have suggested the possibility that this compound may also have tumor suppressive properties in some settings. For these reasons, we have studied the subcellular pharmacological profile of elemental cadmium in human ovarian cancer cells, when administered as cadmium dichloride. The cell lines A2780 and A2780/CP70 were used, which are well characterized with respect to their cellular response to platinum-based compounds. Cd was measured in all experiments with the use of atomic absorbance spectrometry with Zeeman background correction. In both cell lines, there were direct relationships between; drug dose and cellular accumulation of drug; cellular accumulation of drug and DNA damage levels; and DNA damage levels and cytotoxicity. These cell lines differed in that the cisplatin-resistant A2780/CP70 cell line, was also comparatively resistant to cadmium dichloride. This enhanced cellular resistance appeared to be mediated through decreased drug accumulation, and increased cellular tolerance to higher levels of DNA damage. Total genomic DNA repair and cytosolic inactivation of drug appeared not to differ substantively between these two cell lines.

Inhibition of HIV-1 in monocyte/macrophage cultures by 2',3'-dideoxycytidine-5'-triphosphate, free and in liposomes.

The antiviral effects of 2',3'-dideoxycytidine (ddC), 2',3'-dideoxycytidine-5'-triphosphate (ddCTP) and liposome-encapsulated ddCTP [L(ddCTP)] were compared in cultured human monocyte-macrophages (M/M) infected with HIV-1. These treatments inhibited virus replication at nanomolar drug levels with activities in the order ddC greater than ddCTP = L(ddCTP). Studies on drug stability and uptake suggest that a large part of the free ddCTP is dephosphorylated before entering the cells, whereas L(ddCTP) remains stable over days and is taken up, probably by endocytosis. The response to L(ddCTP) suggests that the capability of liposomes for targeting drugs to macrophages in vivo could potentially be exploited to improve the therapeutic index of dideoxynucleoside drugs.

Cisplatin-DNA damage and repair in peripheral blood leukocytes in vivo and in vitro.

We have extended our studies on the relationship between cisplatin/carboplatin-induced DNA damage in readily accessible tissue(s) and clinical response to therapy. Such an approach may assist in the study of cancer drug resistance and in establishing parameters for assessing human populations for sensitivity to DNA damaging agents in the environment. Platinum-DNA adduct levels were measured by atomic absorbance spectrometry. DNA repair capacity was assessed in human T-lymphocytes by the ability to repair cisplatin lesions in cellular DNA or in transfected plasmid DNA. In a "blinded" study of 21 patients receiving combination cisplatin/carboplatin drug therapy, there was a direct relationship between DNA damage in leukocytes and disease response (summary two-sided p = 0.00011). The cohort of patients had 15 different tumor types, suggesting that blood tissue and tumor tissue of an individual may process platinum-DNA damage similarly regardless of the tissue of origin of the tumor. In leukocytes in vivo, persistence and accumulation were prominent features of the cisplatin-DNA adduct profile. Functional DNA repair capacity has been studied in eight human leukocyte cell lines in vitro (three, T-cells; three, B-cells; one, monocytic; one, promyelocytic), using a host cell reactivation assay with cisplatin-damaged pRSVcat. In the three T cell lines studied, host cell reactivation efficiency was directly related to the cells' abilities to repair cisplatin-damaged cellular DNA (correlation coefficient = 0.993).(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of tolmetin in the treatment of arthritis: open and controlled double-blind studies.

In a 6-week open study in 24 patients with rheumatoid arthritis, tolmetin was shown to have analgesic and anti-inflammatory activity at daily doses in excess of 1200 mg per day and produced statistically significant reductions in overall joint pain, walking time and articular index. The drug was well tolerated, but 2 patients were withdrawn because of persistent indigestion and 1 because of an urticarial type rash. In a double-blind crossover comparison against indomethacin and placebo in 22 patients, 1400 mg tolmetin daily showed efficacy comparable with that of 150 mg indomethacin daily. Few side-effects were reported and did not necessitate any patients being withdrawn.