Accuracy of Cardiac Output Measured by Fourth-Generation FloTrac and LiDCOrapid, and Their Characteristics Regarding Systemic Vascular Resistance in Patients Undergoing Cardiac Surgery.

OBJECTIVES: The clinical use of less-invasive devices that calculate the cardiac output from arterial pressure waveform is increasing. The authors aimed to evaluate the accuracy and characteristics of the systemic vascular resistance index (SVRI) of the cardiac index measured by 2 less-invasive devices, fourth-generation FloTrac (CIFT) and LiDCOrapid (CILR), compared with the intermittent thermodilution technique, using a pulmonary artery catheter (CITD). DESIGN: This was a prospective observational study. SETTING: This study was conducted at a single university hospital. PARTICIPANTS: Twenty-nine adult patients undergoing elective cardiac surgery. INTERVENTIONS: Elective cardiac surgery was used as an intervention. MEASUREMENTS AND MAIN RESULTS: Hemodynamic parameters, CIFT, CILR, and CITD, were measured after the induction of general anesthesia, at the start of cardiopulmonary bypass, after completion of weaning from cardiopulmonary bypass, 30 minutes after weaning, and at sternal closure (135 measurements in total). The CIFT and CILR had moderate correlations with CITD (r = 0.62 and 0.58, respectively). Compared with CITD, CIFT, and CILR had a bias of -0.73 and -0.61 L/min/m2, limit of agreement of -2.14-to-0.68 L/min/m2 and -2.42-to-1.20 L/min/m2, and percentage error of 39.9% and 51.2%, respectively. Subgroup analysis for evaluating SVRI characteristics showed that the percentage errors of CIFT and CILR were 33.9% and 54.5% in low SVRI (<1,200 dyne×s/cm5/m), 37.6% and 47.9% in moderate SVRI (1,200-1,800 dyne×s/cm5/m), 49.3% and 50.6% in high SVRI (>1,800 dyne·s/cm5/m2), respectively. CONCLUSIONS: The accuracy of CIFT or CILR was not clinically acceptable for cardiac surgery. Fourth-generation FloTrac was unreliable in high SVRI. LiDCOrapid was inaccurate across a broad range of SVRI, and minimally affected by SVRI.

Investigation of Risk Factors for Postoperative Delirium after Transcatheter Aortic Valve Implantation: A Retrospective Study.

Transcatheter aortic valve implantation (TAVI) is an effective treatment for severe aortic stenosis (AS); however, postoperative delirium (POD) can worsen patient outcomes. This study aimed to examine the risk factors for POD after TAVI, including possible intervening factors. We included 87 patients (mean age: 83) who underwent TAVI between May 2014 and September 2018. POD was defined by the presence or absence of delirium on ICU admission, assessed using the Confusion Assessment Method for the ICU. Factors that showed significant differences in the univariate analysis were analyzed using a multiple logistic regression analysis. In total, 31 patients (36%) had POD after ICU admission, and 56 (64%) did not. The preoperative frailty score and aortic valve opening area (AVA) were significant risk factors for POD. The multivariate analysis also showed that both factors were independent risk factors for POD (area under the receiver operating characteristic curve: 0.805). There were no significant differences in the number of ICU days. However, postoperative hospitalization was significantly longer in the POD group (19 (17-31) days vs. 16 (13-22) days; p = 0.002). POD was associated with a narrow AVA and frailty; this suggests that frailty prevention interventions according to the AVA may be important.

Automated multi-attribute method sample preparation using high-throughput buffer exchange tips.

RATIONALE: The multi-attribute method (MAM) has become a valuable mass spectrometry (MS)-based tool that can identify and quantify the site-specific product attributes and purity information for biotherapeutics such as monoclonal antibodies (mAbs) and fusion molecules in recent years. As we expand the use of the MAM at various stages of drug development, it is critical to enhance the sample preparation throughput without additional chemical modifications and variability. METHODS: In this study, a fully automated MAM sample preparation protocol is presented, where rapid desalting in less than 15 minutes is achieved using miniaturized size-exclusion chromatography columns in pipette tips on an automated liquid handler. The peptide samples were analyzed using an electrospray ionization (ESI) orbitrap mass spectrometer coupled to an ultra-high-performance liquid chromatography (UHPLC) system with a dual column switching system. RESULTS: No significant change was observed in product attributes and their quantities compared with manual, low-artifact sample preparation. The sample recovery using the buffer exchange tips was greatly enhanced over the manual spin cartridges while still demonstrating excellent reproducibility for a wide variety of starting sample concentrations. Unlike a plate desalting system, the individual columns provide flexibility in the number of samples prepared at a time and sample locations within plates. CONCLUSIONS: This automated protocol enables the preparation of up to 96 samples with less "at-bench" time than the manual preparation of a smaller batch of samples, thereby greatly facilitating support of process development and the use of the MAM in quality control.

Multiple Secondary Healthcare-Associated Infections Due to Carbapenem-Resistant Organisms in a Critically Ill COVID-19 Patient on Extensively Prolonged Venovenous Extracorporeal Membrane Oxygenation Support-A Case Report.

Patients with severe Coronavirus disease 2019 (COVID-19) are at high risk for secondary infection with multidrug-resistant organisms (MDROs). Secondary infections contribute to a more severe clinical course and longer intensive care unit (ICU) stays in patients with COVID-19. A man in his 60s was admitted to the ICU at a university hospital for severe COVID-19 pneumonia requiring mechanical ventilation. His respiratory condition worsened further due to persistent bacteremia caused by imipenem-non-susceptible Klebsiella aerogenes and he required VV-ECMO. Subsequently, he developed a catheter-related bloodstream infection (CRBSI) due to Candida albicans, ventilator-associated pneumonia (VAP) due to multidrug-resistant Pseudomonas aeruginosa (MDRP), and a perianal abscess due to carbapenem-resistant K. aerogenes despite infection control procedures that maximized contact precautions and the absence of MDRO contamination in the patient's room environment. He was decannulated from VV-ECMO after a total of 72 days of ECMO support, and was eventually weaned off ventilator support and discharged from the ICU on day 138. This case highlights the challenges of preventing, diagnosing, and treating multidrug-resistant organisms and healthcare-associated infections (HAIs) in the critical care management of severe COVID-19. In addition to the stringent implementation of infection prevention measures, a high index of suspicion and a careful evaluation of HAIs are required in such patients.

[Immune thrombocytopenia associated with Kimura's disease].

In this study, we report a rare case of immune thrombocytopenic purpura (ITP) associated with the worsening of Kimura's disease. A 47-year-old Japanese man with a pruritic rash and swollen inguinal lymph nodes was diagnosed with Kimura's disease on performing a right inguinal lymph node biopsy. Thrombocytopenia ensued after the diagnosis of Kimura's disease, and fluctuations in the platelet count were observed along with the pathology of Kimura's disease. The platelet count fluctuated repeatedly with the relapse of Kimura's disease and a diagnosis of a combination of Kimura's disease and ITP was made through lymph node regeneration and bone marrow examination. Treatment with prednisolone (1 mg/kg/day) was initiated for Kimura's disease and ITP, and lymphadenopathy and platelet count improved promptly. Since then, the dose of prednisolone has been gradually reduced, and the disease status of both Kimura's disease and ITP has been controlled.

Evaluation of Crystal Zenith Microtiter Plates for High-Throughput Formulation Screening.

Formulation screening for biotherapeutics can cover a vast array of excipients and stress conditions. These studies consume quantities of limited material and, with higher concentrated therapeutics, more material is needed. Here, we evaluate the use of crystal zenith (CZ) microtiter plates in conjunction with FluoroTec-coated butyl rubber mats as a small-volume, high-throughput system for formulation stability studies. The system was studied for evaporation, edge effects, and stability with comparisons to type 1 glass and CZ vials for multiple antibodies and formulations. Evaporation was minimal at 4°C and could be reduced at elevated temperatures using sealed, mylar bags. Edge effects were not observed until 12 weeks at 40°C. The overall stability ranking as measured by the rate of change in high molecular weight and percent main peak species was comparable across both vials and plates at 4°C and 40°C out to 12 weeks. Product quality attributes as measured by the multi-attribute method were also comparable across all containers for each molecule formulation. A potential difference was measured for subvisible particle analysis, with the plates measuring lower particle counts than the vials. Overall, CZ plates are a viable alternative to traditional vials for small-volume, high-throughput formulation stability screening studies.

Quantitative proteomics reveals key roles for post-transcriptional gene regulation in the molecular pathology of facioscapulohumeral muscular dystrophy.

DUX4 is a transcription factor whose misexpression in skeletal muscle causes facioscapulohumeral muscular dystrophy (FSHD). DUX4's transcriptional activity has been extensively characterized, but the DUX4-induced proteome remains undescribed. Here, we report concurrent measurement of RNA and protein levels in DUX4-expressing cells via RNA-seq and quantitative mass spectrometry. DUX4 transcriptional targets were robustly translated, confirming the likely clinical relevance of proposed FSHD biomarkers. However, a multitude of mRNAs and proteins exhibited discordant expression changes upon DUX4 expression. Our dataset revealed unexpected proteomic, but not transcriptomic, dysregulation of diverse molecular pathways, including Golgi apparatus fragmentation, as well as extensive post-transcriptional buffering of stress-response genes. Key components of RNA degradation machineries, including UPF1, UPF3B, and XRN1, exhibited suppressed protein, but not mRNA, levels, explaining the build-up of aberrant RNAs that characterizes DUX4-expressing cells. Our results provide a resource for the FSHD community and illustrate the importance of post-transcriptional processes in DUX4-induced pathology.

High-dose Dexamethasone Therapy as the Initial Treatment for Idiopathic Thrombocytopenic Purpura: Protocol for a Multicenter, Open-label, Single Arm Trial.

Standard therapy for idiopathic thrombocytopenic purpura (ITP) has not been established. We are conducting a multicenter, prospective trial to determine the efficacy and safety of short-term, high-dose dexamethasone therapy in ITP patients aged 18-80 years with platelet counts of <20, 000 /µL, or with <50, 000/ µL and bleeding symptoms. The primary endpoints of this trial are the proportion of responses (complete plus partial response) on day 180 (day 46+180) after the completion of the 46-day high-dose dexamethasone therapy. The results of this investigation of the effectiveness and safety of this regimen will be essential for the establishment of standard therapy for ITP.

KSHV oral shedding and plasma viremia result in significant changes in the extracellular tumorigenic miRNA expression profile in individuals infected with the malaria parasite.

Kaposi's sarcoma herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS). Both KSHV and HIV infections are endemic in Uganda, where KS is among the most common cancers in HIV-infected individuals. Recent studies examined the use of small RNAs as biomarkers of disease, including microRNAs (miRNAs), with viral and tumor-derived miRNAs being detected in exosomes from individuals with KSHV-associated malignancies. In the current study, the host and viral extracellular mature miRNA expression profiles were analyzed in blood of KS-negative individuals in Uganda, comparing those with or without KSHV detectable from the oropharynx. We observed increased levels of cellular oncogenic miRNAs and decreased levels of tumor-suppressor miRNAs in plasma of infected individuals exhibiting oral KSHV shedding. These changes in host oncomiRs were exacerbated in people co-infected with HIV, and partially reversed after 2 years of anti-retroviral therapy. We also detected KSHV miRNAs in plasma of KSHV infected individuals and determined that their expression levels correlated with KSHV plasma viremia. Deep sequencing revealed an expected profile of small cellular RNAs in plasma, with miRNAs constituting the major RNA biotype. In contrast, the composition of small RNAs in exosomes was highly atypical with high levels of YRNA and low levels of miRNAs. Mass spectrometry analysis of the exosomes revealed eleven different peptides derived from the malaria parasite, Plasmodium falciparum, and small RNA sequencing confirmed widespread plasmodium co-infections in the Ugandan cohorts. Proteome analysis indicated an exosomal protein profile consistent with erythrocyte and keratinocyte origins for the plasma exosomes. A strong correlation was observed between the abundance of Plasmodium proteins and cellular markers of malaria. As Plasmodium falciparum is an endemic pathogen in Uganda, our study shows that co-infection with other pathogens, such as KSHV, can severely impact the small RNA repertoire, complicating the use of exosome miRNAs as biomarkers of disease.

Murine chronic graft-versus-host disease proteome profiling discovers CCL15 as a novel biomarker in patients.

Improved diagnostic and treatment methods are needed for chronic graft-versus-host disease (cGVHD), the leading cause of late nonrelapse mortality (NRM) in long-term survivors of allogenic hematopoietic cell transplantation. Validated biomarkers that facilitate disease diagnosis and classification generally are lacking in cGVHD. Here, we conducted whole serum proteomics analysis of a well-established murine multiorgan system cGVHD model. We discovered 4 upregulated proteins during cGVHD that are targetable by genetic ablation or blocking antibodies, including the RAS and JUN kinase activator, CRKL, and CXCL7, CCL8, and CCL9 chemokines. Donor T cells lacking CRK/CRKL prevented the generation of cGVHD, germinal center reactions, and macrophage infiltration seen with wild-type T cells. Whereas antibody blockade of CCL8 or CXCL7 was ineffective in treating cGVHD, CCL9 blockade reversed cGVHD clinical manifestations, histopathological changes, and immunopathological hallmarks. Mechanistically, elevated CCL9 expression was present predominantly in vascular smooth muscle cells and uniquely seen in cGVHD mice. Plasma concentrations of CCL15, the human homolog of mouse CCL9, were elevated in a previously published cohort of 211 cGVHD patients compared with controls and associated with NRM. In a cohort of 792 patients, CCL15 measured at day +100 could not predict cGVHD occurring within the next 3 months with clinically relevant sensitivity/specificity. Our findings demonstrate for the first time the utility of preclinical proteomics screening to identify potential new targets for cGVHD and specifically CCL15 as a diagnosis marker for cGVHD. These data warrant prospective biomarker validation studies.

Laser Capture Microdissection of Pancreatic Acinar Cells to Identify Proteomic Alterations in a Murine Model of Caerulein-Induced Pancreatitis.

OBJECTIVES: Chronic pancreatitis (CP) is characterized by inflammation and fibrosis of the pancreas, leading to pain, parenchymal damage, and loss of exocrine and endocrine function. There are currently no curative therapies; diagnosis remains difficult and aspects of pathogenesis remain unclear. Thus, there is a need to identify novel biomarkers to improve diagnosis and understand pathophysiology. We hypothesize that pancreatic acinar regions contain proteomic signatures relevant to disease processes, including secreted proteins that could be detected in biofluids. METHODS: Acini from pancreata of mice injected with or without caerulein were collected using laser capture microdissection followed by mass spectrometry analysis. This protocol enabled high-throughput analysis that captured altered protein expression throughout the stages of CP. RESULTS: Over 2,900 proteins were identified, whereas 331 were significantly changed ≥2-fold by mass spectrometry spectral count analysis. Consistent with pathogenesis, we observed increases in proteins related to fibrosis (e.g., collagen, P<0.001), several proteases (e.g., trypsin 1, P<0.001), and altered expression of proteins associated with diminished pancreas function (e.g., lipase, amylase, P<0.05). In comparison with proteomic data from a public data set of CP patients, a significant correlation was observed between proteomic changes in tissue from both the caerulein model and CP patients (r=0.725, P<0.001). CONCLUSIONS: This study illustrates the ability to characterize proteome changes of acinar cells isolated from pancreata of caerulein-treated mice and demonstrates a relationship between signatures from murine and human CP.

AEE788 Inhibits Basal Body Assembly and Blocks DNA Replication in the African Trypanosome.

Trypanosoma brucei causes human African trypanosomiasis (HAT). The pyrrolopyrimidine AEE788 (a hit for anti-HAT drug discovery) associates with three trypanosome protein kinases. Herein we delineate the effects of AEE788 on T. brucei using chemical biology strategies. AEE788 treatment inhibits DNA replication in the kinetoplast (mitochondrial nucleoid) and nucleus. In addition, AEE788 blocks duplication of the basal body and the bilobe without affecting mitosis. Thus, AEE788 prevents entry into the S-phase of the cell division cycle. To study the kinetics of early events in trypanosome division, we employed an "AEE788 block and release" protocol to stage entry into the S-phase. A time-course of DNA synthesis (nuclear and kinetoplast DNA), duplication of organelles (basal body, bilobe, kinetoplast, nucleus), and cytokinesis was obtained. Unexpected findings include the following: 1) basal body and bilobe duplication are concurrent; 2) maturation of probasal bodies, marked by TbRP2 recruitment, is coupled with nascent basal body assembly, monitored by localization of TbSAS6 at newly forming basal bodies; and 3) kinetoplast division is observed in G2 after completion of nuclear DNA synthesis. Prolonged exposure of trypanosomes to AEE788 inhibited transferrin endocytosis, altered cell morphology, and decreased cell viability. To discover putative effectors for the pleiotropic effects of AEE788, proteome-wide changes in protein phosphorylation induced by the drug were determined. Putative effectors include an SR protein kinase, bilobe proteins, TbSAS4, TbRP2, and BILBO-1. Loss of function of one or more of these effectors can, from published literature, explain the polypharmacology of AEE788 on trypanosome biology.

Novel Effects of Lapatinib Revealed in the African Trypanosome by Using Hypothesis-Generating Proteomics and Chemical Biology Strategies.

Human African trypanosomiasis is a neglected tropical disease caused by the protozoan parasite Trypanosoma brucei Lapatinib, a human epidermal growth factor receptor (EGFR) inhibitor, can cure 25% of trypanosome-infected mice, although the parasite lacks EGFR-like tyrosine kinases. Four trypanosome protein kinases associate with lapatinib, suggesting that the drug may be a multitargeted inhibitor of phosphoprotein signaling in the bloodstream trypanosome. Phosphoprotein signaling pathways in T. brucei have diverged significantly from those in humans. As a first step in the evaluation of the polypharmacology of lapatinib in T. brucei, we performed a proteome-wide phosphopeptide analysis before and after drug addition to cells. Lapatinib caused dephosphorylation of Ser/Thr sites on proteins predicted to be involved in scaffolding, gene expression, and intracellular vesicle trafficking. To explore the perturbation of phosphotyrosine (pTyr)-dependent signaling by lapatinib, proteins in lapatinib-susceptible pTyr complexes were identified by affinity chromatography; they included BILBO-1, MORN, and paraflagellar rod (PFR) proteins PFR1 and PFR2. These data led us to hypothesize that lapatinib disrupts PFR functions and/or endocytosis in the trypanosome. In direct chemical biology tests of these speculations, lapatinib-treated trypanosomes (i) lost segments of the PFR inside the flagellum, (ii) were inhibited in the endocytosis of transferrin, and (iii) changed morphology from long and slender to rounded. Thus, our hypothesis-generating phosphoproteomics strategy predicted novel physiological pathways perturbed by lapatinib, which were verified experimentally. General implications of this workflow for identifying signaling pathways perturbed by drug hits discovered in phenotypic screens are discussed.

Biomarker Panel for Chronic Graft-Versus-Host Disease.

PURPOSE: To identify diagnostic and prognostic markers of chronic graft-versus-host disease (cGVHD), the major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). PATIENTS AND METHODS: Using a quantitative proteomics approach, we compared pooled plasma samples obtained at matched time points after HCT (median, 103 days) from 35 patients with cGVHD and 18 without cGVHD (data are available via ProteomeXchange with identifier PXD002762). Of 105 proteins showing at least a 1.25-fold difference in expression, 22 were selected on the basis of involvement in relevant pathways and enzyme-linked immunosorbent assay availability. Chemokine (C-X-C motif) ligand 9 (CXCL9) and suppression of tumorigenicity 2 (ST2) also were measured on the basis of previously determined associations with GVHD. Concentrations of the four lead biomarkers were measured at or after diagnosis in plasma from two independent verification cohorts (n = 391) to determine their association with cGVHD. Their prognostic ability when measured at approximately day +100 after HCT was evaluated in plasma of a second verification cohort (n = 172). RESULTS: Of 24 proteins measured in the first verification cohort, nine proteins were associated with cGVHD, and only four (ST2, CXCL9, matrix metalloproteinase 3, and osteopontin) were necessary to compose a four-biomarker panel with an area under the receiver operating characteristic curve (AUC) of 0.89 and significant correlation with cGVHD diagnosis, cGVHD severity, and nonrelapse mortality. In a second verification cohort, this panel distinguished patients with cGVHD (AUC, 0.75), and finally, the panel measured at day +100 could predict cGVHD occurring within the next 3 months with an AUC of 0.67 and 0.79 without and with known clinical risk factors, respectively. CONCLUSION: We conclude that the biomarker panel measured at diagnosis or day +100 after HCT may allow patient stratification according to risk of cGVHD.

Aberrant glycosylation of plasma proteins in severe preeclampsia promotes monocyte adhesion.

Glycosylation of plasma proteins increases during pregnancy. Our objectives were to investigate an anti-inflammatory role of these proteins in normal pregnancies and determine whether aberrant protein glycosylation promotes monocyte adhesion in preeclampsia. Plasma was prospectively collected from nonpregnant controls and nulliparous patients in all 3 trimesters. Patients were divided into cohorts based on the applicable postpartum diagnosis. U937 monocytes were preconditioned with enzymatically deglycosylated plasma, and monocyte adhesion to endothelial cell monolayers was quantified by spectrophotometry. Plasma from nonpregnant controls, first trimester normotensives, and first trimester patients with mild preeclampsia inhibited monocyte-endothelial cell adhesion (P < .05), but plasma from first trimester patients with severe preeclampsia and second and third trimester normotensives did not. Deglycosylating plasma proteins significantly increased adhesion in all the cohorts. These results support a role of plasma glycoprotein interaction in monocyte-endothelial cell adhesion and could suggest a novel therapeutic target for severe preeclampsia.

Metabolomic profiling of urine: response to a randomised, controlled feeding study of select fruits and vegetables, and application to an observational study.

Metabolomic profiles were used to characterise the effects of consuming a high-phytochemical diet compared with a diet devoid of fruits and vegetables (F&V) in a randomised trial and cross-sectional study. In the trial, 8 h fasting urine from healthy men (n 5) and women (n 5) was collected after a 2-week randomised, controlled trial of two diet periods: a diet rich in cruciferous vegetables, citrus and soya (F&V), and a fruit- and vegetable-free (basal) diet. Among the ions found to differentiate the diets, 176 were putatively annotated with compound identifications, with forty-six supported by MS/MS fragment evidence. Metabolites more abundant in the F&V diet included markers of the dietary intervention (e.g. crucifers, citrus and soya), fatty acids and niacin metabolites. Ions more abundant in the basal diet included riboflavin, several acylcarnitines and amino acid metabolites. In the cross-sectional study, we compared the participants based on the tertiles of crucifers, citrus and soya from 3 d food records (n 36) and FFQ (n 57); intake was separately divided into the tertiles of total fruit and vegetable intake for FFQ. As a group, ions individually differential between the experimental diets differentiated the observational study participants. However, only four ions were significant individually, differentiating the third v. first tertile of crucifer, citrus and soya intake based on 3 d food records. One of these ions was putatively annotated: proline betaine, a marker of citrus consumption. There were no ions significantly distinguishing tertiles by FFQ. The metabolomic assessment of controlled dietary interventions provides a more accurate and stronger characterisation of the diet than observational data.

Lapatinib-binding protein kinases in the African trypanosome: identification of cellular targets for kinase-directed chemical scaffolds.

Human African trypanosomiasis is caused by the eukaryotic microbe Trypanosoma brucei. To discover new drugs against the disease, one may use drugs in the clinic for other indications whose chemical scaffolds can be optimized via a medicinal chemistry campaign to achieve greater potency against the trypanosome. Towards this goal, we tested inhibitors of human EGFR and/or VEGFR as possible anti-trypanosome compounds. The 4-anilinoquinazolines canertinib and lapatinib, and the pyrrolopyrimidine AEE788 killed bloodstream T. brucei in vitro with GI(50) in the low micromolar range. Curiously, the genome of T. brucei does not encode EGFR or VEGFR, indicating that the drugs recognize alternate proteins. To discover these novel targets, a trypanosome lysate was adsorbed to an ATP-sepharose matrix and washed with a high salt solution followed by nicotinamide adenine dinucleotide (NAD(+)). Proteins that remained bound to the column were eluted with drugs, and identified by mass spectrometry/bioinformatics. Lapatinib bound to Tb927.4.5180 (termed T. brucei lapatinib-binding protein kinase-1 (TbLBPK1)) while AEE788 bound Tb927.5.800 (TbLBPK2). When the NAD(+) wash was omitted from the protocol, AEE788, canertinib and lapatinib eluted TbLBPK1, TbLBPK2, and Tb927.3.1570 (TbLBPK3). In addition, both canertinib and lapatinib eluted Tb10.60.3140 (TbLBPK4), whereas only canertinib desorbed Tb10.61.1880 (TbCBPK1). Lapatinib binds to a unique conformation of protein kinases. To gain insight into the structural basis for lapatinib interaction with TbLBPKs, we constructed three-dimensional models of lapatinib•TbLBPK complexes, which confirmed that TbLBPKs can adopt lapatinib-compatible conformations. Further, lapatinib, AEE788, and canertinib were docked to TbLBPKs with favorable scores. Our studies (a) present novel targets of kinase-directed drugs in the trypanosome, and (b) offer the 4-anilinoquinazoline and pyrrolopyrimidines as scaffolds worthy of medicinal chemistry and structural biology campaigns to develop them into anti-trypanosome drugs.

[Intravascular large B-cell lymphoma with low signal intensity lesions on T2 weighted spinal magnetic resonance image that were suspected to be hemorrhages].

A 79-year-old female had a spinal lesion that was definitely diagnosed as intravascular large B-cell lymphoma on the basis of skin biopsy findings, and she was treated by rituximab-containing chemotherapy. The spinal lesion showed high and low signal intensities on T2 weighted magnetic resonance imaging (MRI) scans, those low signal intensity lesions were suspected to be hemorrhages. The hemorrhages were thought to have been caused by interaction between atypical lymphoma cells and the endothelial cells of spinal blood vessels, by hemorrhagic infarction or by rupture of the capillary endothelium due to interaction between rituximab and lymphoma cells. Intravascular large B-cell lymphoma cases rarely show low signal intensity on spinal T2 weighted MRI scans.

Measurement of persistent organic pollutants (POPs) in plastic resin pellets from remote islands: toward establishment of background concentrations for International Pellet Watch.

Plastic resin pellets collected from remote islands in the Pacific, Atlantic, and Indian Oceans and the Caribbean Sea were analyzed for polychlorinated biphenyls (PCBs), dichloro-diphenyltrichloroethane and its degradation products (DDTs), and hexachlorocyclohexanes (HCHs). Concentrations of PCBs (sum of 13 congeners) in the pellets were 0.1-9.9 ng/g-pellet. These were 1-3 orders of magnitude smaller than those observed in pellets from industrialized coastal shores. Concentrations of DDTs in the pellets were 0.8-4.1 ng/g-pellet. HCH concentrations were 0.6-1.7 ng/g-pellet, except for 19.3 ng/g-pellet on St. Helena, where current use of lindane is likely influence. This study provides background levels of POPs (PCBs<10 ng/g-pellet, DDTs <4 ng/g-pellet, HCHs <2 ng/g-pellet) for International Pellet Watch. Sporadic large concentrations of POPs were found in some pellet samples from remote islands and should be considered in future assessments of pollutants on plastic debris.

Organic micropollutants in marine plastics debris from the open ocean and remote and urban beaches.

To understand the spatial variation in concentrations and compositions of organic micropollutants in marine plastic debris and their sources, we analyzed plastic fragments (∼10 mm) from the open ocean and from remote and urban beaches. Polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), dichloro-diphenyl-trichloroethane and its metabolites (DDTs), polybrominated diphenyl ethers (PBDEs), alkylphenols and bisphenol A were detected in the fragments at concentrations from 1 to 10,000 ng/g. Concentrations showed large piece-to-piece variability. Hydrophobic organic compounds such as PCBs and PAHs were sorbed from seawater to the plastic fragments. PCBs are most probably derived from legacy pollution. PAHs showed a petrogenic signature, suggesting the sorption of PAHs from oil slicks. Nonylphenol, bisphenol A, and PBDEs came mainly from additives and were detected at high concentrations in some fragments both from remote and urban beaches and the open ocean.