Inhibition of monocyte chemoattractant protein-1 expression in tubular epithelium attenuates tubulointerstitial alteration in rat Goodpasture syndrome

Inhibition of monocyte chemoattractant protein-1 expression in tubular epithelium attenuates tubulointerstitial alteration in rat Goodpasture syndrome.BackgroundTo examine the role of monocyte chemoattractant protein-1 (MCP-1) expressed by tubular epithelium in tubulointerstitial alterations in situ, the level of MCP-1 mRNA in tubular epithelium was lowered selectively in the rat model of Goodpasture syndrome (GPS).MethodsIntravenously administered antisense oligodeoxynucleotide (ODN) is taken up by renal tubular epithelium and has been found to block expression of target genes in rats. MCP-1 antisense ODN was injected into GPS rats every second day from days 27 to 35 after immunization (this represents the time when renal MCP-1 mRNA level was increased and interstitial mononuclear cell infiltration was aggravated).ResultsIn addition to a reduction in the level of tubular MCP-1 mRNA, antisense ODN treatment attenuated monocyte infiltration significantly and preserved renal function in GPS rats. However, ODN injection did not affect glomerular MCP-1 expression and glomerular histopathology, and there were no significant changes in the urinary protein excretion rate.ConclusionOur findings provide direct evidence that MCP-1, expressed by tubular epithelium, plays a pivotal role in mediating secondary tubulointerstitial alterations in the GPS model

Spectropolarimetric Study on Circumstellar Structure of Microquasar LS I +61deg 303

We present optical linear spectropolarimetry of the microquasar LS I +61$^{\circ}$ 303. The continuum emission is mildly polarized (up to 1.3 %) and shows almost no temporal change. We find a distinct change of polarization across the H$\alpha$ emission line, indicating the existence of polarization component intrinsic to the microquasar. We estimate the interstellar polarization (ISP) component from polarization of the H$\alpha$ line and derive the intrinsic polarization component. The wavelength dependence of the intrinsic component is well explained by Thomson scattering in equatorial disk of the Be-type mass donor. The position angle (PA) of the intrinsic polarization $\sim 25^{\circ}$ represents the rotational axis of the Be disk. This PA is nearly perpendicular to the PA of the radio jet found during quiescent phases. Assuming an orthogonal disk-jet geometry around the compact star, the rotational axis of the accretion disk is almost perpendicular to that of the Be disk. Moreover, according to the orbital parameters of the microquasar, the compact star is likely to get across the Be disk around their periastron passage. We discuss the peculiar circumstellar structure of this microquasar inferred from our observation and possible connection with its high-energy activities.Comment: 17pages, 7figures; accepted for Publications of the Astronomical Society of Japa

LPS-CXCL10 Predicts Responses to Bortezomib in Myeloma Patients

To identify predictive biomarkers for clinical responses to bortezomib treatment, 0.06 mL of each whole blood without any cell separation procedures was stimulated ex vivo using five agents, and eight mRNAs were quantified. In six centers, heparinized peripheral blood was prospectively obtained from 80 previously treated or untreated, symptomatic multiple myeloma (MM) patients with measurable levels of M-proteins. The blood sample was procured prior to treatment as well as 2-3 days and 1-3 weeks after the first dose of bortezomib, which was intravenously administered biweekly or weekly, during the first cycle. Six stimulant-mRNA combinations; that is, lipopolysaccharide (LPS)-granulocyte-macrophage colony-stimulating factor (GM-CSF), LPS-CXCL chemokine 10 (CXCL10), LPS-CCL chemokine 4 (CCL4), phytohemagglutinin-CCL4, zymosan A (ZA)-GMCSF and ZA-CCL4 showed significantly higher induction in the complete and very good partial response group than in the stable and progressive disease group, as determined by both parametric (t-test) and non-parametric (unpaired Mann-Whitney test) tests. Moreover, LPS-induced CXCL10 mRNA expression was significantly suppressed 2-3 days after the first dose of bortezomib in all patients, as determined by both parametric (t-test) and non-parametric (paired Wilcoxon test) tests, whereas the complete and very good partial response group showed sustained suppression 1-3 weeks after the first dose. Thus, pretreatment LPS-CXCL10 mRNA and/or the six combinations may serve as potential biomarkers for the response to bortezomib treatment in MM patients

Exposure-Response and Population Pharmacokinetic Analyses of a Novel Subcutaneous Formulation of Daratumumab Administered to Multiple Myeloma Patients

We report the population pharmacokinetic (PK) and exposure-response analyses of a novel subcutaneous formulation of daratumumab (DARA) using data from 3 DARA subcutaneous monotherapy studies (PAVO Part 2, MMY1008, COLUMBA) and 1 combination therapy study (PLEIADES). Results were based on 5159 PK samples from 742 patients (DARA 1800 mg subcutaneously, n = 487 [monotherapy, n = 288; combination therapy, n = 199]; DARA 16 mg/kg intravenously, n = 255 [all monotherapy, in COLUMBA]; age, 33-92 years; weight, 28.6-147.6 kg). Subcutaneous and intravenous DARA monotherapies were administered once every week for cycles 1-2, once every 2 weeks for cycles 3-6, and once every 4 weeks thereafter (1 cycle is 28 days). The subcutaneous DARA combination therapy was administered with the adaptation of corresponding standard-of-care regimens. PK samples were collected between cycle 1 and cycle 12. Among monotherapy studies, throughout the treatment period, subcutaneous DARA provided similar/slightly higher trough concentrations (Ctrough) versus intravenous DARA, with lower maximum concentrations and smaller peak-to-trough fluctuations. The PK profile was consistent between subcutaneous DARA monotherapy and combination therapies. The exposure-response relationship between daratumumab PK and efficacy or safety end points was similar for subcutaneous and intravenous DARA. Although the ≤65-kg subgroup reported a higher incidence of neutropenia, no relationship was found between the incidence of neutropenia and exposure, which was attributed, in part, to the preexisting imbalance in neutropenia between subcutaneous DARA (45.5%) and intravenous DARA (19%) in patients ≤50 kg. A flat relationship was observed between body weight and any grade and at least grade 3 infections. The results support the DARA 1800-mg subcutaneous flat dose as an alternative to the approved intravenous DARA 16 mg/kg.The clinical studies and the analyses presented here were supported by research funding from Janssen Research & Development, LLC

Quality of life and symptoms among patients with relapsed/refractory AL amyloidosis treated with ixazomib-dexamethasone versus physician's choice

Patient-reported outcomes in AL amyloidosis have not been well-studied. We analyzed health-related quality of life (HRQOL) and AL amyloidosis symptoms data from the phase 3 TOURMALINE-AL1 trial (NCT01659658) (ixazomib-dexamethasone, n = 85; physician's choice of chemotherapy [PC], n = 83). HRQOL and symptom burden were measured with the SF-36v2, Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity subscale (FACT/GOG-Ntx), and an amyloidosis symptom questionnaire (ASQ). Score changes during treatment were analyzed descriptively and using repeated-measures linear mixed models; analyses were not adjusted for multiplicity. Least-squares (LS) mean changes from baseline were significantly higher (better HRQOL) for ixazomib-dexamethasone at several cycles for SF-36v2 Role Physical and Vitality subscales (p <.05); no subscales demonstrated significant differences favoring PC. For FACT/GOG-Ntx, small but significant differences in LS mean changes favored ixazomib-dexamethasone over PC at multiple cycles for seven items and both summary scores; significant differences favored PC for one item (trouble hearing) at multiple cycles. ASQ total score trended downward (lower burden) in both arms; significant LS mean differences favored ixazomib-dexamethasone over PC at some cycles (p <.05). Patients with relapsed/refractory AL amyloidosis treated with ixazomib-dexamethasone experienced HRQOL and symptoms that were similar to or trended better than patients treated with PC despite longer duration of therapy

Metabolic pathway of phenol of a cold-adapted Antarctic bacterium revealed through whole genome sequencing

Phenol is an important pollutant widely discharged as a component of hydrocarbon fuels, but its degradation in cold regions is challenging due to the harsh environmental conditions. To date, there is little information available concerning the capability for phenol biodegradation by indigenous Antarctic bacteria. In this study, enzyme activities and genes encoding phenol degradative enzymes identified using whole genome sequencing (WGS) were investigated to determine the pathway(s) of phenol degradation of Arthrobacter sp. strains AQ5-05 and AQ5-06, originally isolated from Antarctica. Complete phenol degradative genes involved only in the ortho-cleavage were detected in both strains. This was validated using assays of the enzymes catechol 1,2-dioxygenase and catechol 2,3-dioxygenase, which indicated the activity of only catechol 1,2-dioxygenase in both strains, in agreement with the results from the WGS. Both strains were psychrotolerant with the optimum temperature for phenol degradation, being between 10 and 15 °C. This study suggests the potential use of cold-adapted bacteria in the bioremediation of phenol pollution in cold environments