•Hedgehog pathway activity promotes in vitro migration of endoneurial fibroblasts.•Gli1, Ptch and VEGF-A expression increases with pathway stimulation.•Pathway stimulation increases VEGF-A in vivo.
...Peripheral nerve injuries are a common clinical problem which may result in permanent loss of motor or sensory function. A better understanding of the signaling pathways that lead to successful nerve regeneration may help in discovering new therapeutic targets. The Hedgehog (Hh) signaling pathway plays significant roles in nerve development and regeneration. In a mouse model of facial nerve injury, Hedgehog-responsive fibroblasts increase in number both at the site of injury and within the distal nerve. However, the role of these cells in facial nerve regeneration is not fully understood. We hypothesize that the Hh pathway plays an angiogenic and pro-migratory role following facial nerve injury.
Hedgehog pathway modulators were applied to murine endoneurial fibroblasts isolated from the murine facial nerve. The impact of pathway modulation on endoneurial fibroblast migration and cell proliferation was assessed. Gene expression changes of known Hedgehog target genes and the key angiogenic factor Vegf-A were determined by qPCR. In vivo, mice were treated with pathway agonist (SAG21k) and injured facial nerve specimens were analyzed via immunofluorescence and in situ hybridization.
Hedgehog pathway activation in facial nerve fibroblasts via SAG21k treatment increases Gli1 and Ptch1 expression, the rate of cellular migration, and Vegf-A expression in vitro. In vivo, expression of Gli1 and Vegf-A expression appears to increase after injury, particularly at the site of nerve injury and the distal nerve, as detected by immunofluorescence and in situ hybridization. Additionally, Gli1 transcripts co-localize with Vegf-A following transection injury to the facial nerve.
These findings describe an angiogenic and pro-migratory role for the Hedgehog pathway mediated through effects on nerve fibroblasts. Given the critical role of Vegf-A in nerve regeneration, modulation of this pathway may represent a potential therapeutic target to improve facial nerve regeneration following injury.
Primary forms of minimal change disease and focal segmental glomerulosclerosis are rare podocytopathies and clinically characterized by nephrotic syndrome. Glucocorticoids are the cornerstone of the ...initial immunosuppressive treatment in these two entities. Especially among adults with minimal change disease or focal segmental glomerulosclerosis, relapses, steroid dependence or resistance are common and necessitate re-initiation of steroids and other immunosuppressants. Effective steroid-sparing therapies and introduction of less toxic immunosuppressive agents are urgently needed to reduce undesirable side effects, in particular for patients whose disease course is complex. Rituximab, a B cell depleting monoclonal antibody, is increasingly used off-label in these circumstances, despite a low level of evidence for adult patients. Hence, critical questions concerning drug-safety, long-term efficacy and the optimal regimen for rituximab-treatment remain unanswered. Evidence in the form of large, multicenter studies and randomized controlled trials are urgently needed to overcome these limitations.
Objectives Lupus nephritis (LN) is a serious complication of systemic lupus erythematosus (SLE). All current treatment regimens include oral steroids, which are associated with severe adverse events ...and long-term damage. We have piloted a steroid-avoiding protocol (rituxilup) for the treatment of biopsy-proven active International Society of Nephrology/Renal Pathology Society (ISN/RPS) class III, IV, or class V LN. Methods We report the findings from the first 50 consecutive patients, treated with 2 doses of rituximab (1 g) and methyl prednisolone (500 mg) on days 1 and 15, and maintenance treatment of mycophenolate mofetil. Patients on maintenance steroids or with life-threatening SLE or requiring dialysis were excluded. Renal remission was defined as serum creatinine no greater than 15% above baseline; complete biochemical remission (CR) was defined as urine protein : creatinine ratio (PCR)<50 mg/mmol or partial remission (PR) if PCR>50 mg/mmol but non-nephrotic and >50% reduction. Results A total of 45 (90%) patients achieved CR or PR by a median time of 37 weeks (range 4–200). Overall, 72% (n=36) achieved CR (median time 36 weeks (11–58)) and a further 18% (n=9) achieved persistent PR (median time 32 weeks (19–58)). By 52 weeks, CR and PR had been achieved in 52% (n=26) and 34% (n=17) respectively. In all, 12 relapses occurred in 11 patients, at a median time of 65.1 weeks (20–112) from remission. A total of 6/50 patients had systemic flares. Of the 45 responders, only 2 required >2 weeks of oral steroids. Adverse events were infrequent; 18% were admitted, 10% for an infective episode. Conclusions The rituxilup cohort demonstrates that oral steroids can be safely avoided in the treatment of LN. If findings are confirmed, it could mark a step change in the approach to the treatment of LN.
Mycobacterium tuberculosis is a common, devastating cause of meningitis in HIV-infected persons. Due to international rollout programs, access to antiretroviral therapy (ART) is increasing globally. ...Starting patients with HIV-associated tuberculous meningitis (TBM) on ART during tuberculosis (TB) treatment may increase survival in these patients. We undertook this study to describe causes of meningitis at a secondary-level hospital in a high HIV/TB co-infection setting and to determine predictors of mortality in patients with TBM.
A retrospective review of cerebrospinal fluid findings and clinical records over a six-month period (March 2009-August 2009). Definite, probable and possible TBM were diagnosed according to published case definitions.
TBM was diagnosed in 120/211 patients (57%) with meningitis. In 106 HIV-infected patients with TBM, six-month all-cause mortality was lower in those who received antiretroviral therapy (ART) during TB treatment; hazard ratio = 0.30 (95% CI = 0.08-0.82). Factors associated with inpatient mortality in HIV-infected patients were 1) low CD4(+) count at presentation; adjusted odds ratio (AOR) = 1.4 (95% confidence interval CI = 1.03-1.96) per 50 cells/µL drop in CD4(+) count and, 2) higher British Medical Research Council TBM disease grade (2 or 3 versus 1); AOR = 4.8 (95% CI = 1.45-15.87).
Starting ART prior to or during TB treatment may be associated with lower mortality in patients with HIV-associated TBM. Advanced HIV and worse stage of TBM disease predict in-hospital mortality in patients presenting with TBM.
Abstract
The Transiting Exoplanet Survey Satellite (TESS) space telescope is collecting continuous, high-precision optical photometry of stars throughout the sky, including thousands of RR Lyrae ...stars. In this paper, we present results for an initial sample of 118 nearby RR Lyrae stars observed in TESS Sectors 1 and 2. We use differential image photometry to generate light curves and analyze their mode content and modulation properties. We combine accurate light-curve parameters from TESS with parallax and color information from the Gaia mission to create a comprehensive classification scheme. We build a clean sample, preserving RR Lyrae stars with unusual light-curve shapes, while separating other types of pulsating stars. We find that a large fraction of RR Lyrae stars exhibit various low-amplitude modes, but the distribution of those modes is markedly different from those of the bulge stars. This suggests that differences in physical parameters have an observable effect on the excitation of extra modes, potentially offering a way to uncover the origins of these signals. However, mode identification is hindered by uncertainties when identifying the true pulsation frequencies of the extra modes. We compare mode amplitude ratios in classical double-mode stars to stars with extra modes at low amplitudes and find that they separate into two distinct groups. Finally, we find a high percentage of modulated stars among the fundamental mode pulsators, but also find that at least 28% of them do not exhibit modulation, confirming that a significant fraction of stars lack the Blazhko effect.
We study the very early light curve of supernova 2014J (SN 2014J) using the high-cadence broad-band imaging data obtained by the Kilodegree Extremely Little Telescope, which fortuitously observed M ...82 around the time of the explosion, starting more than 2 months prior to detection, with up to 20 observations per night. These observations are complemented by observations in two narrow-band filters used in an H alpha survey of nearby galaxies by the intermediate Palomar Transient Factory that also captured the first days of the brightening of the supernova. The evolution of the light curves is consistent with the expected signal from the cooling of shock heated material of large scale dimensions, > ~1R sub(middot in circle). This could be due to heated material of the progenitor, a companion star or pre-existing circumstellar environment, e.g., in the form of an accretion disk. Structure seen in the light curves during the first days after explosion could also originate from radioactive material in the outer parts of an exploding white dwarf, as suggested from the early detection of gamma-rays. The model degeneracy translates into a systematic uncertainty of + or -0.3 days on the estimate of the first light from SN 2014J.
Abstract
We present the first results from the Transiting Exoplanet Survey Satellite (TESS) on the rotational and pulsational variability of magnetic chemically peculiar A-type stars. We analyse TESS ...2-min cadence data from sectors 1 and 2 on a sample of 83 stars. Five new rapidly oscillating Ap (roAp) stars are announced. One of these pulsates with periods around 4.7 min, making it the shortest period roAp star known to date. Four out of the five new roAp stars are multiperiodic. Three of these and the singly periodic one show the presence of rotational mode splitting. Individual frequencies are provided in all cases. In addition, seven previously known roAp stars are analysed. Additional modes of oscillation are found in some stars, while in others we are able to distinguish the true pulsations from possible aliases present in the ground-based data. We find that the pulsation amplitude in the TESS filter is typically a factor of 6 smaller than that in the B filter, which is usually used for ground-based observations. For four roAp stars we set constraints on the inclination angle and magnetic obliquity, through the application of the oblique pulsator model. We also confirm the absence of roAp-type pulsations down to amplitude limits of 6 and 13 $\mu$mag, respectively, in two of the best characterized non-oscillating Ap (noAp) stars. We announce 27 new rotational variables along with their rotation periods, and provide different rotation periods for seven other stars. Finally, we discuss how these results challenge state-of-the-art pulsation models for roAp stars.
ABSTRACT
HD 62658 (B9p V) is a little-studied chemically peculiar star. Light curves obtained by the Kilodegree Extremely Little Telescope (KELT) and Transiting Exoplanet Survey Satellite (TESS) show ...clear eclipses with a period of about 4.75 d, as well as out-of-eclipse brightness modulation with the same 4.75 d period, consistent with synchronized rotational modulation of surface chemical spots. High-resolution ESPaDOnS circular spectropolarimetry shows a clear Zeeman signature in the line profile of the primary; there is no indication of a magnetic field in the secondary. PHOEBE modelling of the light curve and radial velocities indicates that the two components have almost identical masses of about 3 M⊙. The primary’s longitudinal magnetic field 〈Bz〉 varies between about +100 and −250 G, suggesting a surface magnetic dipole strength Bd = 850 G. Bayesian analysis of the Stokes V profiles indicates Bd = 650 G for the primary and Bd < 110 G for the secondary. The primary’s line profiles are highly variable, consistent with the hypothesis that the out-of-eclipse brightness modulation is a consequence of rotational modulation of that star’s chemical spots. We also detect a residual signal in the light curve after removal of the orbital and rotational modulations, which might be pulsational in origin; this could be consistent with the weak line profile variability of the secondary. This system represents an excellent opportunity to examine the consequences of magnetic fields for stellar structure via comparison of two stars that are essentially identical with the exception that one is magnetic. The existence of such a system furthermore suggests that purely environmental explanations for the origin of fossil magnetic fields are incomplete.
Postpartum mammary gland involution is a tissue remodeling event that occurs in all mammals in the absence of nursing or after weaning to return the gland to the pre-pregnant state. The tissue ...microenvironment created by involution has proven to be tumor promotional. Here we report that the GPI-linked protein semaphorin 7A (SEMA7A) is expressed on mammary epithelial cells during involution and use preclinical models to demonstrate that tumors induced during involution express high levels of SEMA7A. Overexpression of SEMA7A promoted the presence of myeloid-derived podoplanin (PDPN)-expressing cells in the tumor microenvironment and during involution. SEMA7A drove the expression of PDPN in macrophages, which led to integrin- and PDPN-dependent motility and adherence to lymphatic endothelial cells to promote lymphangiogenesis. In support of this mechanism, mammary tissue from SEMA7A-knockout mice exhibited decreased myeloid-derived PDPN-expressing cells, PDPN-expressing endothelial cells, and lymphatic vessel density. Furthermore, coexpression of
, and macrophage marker
predicted for decreased distant metastasis-free survival in a cohort of over 600 cases of breast cancer as well as in ovarian, lung, and gastric cancers. Together, our results indicate that SEMA7A may orchestrate macrophage-mediated lymphatic vessel remodeling, which in turn drives metastasis in breast cancer.
SEMA7A, which is expressed on mammary cells during glandular involution, alters macrophage biology and lymphangiogenesis to drive breast cancer metastasis.
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Systematically identifying synergistic combinations of targeted agents and immunotherapies for cancer treatments remains difficult. In this study, we integrated high-throughput and high-content ...techniques-an implantable microdevice to administer multiple drugs into different sites in tumors at nanodoses and multiplexed imaging of tumor microenvironmental states-to investigate the tumor cell and immunological response signatures to different treatment regimens. Using a mouse model of breast cancer, we identified effective combinations from among numerous agents within days. In vivo studies in three immunocompetent mammary carcinoma models demonstrated that the predicted combinations synergistically increased therapeutic efficacy. We identified at least five promising treatment strategies, of which the panobinostat, venetoclax and anti-CD40 triple therapy was the most effective in inducing complete tumor remission across models. Successful drug combinations increased spatial association of cancer stem cells with dendritic cells during immunogenic cell death, suggesting this as an important mechanism of action in long-term breast cancer control.
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