Complement deficiencies limit CD20 monoclonal antibody treatment efficacy in CLL

Monoclonal antibodies (MAbs) form a central part of chronic lymphocytic leukaemia (CLL) treatment. We therefore evaluated whether complement defects in CLL patients reduced the induction of complement-dependent cytotoxicity (CDC) by using anti-CD20 MAbs rituximab (RTX) and ofatumumab (OFA). Ofatumumab elicited higher CDC levels than RTX in all CLL samples examined, particularly in poor prognosis cohorts (11q− and 17p−). Serum sample analyses revealed that 38.1% of patients were deficient in one or more complement components, correlating with reduced CDC responses. Although a proportion of patients with deficient complement levels initially induced high levels of CDC, on secondary challenge CDC activity in sera was significantly reduced, compared with that in normal human serum (NHS; P<0.01; n=52). In addition, a high CLL cell number contributed to rapid complement exhaustion. Supplementing CLL serum with NHS or individual complement components, particularly C2, restored CDC on secondary challenge to NHS levels (P<0.0001; n=9). In vivo studies revealed that complement components were exhausted in CLL patient sera post RTX treatment, correlating with an inability to elicit CDC. Supplementing MAb treatment with fresh-frozen plasma may therefore maintain CDC levels in CLL patients with a complement deficiency or high white blood cell count. This study has important implications for CLL patients receiving anti-CD20 MAb therapy

An Unbiassed Census of Active Galactic Nuclei in the Two Micron All Sky Survey

(Abridged) We present an unbiassed near-IR selected AGN sample, covering 12.56 square degrees down to K ~ 15.5, selected from the Two Micron All Sky Survey (2MASS). Our only selection effect is a moderate color cut (J-K>1.2) designed to reduce contamination from galactic stars. We observed both point-like and extended sources. Using the brute-force capabilities of the 2dF multi-fiber spectrograph on the Anglo-Australian Telescope, we obtained spectra of 65% of the target list: an unbiassed sub-sample of 1526 sources. 80% of the 2MASS sources in our fields are galaxies, with a median redshift of 0.15. The remainder are K- and M-dwarf stars. Seyfert-2 Galaxies are roughly three times more common in this sample than in optically selected galaxy samples (once corrections have been made for the equivalent width limit and for different aperture sizes). We find 14 broad-line (Type-1) AGNs, giving a surface density down to K<15 comparable to that of optical samples down to B=18.5. Half of our Type-1 AGNs could not have been found by normal color selection techniques. In all cases this was due host galaxy light contamination rather than intrinsically red colors. We conclude that the Type-1 AGN population found in the near-IR is not dramatically different from that found in optical samples. There is no evidence for a large population of AGNs that could not be found at optical wavelengths, though we can only place very weak constraints on any population of dusty high-redshift QSOs.Comment: AJ in pres

An Unbiassed Census of Active Galactic Nuclei in the Two Micron All Sky Survey

(Abridged) We present an unbiassed near-IR selected AGN sample, covering 12.56 square degrees down to K ~ 15.5, selected from the Two Micron All Sky Survey (2MASS). Our only selection effect is a moderate color cut (J-K>1.2) designed to reduce contamination from galactic stars. We observed both point-like and extended sources. Using the brute-force capabilities of the 2dF multi-fiber spectrograph on the Anglo-Australian Telescope, we obtained spectra of 65% of the target list: an unbiassed sub-sample of 1526 sources. 80% of the 2MASS sources in our fields are galaxies, with a median redshift of 0.15. The remainder are K- and M-dwarf stars. Seyfert-2 Galaxies are roughly three times more common in this sample than in optically selected galaxy samples (once corrections have been made for the equivalent width limit and for different aperture sizes). We find 14 broad-line (Type-1) AGNs, giving a surface density down to K<15 comparable to that of optical samples down to B=18.5. Half of our Type-1 AGNs could not have been found by normal color selection techniques. In all cases this was due host galaxy light contamination rather than intrinsically red colors. We conclude that the Type-1 AGN population found in the near-IR is not dramatically different from that found in optical samples. There is no evidence for a large population of AGNs that could not be found at optical wavelengths, though we can only place very weak constraints on any population of dusty high-redshift QSOs.Comment: AJ in pres

Proliferation and patterning are mediated independently in the dorsal spinal cord downstream of canonical Wnt signaling

AbstractCanonical Wnt signaling can regulate proliferation and patterning in the developing spinal cord, but the relationship between these functions has remained elusive. It has been difficult to separate the distinct activities of Wnts because localized changes in proliferation could conceivably alter patterning, and gain and loss of function experiments have resulted in both types of defects. To resolve this issue we have investigated canonical Wnt signaling in the zebrafish spinal cord using multiple approaches. We demonstrate that Wnt signaling is required initially for proliferation throughout the entire spinal cord, and later for patterning dorsal progenitor domains. Furthermore, we find that spinal cord patterning is normal in embryos after cell division has been pharmacologically blocked. Finally, we determine the transcriptional mediators of Wnt signaling that are responsible for patterning and proliferation. We show that tcf7 gene knockdown results in dorsal patterning defects without decreasing the mitotic index in dorsal domains. In contrast, tcf3 gene knockdown results in a reduced mitotic index without affecting dorsal patterning. Together, our work demonstrates that proliferation and patterning in the developing spinal cord are separable events that are regulated independently by Wnt signaling

An HST/WFPC2 Snapshot Survey of 2MASS-Selected Red QSOs

Using simple infrared color selection, 2MASS has found a large number of red, previously unidentified, radio-quiet QSOs. Although missed by UV/optical surveys, the 2MASS QSOs have K-band luminosities that are comparable to "classical" QSOs. This suggests the possible discovery of a previously predicted large population of dust-obscured radio-quiet QSOs. We present the results of an imaging survey of 29 2MASS QSOs observed with WFPC2 onboard the Hubble Space Telescope. I-band images, which benefit from the relative faintness of the nuclei at optical wavelengths, are used to characterize the host galaxies, measure the nuclear contribution to the total observed I-band emission, and to survey the surrounding environments. The 2MASS QSOs are found to lie in galaxies with a variety of morphologies, luminosities, and dynamical states, not unlike those hosting radio-quiet PG QSOs. Our analysis suggests that the extraordinary red colors of the 2MASS QSOs are caused by extinction of an otherwise typical QSO spectrum due to dust near the nucleus.Comment: 23 pages including 9 figures and 7 tables, accepted for publication in ApJ, higher resolution HST images at: http://shapley.as.arizona.edu/~amarble/papers/twomq

Busca de fontes de resistência ao Groundnut ringspot vírus (GRSV) e Potato virus Y (PVY).

Resumo 182_2

Neurturin enhances the recovery of erectile function following bilateral cavernous nerve crush injury in the rat

BACKGROUND: The molecular mechanisms responsible for the survival and preservation of function for adult parasympathetic ganglion neurons following injury remain incompletely understood. However, advances in the neurobiology of growth factors, neural development, and prevention of cell death have led to a surge of clinical interest for protective and regenerative neuromodulatory strategies, as surgical therapies for prostate, bladder, and colorectal cancers often result in neuronal axotomy and debilitating loss of sexual function or continence. In vitro studies have identified neurturin, a glial cell line-derived neurotrophic factor, as a neuromodulator for pelvic cholinergic neurons. We present the first in vivo report of the effects of neurturin upon the recovery of erectile function following bilateral cavernous nerve crush injury in the rat. METHODS: In these experiments, groups (n = 8 each) consisted of uninjured controls and animals treated with injection of albumin (blinded crush control group), extended release neurotrophin-4 or neurturin to the site of cavernous nerve crush injury (100 μg per animal). After 5 weeks, recovery of erectile function (treatment effect) was assessed by cavernous nerve electrostimulation and peak aortic pressures were measured. Investigators were unblinded to specific treatments after statistical analyses were completed. RESULTS: Erectile dysfunction was not observed in the sham group (mean maximal intracavernous pressure [ICP] increase of 117.5 ± 7.3 cmH(2)O), whereas nerve injury and albumin treatment (control) produced a significant reduction in ICP elevation of 40.0 ± 6.3 cmH(2)O. Neurturin facilitated the preservation of erectile function, with an ICP increase of 55% at 62.0 ± 9.2 cmH(2)O (p < 0.05 vs control). Extended release neurotrophin-4 did not significantly enhance recovery of erectile function with an ICP change of 46.9 ± 9.6. Peak aortic blood pressures did not differ between groups. No significant pre- and post-treatment weight differences were observed between control, neurotrophin-4 and neurturin cohorts. All animals tolerated the five-week treatment course. CONCLUSION: Treatment with neurturin at the site of cavernous nerve crush injury facilitates recovery of erectile function. Results support further investigation of neurturin as a neuroprotective and/or neuroregenerative agent facilitating functional recovery after cavernous or other pelvic autonomic nerve injuries