The T-cell leukemia-associated ribosomal RPL10 R98S mutation enhances JAK-STAT signaling.

Several somatic ribosome defects have recently been discovered in cancer, yet their oncogenic mechanisms remain poorly understood. Here we investigated the pathogenic role of the recurrent R98S mutation in ribosomal protein L10 (RPL10 R98S) found in T-cell acute lymphoblastic leukemia (T-ALL). The JAK-STAT signaling pathway is a critical controller of cellular proliferation and survival. A proteome screen revealed overexpression of several Jak-Stat signaling proteins in engineered RPL10 R98S mouse lymphoid cells, which we confirmed in hematopoietic cells from transgenic Rpl10 R98S mice and T-ALL xenograft samples. RPL10 R98S expressing cells displayed JAK-STAT pathway hyper-activation upon cytokine stimulation, as well as increased sensitivity to clinically used JAK-STAT inhibitors like pimozide. A mutually exclusive mutation pattern between RPL10 R98S and JAK-STAT mutations in T-ALL patients further suggests that RPL10 R98S functionally mimics JAK-STAT activation. Mechanistically, besides transcriptional changes, RPL10 R98S caused reduction of apparent programmed ribosomal frameshifting at several ribosomal frameshift signals in mouse and human Jak-Stat genes, as well as decreased Jak1 degradation. Of further medical interest, RPL10 R98S cells showed reduced proteasome activity and enhanced sensitivity to clinical proteasome inhibitors. Collectively, we describe modulation of the JAK-STAT cascade as a novel cancer-promoting activity of a ribosomal mutation, and expand the relevance of this cascade in leukemia.

Size and albedo of Kuiper belt object 55636 from a stellar occultation.

The Kuiper belt is a collection of small bodies (Kuiper belt objects, KBOs) that lie beyond the orbit of Neptune and which are believed to have formed contemporaneously with the planets. Their small size and great distance make them difficult to study. KBO 55636 (2002 TX(300)) is a member of the water-ice-rich Haumea KBO collisional family. The Haumea family are among the most highly reflective objects in the Solar System. Dynamical calculations indicate that the collision that created KBO 55636 occurred at least 1 Gyr ago. Here we report observations of a multi-chord stellar occultation by KBO 55636, which occurred on 9 October 2009 ut. We find that it has a mean radius of 143 +/- 5 km (assuming a circular solution). Allowing for possible elliptical shapes, we find a geometric albedo of in the V photometric band, which establishes that KBO 55636 is smaller than previously thought and that, like its parent body, it is highly reflective. The dynamical age implies either that KBO 55636 has an active resurfacing mechanism, or that fresh water-ice in the outer Solar System can persist for gigayear timescales.

Highly active antiretroviral therapy-associated regression of cytomegalovirus retinitis: long-Term results in a small case series.

PURPOSE: To report the stability of acquired immunodeficiency syndrome (AIDS)-associated cytomegalovirus (CMV) retinitis lesions that have undergone regression in the absence of specific anti-CMV medications owing to highly active antiretroviral therapy (HAART)-generated immune recovery. METHODS: The initial examination revealed HAART-associated regression of CMV retinitis lesions in eight subjects at two institutions. Patients were monitored for recurrences of CMV activity. CD4+ T-lymphocyte counts and human immunodeficiency virus (HIV) loads were measured. RESULTS: All patients had positive initial responses to HAART with an average HIV load decrease of 2.26 log units (range 0.3-5.57). Mean CD4+ T-lymphocyte count at baseline was 45.6 (range 4-107) and increased by an average of 132.5 (range 7-266) within the first 2 to 4 months of HAART. Patients were observed for an average of 15.5 months (range 11-20 months). Six subjects had a vigorous and sustained response to therapy, achieving an average HIV load of 9,400 copies/mL (3.32 log10 decrease) and CD4+ T-lymphocyte count of 158.2 cells/microL. These patients had no CMV retinitis progression. By contrast, two others who attained an average log10 decrease of only 0.48 had modest and short-lived increases in the CD4+ T-lymphocyte count. These patients experienced reactivation of CMV retinitis after 5 and 7 months, respectively. CONCLUSIONS: Regressed CMV retinitis may remain healed for long periods. However, failure of HAART to induce substantial decreases in HIV load may predict poor or unsustainable rises in the CD4+ T-lymphocyte count and presage recurrence of CMV retinitis. Vigilance in ophthalmic examinations is especially mandatory in these subjects.

Experimental Bacillus cereus post-traumatic endophthalmitis and treatment with ciprofloxacin.

BACKGROUND: Bacillus species remain an important cause of post-traumatic endophthalmitis, often causing permanent visual loss. METHODS: Twenty two rabbits were used to evaluate the clinical and histological findings of Bacillus cereus experimental post-traumatic endophthalmitis. Eyes that had received a scleral laceration and surgical repair were inoculated with Bacillus cereus. Thirty four other rabbits were used to evaluate the efficacy of intravitreal ciprofloxacin in treating experimental disease. RESULTS: Animals developed a post-traumatic endophthalmitis that closely mimicked human disease, characterised by a rapidly progressive and destructive endophthalmitis. Histological evaluation revealed retinal detachment, retinal necrosis, and the infiltration of inflammatory cells into the subretinal space. Intravitreal ciprofloxacin (100 micrograms) prevented the development of disease when given 1 hour and 6 hours after trauma and inoculation. CONCLUSIONS: Clinical and histological examination of experimental Bacillus cereus post-traumatic endophthalmitis suggests that retinal detachment and retinal necrosis play important roles in visual loss. Ciprofloxacin may be of benefit in the management of certain intraocular infections following penetrating injury.