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Ki-67 Staining Is a Strong Predictor of Distant Metastasis and Mortality for Men With Prostate Cancer Treated With Radiotherapy Plus Androgen Deprivation: Radiation Therapy Oncology Group Trial 92–02
Purpose The Ki-67 staining index (Ki67-SI) has been associated with prostate cancer patient outcome; however, few studies have involved radiotherapy (RT) -treated patients. The association of Ki67-SI to local failure (LF), biochemical failure (BF), distant metastasis (DM), cause-specific death (CSD) and overall death (OD) was determined in men randomly assigned to short term androgen deprivation (STAD) + RT or long-term androgen deprivation (LTAD) + RT. Patients and Methods There were 537 patients (35.5%) on Radiation Therapy Oncology Group (RTOG) 92-02 who had sufficient tissue for Ki67-SI analysis. Median follow-up was 96.3 months. Ki67-SI cut points of 3.5% and 7.1% were previously found to be related to patient outcome and were examined here in a Cox proportional hazards multivariate analysis (MVA). Ki67-SI was also tested as a continuous variable. Covariates were dichotomized in accordance with stratification and randomization criteria. Results Median Ki67-SI was 6.5% (range, 0% to 58.2%). There was no difference in the distribution of patients in the Ki-67 analysis cohort (n = 537) and the other patients in RTOG 92-02 (n = 977) by any of the covariates or end points tested. In MVAs, Ki67-SI (continuous) was associated with LF (P = .08), BF (P = .0445), DM (P < .0001), CSD (P < .0001), and OD (P = .0094). When categoric variables were used in MVAs, the 3.5% Ki67-SI cut point was not significant. The 7.1% cut point was related to BF (P = .09), DM (P = .0008), and CSD (P = .017). Ki67-SI was the most significant correlate of DM and CSD. A detailed analysis of the hazard rates for DM in all possible covariate combinations revealed subgroups of patients treated with STAD + RT that did not require LTAD. Conclusion Ki67-SI was the most significant determinant of DM and CSD and was also associated with OD. The Ki67-SI should be considered for the stratification of patients in future trials
Protein kinase C zeta plays an essential role for Mycobacterium tuberculosis-induced extracellular signal-regulated kinase 1/2 activation in monocytes/macrophages via Toll-like receptor 2.
This study characterized the upstream signalling molecules involved in extracellular signal-regulated kinase (ERK) 1/2 activation and determined their effects on differential tumour necrosis factor (TNF)-alpha expression by monocytes/macrophages infected with virulent or avirulent mycobacteria. The avirulent Mycobacterium tuberculosis (MTB) strain H37Ra (MTBRa) induced higher levels of activation of ERK 1/2 and the upstream MAPK kinase (MEK)1 and, subsequently, higher levels of TNF-alpha expression in human primary monocytes and monocyte-derived macrophages, as compared with MTB strain H37Rv (MTBRv). The MTB-induced activation of ERK 1/2 was not dependent on Ras or Raf. However, inhibition of the activity of atypical protein kinase C (PKC) zeta decreased the in vitro phosphorylation of MEK, ERK 1/2 activation and subsequent TNF-alpha induction caused by MTBRv or MTBRa. Toll-like receptor (TLR) 2 was found to play a major role in MTB-induced TNF-alpha expression and PKCzeta phosphorylation. Co-immunoprecipitation experiments showed that PKCzeta interacts physically with TLR2 after MTB stimulation. Moreover, PKCzeta phosphorylation was increased more in macrophages following MTBRa, versus MTBRv, infection. This is the first demonstration that PKCzeta interacts with TLR2 to play an essential role in MTB-induced ERK 1/2 activation and subsequent TNF-alpha expression in monocytes/macrophages
Extraction of americium and europium with functionalized calixarenes from alkaline solutions
Virulence Attenuation of a UDP-galactose/ N-acetylglucosamine β1,4 Galactosyltransferase Expressing Leishmania donovani Promastigote
Protozoan parasites of the genus Leishmania are
the causative agent of leishmaniasis, a disease whose
manifestations in humans range from mild cutaneous
lesions to fatal visceral infections. Human visceral leishmaniasis
is caused by Leishmania donovani. Long-term
culture in vitro leads to the attenuation of the parasite. This
loss of parasite virulence is associated with the expression
of a developmentally regulated UDP-Galactose/N-acetylglucosamine
β 1–4 galactosyltransferase and galactose
terminal glycoconjugates as determined by their agglutination
with the pea nut agglutinin (PNA). Thus, all promastigotes
passaged for more than 11 times were 100%
agglutinated with PNA, and represent a homogeneous
population of avirulent parasites. Identical concentrations
of PNA failed to agglutinate promastigotes passaged for ≤5
times. These PNA− promastigotes were virulent. Promastigotes
passaged from 5 to 10 times showed a mixed
population. The identity of populations defined by virulence
and PNA agglutination was confirmed by isolating
PNA+ avirulent and PNA− virulent clones from the 7th
passage promastigotes. Only the PNA+ clones triggered
macrophage microbicidal activity. The PNA+ clones lacked lipophosphoglycan. Intravenous administration of [14C]
galactose-labeled parasite in BALB/c mice resulted in rapid
clearance of the parasite from blood with a concomitant
accumulation in the liver. By enzymatic assay and RT-PCR
we have shown the association of a UDP-Galactose/Nacetylglucosamine
β1,4 galactosyltransferase with only the
attenuated clones. By immunofluorescence we demonstrated
that the enzyme is located in the Golgi apparatus. By
western blot analysis and SDS-PAGE of the affinitypurified
protein, we have been able to identify a 29 KDa
galactose terminal protein from the avirulent clones