Mammalian cells possess two isoforms of the histone H3–H4 chaperone anti‐silencing function 1 (Asf1), Asf1a and Asf1b. However to date, whether they have individual physiological roles has remained elusive. Here, we aim to elucidate the functional importance of Asf1 isoforms concerning both basic and applied aspects. First, we reveal a specific proliferation‐dependent expression of human Asf1b unparalleled by Asf1a. Strikingly, in cultured cells, both mRNA and protein corresponding to Asf1b decrease upon cell cycle exit. Depletion of Asf1b severely compromises proliferation, leads to aberrant nuclear structures and a distinct transcriptional signature. Second, a major physiological implication is found in the applied context of tissue samples derived from early stage breast tumours in which we examined Asf1a/b levels. We reveal that overexpression of Asf1b mRNA correlate with clinical data and disease outcome. Together, our results highlight a distribution of tasks between the distinct Asf1 isoforms, which emphasizes a specialized function of Asf1b required for proliferation capacity. We discuss the implications of these results for breast cancer diagnosis and prognosis.
were 18 CR/uCR (40%) and 12 PR (27%) during the induction phase. The maintenance phase was started and completed by 18 and 5 patients, respectively. With a median follow-up of 19.2 months (range 1.5-31), the median progression-free survival (PFS) and overall survival (OS) were 7.8 months (95% CI 3.9-11.3) and 17.7 months (95% CI 12.9 to not reached), respectively. No unexpected toxicity was observed. The peripheral baseline CD4/CD8 ratio impacted PFS [median PFS ¼ 9.5 months (95% CI, 8.1-14.8] for CD4/CD8 1.6; median PFS ¼ 2.8 months, [95% CI, 1.1-7.8) for CD4/CD8 < 1.6, P ¼ 0.03).Conclusions: The R 2 regimen showed significant activity in R/R PCNSL and PVRL patients. These results support assessments of the efficacy of R 2 combined with methotrexate-based chemotherapy as a first-line treatment of PCNSL.
Histone synthesis and chromatin assembly are mainly associated with DNA replication and are thus intimately involved in cell cycle regulation. The expression of key components involved in these events in human cells was studied in relation to cell-proliferative status. Among several chromatin assembly factors, chromatin assembly factor (CAF)-1 stood out as the most discriminating marker of the proliferative state. We show, using both immunofluorescence and Western blot analysis, that the expression of both CAF-1 large subunits, p150 and p60, is massively down-regulated during quiescence in several cell lines. Upon exit from the quiescent state, the CAF-1 subunits are re-expressed early, before DNA replication. The amounts of either total or chromatin-associated pools of CAF-1 proteins correlate directly with cell proliferation. Regulation of CAF-1 expression is partly controlled at the RNA level, as shown by quantitative reverse transcription-PCR and Northern blot experiments. Biological material from benign and malignant human breast tumors analyzed by immunocytochemistry and immunohistochemistry exhibits a strong positive correlation between CAF-1 p60 expression and the following proliferation markers: S-phase fraction (r ؍ 0.84, P < 0.0001); Ki-67 (r ؍ 0.94, P < 0.0001); and proliferating cell nuclear antigen (r ؍ 0.95, P ؍ 0.0001). We discuss the advantages of using CAF-1 to assess cell proliferation. High CAF-1 p60 levels are also shown to be associated with various prognostic factors. Our data highlight the precise association of CAF-1 expression with the proliferative state and validate the use of this factor as a useful proliferation marker and prognostic indicator in malignant and benign breast lesions.
Mammalian cells contain three closely related heterochromatin protein 1 (HP1) isoforms, HP1α, β and γ, which, by analogy to their unique counterpart in Schizosaccharomyces pombe, have been implicated in gene silencing, genome stability and chromosome segregation. However, the individual importance of each isoform during normal cell cycle and disease has remained an unresolved issue. Here, we reveal that HP1α shows a proliferation-dependent regulation, which neither HP1β nor γ display. During transient cell cycle exit, the HP1α mRNA and protein levels diminish. Transient depletion of HP1α, but not HP1β or γ, in tumoural and primary human cells leads to defects in chromosome segregation. Notably, analysis of an annotated collection of samples derived from carcinomas reveals an overexpression of HP1α mRNA and protein, which correlates with clinical data and disease outcome. Our results unveil a specific expression pattern for the HP1α isoform, suggesting a unique function related to cell division and tumour growth. The overexpression of HP1α constitutes a new example of a potential epigenetic contribution to tumourigenesis that is of clinical interest for cancer prognosis.
Our results suggest that MRI is more relevant than CT for preoperative detection of optic nerve invasion in patients with retinoblastoma. Tumour diameter is the only indirect sign significantly associated with postlaminar invasion.
As tumours in BRCA1/2 mutation carriers might be more sensitive to radiation, we investigated after long-term follow-up whether mutation status influenced the rate of ipsilateral and contralateral breast cancers after breast-conserving treatment (BCT). BRCA1 and BRCA2 genes were screened for germline mutations in 131 patients with a family history of breast and/or ovarian cancer who had undergone BCT and radiotherapy. Patients were matched to 261 controls with sporadic breast cancer according to age at diagnosis and year of treatment. Controls were followed up for at least as long as the interval between diagnosis and genetic screening in familial cases. Rates of ipsilateral and contralateral cancer between groups were compared by the log-rank test. The BRCA1/2 mutations occurred in 20.6% of tested patients. Tumours in mutation carriers were more likely to be grade III (P < 10(-4)) and oestrogen receptor negative (P = 0.005) than in non-carriers and controls. Overall median follow-up was 161 months. There was no significant difference in ipsilateral tumours between mutation carriers, non-carriers and controls (P = 0.13). On multivariate analysis, age was the most significant predictor for ipsilateral recurrence (P < 10(-3)). The rate of contralateral cancer was significantly higher in familial cases: 40.7% (mutation carriers), 20% (non-carriers), and 11% (controls) (P < 10(-4)). After 13.4 years of follow-up, the rate of ipsilateral tumours was no higher in mutation carriers than in non-carriers or controls. As tumours in BRCA1/2 mutation carriers might be more sensitive to radiation, BCT is a possible treatment option.
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