Brain-borne IL-1 adjusts glucoregulation and provides fuel support to astrocytes and neurons in an autocrine/paracrine manner.

It is still controversial which mediators regulate energy provision to activated neural cells, as insulin does in peripheral tissues. Interleukin-1ß (IL-1ß) may mediate this effect as it can affect glucoregulation, it is overexpressed in the 'healthy' brain during increased neuronal activity, and it supports high-energy demanding processes such as long-term potentiation, memory and learning. Furthermore, the absence of sustained neuroendocrine and behavioral counterregulation suggests that brain glucose-sensing neurons do not perceive IL-1ß-induced hypoglycemia. Here, we show that IL-1ß adjusts glucoregulation by inducing its own production in the brain, and that IL-1ß-induced hypoglycemia is myeloid differentiation primary response 88 protein (MyD88)-dependent and only partially counteracted by Kir6.2-mediated sensing signaling. Furthermore, we found that, opposite to insulin, IL-1ß stimulates brain metabolism. This effect is absent in MyD88-deficient mice, which have neurobehavioral alterations associated to disorders in glucose homeostasis, as during several psychiatric diseases. IL-1ß effects on brain metabolism are most likely maintained by IL-1ß auto-induction and may reflect a compensatory increase in fuel supply to neural cells. We explore this possibility by directly blocking IL-1 receptors in neural cells. The results showed that, in an activity-dependent and paracrine/autocrine manner, endogenous IL-1 produced by neurons and astrocytes facilitates glucose uptake by these cells. This effect is exacerbated following glutamatergic stimulation and can be passively transferred between cell types. We conclude that the capacity of IL-1ß to provide fuel to neural cells underlies its physiological effects on glucoregulation, synaptic plasticity, learning and memory. However, deregulation of IL-1ß production could contribute to the alterations in brain glucose metabolism that are detected in several neurologic and psychiatric diseases.

Therapeutic efficacy of metronomic chemotherapy with cyclophosphamide and doxorubicin on murine mammary adenocarcinomas.

BACKGROUND: Metronomic chemotherapy (MCT) refers to the chronic and equally spaced administration of low doses of different chemotherapy drugs, without extended rest periods. Herein, we investigated the therapeutic efficacy of metronomic cyclophosphamide (Cy) combined with doxorubicin (Dox) in two mouse mammary adenocarcinoma models. MATERIALS AND METHODS: Mice were s.c. challenged with M-234p or M-406 mammary tumors, and when the tumors reached ∼150 mm(3), they were treated with: (I) no treatment (controls); (II) Cy in the drinking water (30 mg/kg body weight/day); (III) Dox (0.5 mg/kg body weight i.p. three times/week); (IV) treated as (II) + (III). Mice challenged i.v. with M-234p or M-406 tumor cells received, on day 3, the same treatments. RESULTS: We found that MCT with Cy plus Dox inhibited tumor growth, decreased lung metastases, and increased the median survival time, while having low toxic effect. Combined MCT was more effective than each monotherapy causing decrease in VEGF serum concentration and tumor proliferation rate plus increase in tumor apoptosis. CONCLUSION(S): The therapeutic benefits of combined MCT with Cy and Dox on mammary adenocarcinomas together with its low toxic effect profile suggest the possibility of future translation into the clinic.

Deficient control of Trypanosoma cruzi infection in C57BL/6 mice is related to a delayed specific IgG response and increased macrophage production of pro-inflammatory cytokines.

Earlier work in Trypanosoma cruzi-infected C57BL/6 and BALB/c mice revealed an acute disease, of lethal outcome in the former group and lesser severity in BALB/c mice. Fatal course was not accompanied by an increased parasite load, but by a substantial imbalance between pro- and anti-inflammatory cytokine serum levels. To better characterise the mechanisms allowing the host to restrain the infection, we have now studied the specific IgG production and in vitro behaviour of peritoneal macrophages (PMs) when exposed to T. cruzi. BALC/c mice displayed higher serum levels of specific immunoglobulins in the first weeks of acute infection. In vitro infected PMs showed no between-group differences in the number of intracellular parasites, although TNFalpha levels were significantly higher in culture supernatants from C57BL/6 mice. Because an LPS-based pretreatment (desensitisation protocol followed by a sublethal LPS dose) reduced disease severity of C57BL/6 mice, we next explored the features of the in vitro infection in PMs from mice subjected to such protocol. PMs from LPS-pretreated mice had a decreased production of TNFalpha and IL-1beta, becoming more permissive to parasite replication. It is concluded that deficient control of T. cruzi infection in C57BL/6 mice may also involve a less satisfactory specific IgG response and increased TNFalpha production by PMs. Improved disease outcome in LPS-pretreated mice may be associated with the reduced inflammatory cytokine production by PMs, but the impaired ability of these cells to control parasite growth suggests that compensatory mechanisms are operating in the in vivo situation.

Lack of CD95/FAS gene somatic mutations in extranodal, nodal and splenic marginal zone B cell lymphomas.

Germline CD95 (also known as FAS, APT1 and APO1) gene mutations have been associated with benign lymphoproliferative diseases and autoimmune processes. Somatic mutations have been reported in human tumours, including lymphomas. Since marginal zone B cell lymphomas usually arise in a background of chronic inflammation, often of autoimmune origin, we searched for CD95 gene mutations in an unselected series of marginal zone B cell lymphomas. The CD95/FAS full coding region, comprising exon-intron junctions, was amplified from genomic DNA by polymerase chain reaction (PCR) in 10 separate reactions. PCR products were analysed by single-strand conformation polymorphism (SSCP) and visualised by silver staining. Bands exhibiting an altered electrophoretic mobility were sequenced. Twenty-seven cases of marginal zone B cell lymphomas of whom fresh or frozen tumour material was available (18 extranodal, five splenic and four nodal) were studied. Previously described silent polymorphisms in exons 7 (C836T) and 3 (T416C) were detected in 42% and in 19% of the cases, respectively. One silent T-to-A substitution at bp 431, within exon 3, was found in one case. Our results did not reveal the presence of CD95 somatic mutations in unselected cases of marginal zone B cell lymphomas. On the basis of our data, we cannot rule out that other genes coding for proteins involved in the CD95-induced apoptotic pathway might be altered. However, this pathway does not seem to play an important role in the pathogenesis of these lymphoma subtypes.

Inhibitory effect of Lovastatin on spontaneous metastases derived from a rat lymphoma.

The HMGCoA reductase inhibitor Lovastatin (LOV) has previously shown to abrogate p21ras farnesylation, which is associated with invasive and metastatic abilities in many tumor models. Considering the scarcity of therapeutic resources against metastasis, our objective was to study LOV as an antimetastatic agent on L-TACB rat lymphoma, which as a syngeneic tumor model resembles more closely the situation in human cancer. We also aimed to analyze the effect of LOV on chemoinvasion, motility, metalloproteases secretion, angiogenic capacity, and adhesion to the reconstituted basement membrane Matrigel. Our results showed that LOV caused no effect on cell motility, metalloprotease secretion and neovascularization. Conversely, LOV produced a significant inhibition of invasiveness, which could be a consequence of an impaired cell adhesion to the basement membrane observed. These effects could explain, at least in part, the inhibitory action of LOV on L-TACB rat lymphoma metastases.

Effect of acute administration of N-nitrosopyrrolidine to male Syrian golden hamsters.

A protocol has been developed which decreases the time for administration of N-nitrosopyrrolidine (NPYR) to male Syrian golden hamsters from 25 weeks to a single i.p. injection. Animals were divided into five groups: group I received two 0.5-mmol doses on alternate days; group II was given three 0.33-mmol doses on alternate days; group III received a single dose of 0.5 mmol; group IV was given a single dose of 0.25 mmol and group V served as a control and received saline. Preneoplastic and neoplastic changes in the upper respiratory tract and liver were observed in all carcinogen-treated groups. The number of animals with laryngeal and tracheal tumors in the NPYR-treated groups was dose-dependent. Groups I and II, respectively, had 21 of 26 (81%) and 18 of 24 (75%) animals with either laryngeal or tracheal tumors. Groups III and IV showed 4 of 12 (33%) and 3 of 13 (23%) hamsters with these tumors. No laryngeal or tracheal tumors were observed in control animals. These results indicate that a single dose of NPYR is sufficient to induce respiratory tract tumors in Syrian golden hamsters.

Eradication of Borrelia burgdorferi infection in primary marginal zone B-cell lymphoma of the skin.

Primary cutaneous B-cell lymphomas have been associated with Borrelia burgdorferi, the spirochete responsible for Lyme disease. Recently, cutaneous marginal zone B-cell lymphoma has been proposed as a distinct clinical-pathological entity. We report a case of primary cutaneous marginal zone lymphoma, associated with B burgdorferi infection. Polymerase chain reaction (PCR) amplification of the third complementarity determining region (CDR3) of the immunoglobulin heavy chain gene showed the presence of a monoclonal lymphoproliferation, therefore strengthening the histological diagnosis of a malignant process. B burgdorfer-specific hbb gene sequences were detected by PCR in the lymphoma tissue at diagnosis but not after antibiotic treatment. A nearly complete clinical and histological regression was observed after B burgdorferi eradication, with immunohistochemistry studies showing disappearance of plasma cell differentiation and a marked decline in the number of CD3+ T cells and Ki-67+ cells. Our case confirms the link between B burgdorferi and some cutaneous lymphomas. The disappearance of the microorganism accompanied by the unequivocal decrease of most indicators of active T- and B-cell immune response strongly supported a pathogenetic role for B burgdorferi in sustaining an antigen-driven development and growth of this cutaneous marginal zone lymphoma. Antibiotic therapy (analogous to Helicobacter pylori infection in gastric MALT lymphoma) might be helpful with the aim of averting or at least deferring the indication for more aggressive treatment.

Treatment and prognosis of centrocytic (mantle cell) lymphoma: a retrospective analysis of twenty-six patients treated in one institution.

We retrospectively attempted to analyse prognostic factors in a group of 26 patients with centrocytic lymphomas (CCL) treated from 1979 to 1991 (representing 7% of all cases of NHL diagnosed in our institution during that period). Ten of the patients were females and 16 males, and their median age at diagnosis was 69 years (range 38-85). The majority of patients (77%) had advanced disease (Ann Arbor stage III-IV) at presentation. Twenty-two patients (85%) had good performance status (0-1 ECOG). B-symptoms were present in 10 cases. Most patients (87%) presented with generalized adenopathies. Bone marrow involvement was observed in 12 patients (46%) and Waldeyer's ring involvement in 5 (4 of them with stage I-II). In 5 cases the liver was involved and 3 pts had gastrointestinal localizations; 15 patients had more than 2 sites of disease: LDH elevation was observed in 8/24 pts. Fourteen patients (54%) received single-agent chlorambucil (3 pts) or CVP (11 pts). Eleven patients were treated with ADM-containing regimens (7 with CHOP or M-ACOD and 4 with 3rd generation regimens). One patient had radiotherapy alone. The complete response (CR) rate was 50% (13/26); 8 patients relapsed with a median time to progression of 19 months, and only 3 responded to salvage treatment. The median overall survival was 33 months, with fewer than 40% of patients surviving longer than 3 years. At univariate analysis the use of ADM-containing regimens seems significantly correlated with the CR rate (p = 0.047), the failure-free survival (p = 0.023), and the overall survival (p = 0.004).(ABSTRACT TRUNCATED AT 250 WORDS)

Extranodal marginal zone B-cell lymphoma genotyping by Alu-polymerase chain reaction.

DNA amplification by polymerase chain reaction (PCR) with primers designed on the widely distributed Alu sequences allows the production of specific inter-Alu DNA-fingerprints. Amplification of tumour and matched normal DNA can show differences due to genetic alterations within the tumour genome. We applied this approach to study low-grade extranodal marginal zone B-cell lymphoma (of MALT type). After digestion with restriction enzymes, DNA samples were separately amplified by PCR with three different Alu-primers. A comparison between the fingerprint pattern from lymphoma and normal samples was made. Inter-Alu bands differing between the two samples were excised from the gel, cloned and sequenced. Nine cases of low-grade MALT-lymphomas have been analysed, giving seventeen different bands between tumour and normal. DNA sequence analysis showed identities for three of them with sequences available at the GenBank. The methodology of Alu-PCR to detect DNA-based abnormalities, in addition or combination with RNA-based methods, is a powerful tool to identify candidate regions frequently altered in tumours. With the increased available genomic sequences through the Human Genome Project, there will be an increasing probability of picking up perfect homologies with these sequences using cloned differential Alu-PCR bands in BLAST searches through genome databases.

Immunoglobulin light chain kappa deletion rearrangement as a marker of clonality in mantle cell lymphoma.

Mantle cell lymphoma (MCL) express immunoglobulin light chain lambda (IgL-lambda) more frequently than other non-Hodgkin's lymphomas, and IgL-lambda producing B-cells usually delete one or both alleles of their IgL-kappa genes. This inactivation is mediated by a rearrangement between the kappa deletion element (kappa de) and the Recombinant Signal Sequence (RSS) in the region between the Joining genes and the Constant region, or the RSS at the 3'-site of a Variable (Vkappa) segment. This deletion appears as a feasible tool for detecting monoclonality and minimal residual disease by polymerase chain reaction (PCR). Among twelve MCL patients studied, ten presented IgL-lambda expression, and all but one among these revealed a monoclonal kappa de rearrangement by PCR analysis. Six of the nine cases showed a fusion between the kappa de and the intron RSS, whilst three with a Vkappa segment. Since MCL has the worst prognosis of all B-cell lymphomas and high-dose chemotherapy regimens have been proposed, PCR for the kappa de rearrangement might be a useful molecular tool to evaluate the ability of the different treatment modalities to eradicate the malignant clones.

Clonality assessment in blood of patients with mantle cell lymphoma.

The presence of circulating neoplastic cells at diagnosis was assessed in the blood of patients presenting with mantle cell lymphoma (MCL) to determine the feasibility of a diagnostic molecular assay. Blood samples from 16 patients with pathologically reviewed MCL were analysed for the t(11;14)(q13;q32) translocation by the polymerase chain reaction (PCR): 7 (44%) were found positive. The remaining cases were examined by PCR for the presence of circulating neoplastic B-cells by amplifying the third complementarity region (CDR3) of immunoglobulin heavy chain genes and the immunoglobulin light kappa chain deletion rearrangements. A further 7 (44%) patients showed the presence of clonal lymphoma cells, leaving only 2 (12%) of cases negative for circulating lymphomatous cells. This study suggests that there is a high incidence of lymphoma cells in the blood of patients presenting with MCL. PCR for these clonal cells may be diagnostically useful.

Primary mediastinal large B-cell lymphoma (PMLCL): the need for prospective controlled clinical trials.

Primary mediastinal large-B cell lymphomas (PMLCL) are considered to be a distinct clinicopathologic entity among the diffuse large B-cell lymphomas. This study evaluated the prognostic factors and therapeutic outcome of PMLCL in a single-institution series. Twenty seven patients were reviewed. Nineteen of the 27 had Stage I-II and 8 had Stage III-IV disease. B-symptoms were found in 11 (41%) patients and bulky disease in 10 (37%). All patients were initially given combination chemotherapy (CT): doxorubicin-containing regimens to 23 patients (11 patients had CHOP, 12 more intensive third-generation regimens) and 4 elderly (>70 years) patients received CVP. Eleven responders were consolidated with irradiation (RT) as part of their initial treatment, with a median total dose of 39 Gy. Nineteen patients (70%) achieved clinical remission (15 CR and 4 PR) with their initial therapy. Forty-four percent of patients remained progression-free and 59% are alive at 3 years. The actuarial 10-year TTP and OS were 44% and 50%, respectively. Age >60 years, performance status >1 and IPI intermediate-high to high risk were significantly associated with poorer OS and TTP by univariate analysis (log-rank test). A better outcome was associated with the use of more aggressive chemotherapy regimens or with the inclusion of RT in the first-line treatment. In conclusion our analyses suggest that the application of radiotherapy in combination regimens and the use of more aggressive chemotherapy in the treatment of this particular lymphoma entity should be evaluated in prospective randomized trials.

Primary mediastinal large B-cell lymphoma: the need for prospective controlled clinical trials.

Primary mediastinal large-B cell lymphomas (PMLCL) are considered to be a distinct clinicopathologic entity among the diffuse large B-cell lymphomas. This study evaluated the prognostic factors and therapeutic outcome of PMLCL in a single-institution series. Twenty seven patients were reviewed. Nineteen of the 27 had Stage I-II and 8 had Stage III-IV disease. B-symptoms were found in 11 (41%) and bulky disease in 10 (37%) patients. All were initially given combination chemotherapy (CT): doxorubicin-containing regimens to 23 patients (11 patients had CHOP, 12 received more intensive third-generation regimens) and 4 elderly (>70 years) patients received CVP. Eleven responders were consolidated with irradiation (RT) as part of their initial treatment, with a median total dose of 39 Gy. Nineteen patients (70%) achieved clinical remission (15 CR and 4 PR) with their initial therapy. Forty-four percent of patients remained progression-free and 59% are alive at 3 years. The actuarial 10-year time to progression (TTP) and overall survival (OS) were 44% and 50%, respectively. Age >60 years, performance status >1 and IPI intermediate-high to high risk were significantly associated with poorer OS and TTP by univariate analysis (log-rank test). A better outcome was associated with the use of more aggressive chemotherapy regimens or with the inclusion of RT in the first-line treatment. Our analyses suggest that the application of radiotherapy in combination regimens and the use of more aggressive chemotherapy in the treatment of this particular type of lymphoma should now be evaluated in prospective randomized trials.

Clinical features, treatment and outcome in a series of 93 patients with low-grade gastric MALT lymphoma.

The purpose of this paper is to report the clinical characteristics and treatment outcome following different therapeutic approaches in a large series of patients with primary low-grade MALT lymphoma of the stomach. A total of ninety-three patients (median age 63 years) were reviewed. The patients were treated by different modalities (local treatment alone, combined treatment, chemotherapy, antibiotics alone); seven patients refused any treatment. The antibiotic-treated group of patients was prospectively followed with regular endoscopic biopsies, and their responses were histologically evaluated. The 5-years projected overall survival is 82% (95% C.I.; 67%-91%) in the series as a whole. Second tumors were observed in 21.5% of the patients in this series (95% CI 14%v to 31%). There was no apparent difference in overall survival and event-free survival between patients who received different treatments. In the antibiotic-treated group histologic regression of MALT lymphoma was documented in 67% of patients (95% CI 51% to 80%). In conclusion the indolent nature of the disease justifies a conservative approach. The use of antibiotics as first-line therapy may avert or at least postpone the indication for surgical resection in the majority of patients.

Primary extranodal lymphoma of skeletal muscles: a report of four cases.

Approximately one-fourth of non-Hodgkin's lymphomas originate in extranodal sites. True primary involvement of soft tissues is quite uncommon and only a few well-documented cases are reported in the literature. We report four cases of primary skeletal muscle lymphoma. Three of the four cases presented with a diffuse large B-cell lymphoma. The clinical history of two cases confirmed that soft tissue masses should be promptly biopsied, since the differential diagnosis comprises benign lesions, as well as sarcoma, primary or metastatic carcinoma, melanoma and lymphoma. As lymphomas have to be treated primarily according to the tumour histology and disease extent, treatment of primary skeletal muscle lymphomas must be planned with these factors in mind. For patients presenting with diffuse large cell histology, a CHOP-like regimen alone or a combined modality with radiotherapy seem to be proper approaches.

Molecular detection of circulating neoplastic cells in patients with clinically localised gastric and non-gastric mucosa-associated lymphoid tissue lymphoma.

BACKGROUND: Unlike other low-grade lymphomas, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type usually presents with localised disease. AIM: To detect peripheral blood lymphoma involvement to establish the incidence of occult lymphoma dissemination. PATIENTS AND METHODS: In a series of 18 cases, peripheral blood was analysed by polymerase chain reaction, with primers directed to the third-complementarity determining region of the immunoglobulin heavy chain gene. RESULTS AND CONCLUSION: The presence of circulating neoplastic cells was detected in 21% of clinically localised cases. Moreover lymphoma cells were detected in 2 out of 6 morphologically normal bone marrow specimens. The present data show that, combining morphological and molecular methods, occult dissemination can be found in a large proportion of cases thus stressing the need for careful staging procedures. However, it has still to be clarified whether the presence of polymerase chain reaction-detectable circulating lymphoma cells can influence the outcome of mucosa-associated lymphoid tissue lymphoma patients submitted to antibiotic treatment (for gastric localisation) or local therapy (surgery or radiation, for non-gastric tumours).

Lovastatin inhibits tumor growth and metastasis development of a rat fibrosarcoma.

HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, the rate limiting enzyme in cholesterol synthesis, catalyses mevalonate production and, hence, influence the synthesis of isoprenoid metabolites. It has already been demonstrated that products of the mevalonate pathway play an important role in the progress of the cell cycle and cell survival. Lovastatin (LOV) competitively inhibits HMG-CoA reductase, blocking the synthesis of mevalonic acid and the generation of non-sterol isoprenoids, such as farnesyl residues. The posttranslational farnesylation of p21ras protein is essential for its binding to the membrane and, therefore, for its transforming activity. Considering that p21ras protein was reported to have a significant rol in metastatic behavior of tumor cells, we decided to study LOV as an antimetastatic agent on a rat fibrosarcoma. We demonstrated that a short treatment with LOV diminished primary tumor growth and the number and size of lung experimental metastasis.

Angiotropic (intravascular) large cell lymphoma: case report and short discussion of the literature.

We report a case of angiotropic (intravascular) large B-cell lymphoma in an 84-year-old woman who underwent diagnostic procedures for progressive, painful induration of the legs. Physical examination and imaging studies revealed only widespread telangiectasias and significant panniculities-like lymphedema of the legs, with no masses or lymphadenopathies. The patient achieved a complete clinical remission after the first three cycles of polychemotherapy. Although angiotropic lymphoma is a rare entity with polymorphic clinical presentations, its early diagnosis appears very important since it may be curable with appropriate chemotherapy regimens.

[Characterization of experimental infection with Mycobacterium lepraemurium in 2 strains of mice]. / Caracterización de la infección experimental con Mycobacterium lepraemurium en dos cepas de ratones.

A model of experimental leprosy in two strains of mice, namely CBA/J and CBi, has been developed based on: 1) the histological examination of a granuloma in the hind foot pad 200 days after inoculation of 0.30 microliter of Mycobacterium lepraemurium (6 x 10(8) MLm/ml); 2) the assessment of T lymphocytes in the granuloma identified by the alpha-naphthyl acetate method for esterase, and c) dissemination of the infection. The histological findings in the low resistance CBA/J strain included positive acid fast bacilli vacuolated cells, without lymphocytic infiltration, scarce number of T lymphocytes and a generalized and important dissemination, similarly to the one observed in human lepromatous leprosy. The histological findings in the hind foot pad granuloma of 30-40 per cent of the medium to high resistance CBi strain, consisted of vacuolated cells and lymphocytic infiltration, a large number of T cells and a scarce dissemination, similar to the human borderline leprosy. Both strains present a different susceptibility to a unique challenge with the mycobacterium which could be useful to disentangle the immunogenetic components involved, by means of appropriate selection and crosses. Furthermore, it could be of interest to perform immunoprotection assays in CBi mice, which might have some bearing on the development of a vaccine in human leprosy.

The SRA protein UHRF1 promotes epigenetic crosstalks and is involved in prostate cancer progression.

Epigenetic silencing of tumour suppressor genes is an important mechanism involved in cell transformation and tumour progression. The Set and RING-finger-associated domain-containing protein UHRF1 might be an important link between different epigenetic pathways. Here, we report that UHRF1 is frequently overexpressed in human prostate tumours and has an important role in prostate cancer pathogenesis and progression. Analysis of human prostate cancer samples by microarrays and immunohistochemistry showed increased expression of UHRF1 in about half of the cases. Moreover, UHRF1 expression was associated with reduced overall survival after prostatectomy in patients with organ-confined prostate tumours (P < 0.0001). UHRF1 expression was negatively correlated with several tumour suppressor genes and positively with the histone methyltransferase (HMT) EZH2 both in prostate tumours and cell lines. UHRF1 knockdown reduced proliferation, clonogenic capability and anchorage-independent growth of prostate cancer cells. Depletion of UHRF1 resulted in reactivation of several tumour suppressor genes. Gene reactivation upon UHRF1 depletion was associated with changes in histone H3K9 methylation, acetylation and DNA methylation, and impaired binding of the H3K9 HMT Suv39H1 to the promoter of silenced genes. Co-immunoprecipitation experiments showed direct interaction between UHRF1 and Suv39H1. Our data support the notion that UHRF1, along with Suv39H1 and DNA methyltransferases, contributes to epigenetic gene silencing in prostate tumours. This could represent a parallel and convergent pathway to the H3K27 methylation catalyzed by EZH2 to synergistically promote inactivation of tumour suppressor genes. Deregulated expression of UHRF1 is involved in the prostate cancer pathogenesis and might represent a useful marker to distinguish indolent cancer from those at high risk of lethal progression.