Transdermal oestradiol for androgen suppression in prostate cancer: long-term cardiovascular outcomes from the randomised Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme.

BACKGROUND: Androgen suppression is a central component of prostate cancer management but causes substantial long-term toxicity. Transdermal administration of oestradiol (tE2) circumvents first-pass hepatic metabolism and, therefore, should avoid the cardiovascular toxicity seen with oral oestrogen and the oestrogen-depletion effects seen with luteinising hormone releasing hormone agonists (LHRHa). We present long-term cardiovascular follow-up data from the Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme. METHODS: PATCH is a seamless phase 2/3, randomised, multicentre trial programme at 52 study sites in the UK. Men with locally advanced or metastatic prostate cancer were randomly allocated (1:2 from August, 2007 then 1:1 from February, 2011) to either LHRHa according to local practice or tE2 patches (four 100 µg patches per 24 h, changed twice weekly, reducing to three patches twice weekly if castrate at 4 weeks [defined as testosterone ≤1·7 nmol/L]). Randomisation was done using a computer-based minimisation algorithm and was stratified by several factors, including disease stage, age, smoking status, and family history of cardiac disease. The primary outcome of this analysis was cardiovascular morbidity and mortality. Cardiovascular events, including heart failure, acute coronary syndrome, thromboembolic stroke, and other thromboembolic events, were confirmed using predefined criteria and source data. Sudden or unexpected deaths were attributed to a cardiovascular category if a confirmatory post-mortem report was available and as other relevant events if no post-mortem report was available. PATCH is registered with the ISRCTN registry, ISRCTN70406718; the study is ongoing and adaptive. FINDINGS: Between Aug 14, 2007, and July 30, 2019, 1694 men were randomly allocated either LHRHa (n=790) or tE2 patches (n=904). Overall, median follow-up was 3·9 (IQR 2·4-7·0) years. Respective castration rates at 1 month and 3 months were 65% and 93% among patients assigned LHRHa and 83% and 93% among those allocated tE2. 157 events from 145 men met predefined cardiovascular criteria, with a further ten sudden deaths with no post-mortem report (total 167 events in 153 men). 26 (2%) of 1694 patients had fatal cardiovascular events, 15 (2%) of 790 assigned LHRHa and 11 (1%) of 904 allocated tE2. The time to first cardiovascular event did not differ between treatments (hazard ratio 1·11, 95% CI 0·80-1·53; p=0·54 [including sudden deaths without post-mortem report]; 1·20, 0·86-1·68; p=0·29 [confirmed group only]). 30 (34%) of 89 cardiovascular events in patients assigned tE2 occurred more than 3 months after tE2 was stopped or changed to LHRHa. The most frequent adverse events were gynaecomastia (all grades), with 279 (38%) events in 730 patients who received LHRHa versus 690 (86%) in 807 patients who received tE2 (p<0·0001) and hot flushes (all grades) in 628 (86%) of those who received LHRHa versus 280 (35%) who received tE2 (p<0·0001). INTERPRETATION: Long-term data comparing tE2 patches with LHRHa show no evidence of a difference between treatments in cardiovascular mortality or morbidity. Oestrogens administered transdermally should be reconsidered for androgen suppression in the management of prostate cancer. FUNDING: Cancer Research UK, and Medical Research Council Clinical Trials Unit at University College London.

[Decolonization of Health Care Workers In a Neonatal Intensive Care Unit Carrying a Methicillin-Susceptible Staphylococcus aureus Isolate]. / Dekolonisation bei Nachweis von Methicillin-sensiblen Staphylococcus aureus bei Mitarbeitern einer neonatologischen Intensivstation.

BACKGROUND: In 2016, an increased rate of methicillin-susceptible Staphylococcus aureus colonization was detected on a neonatal intensive care unit at the Leipzig University Hospital. Typing results showed a predominant spa-type t091. Considering nosocomial clustering, several infection prevention measures (e. g. intensified standard precautions, single-occupancy room, cohorted patients, continuing education of staff) were introduced, including staff screening followed by decolonization of colonized health care workers. METHODS: Staff members showing positive on screening carried out a 5-day decolonization program at home. Decolonization products containing octenidine as active ingredient were used first. At the earliest, 48 h after completing the procedure, the success of the intervention was tested (3 buccal and nasal swabs were taken on consecutive days). If 2 attempts at decolonization were not successful, staff members were provided with a mupirocin-containing nasal ointment instead of octenidine. RESULTS: Of 128 employees examined, 43 (33.6%) were identified as carriers of S. aureus. In 9 cases (20.9%; 9/43) the S. aureus matched with type t091. 2 carriers (4.7%; 2/43) of MRSA were detected as well. The first decolonization attempt against t091 and MRSA failed altogether. After a second decolonization, 3 cases became negative. Finally, 8 remaining staff members were decolonized successfully with mupirocin containing nasal ointment. CONCLUSIONS: Various reasons might explain the difficulties of decolonization such as the challenge of managing decolonization at home, inhibitory factors as well as inconsistent performance of decolonization measures. Additionally, differences between the preparations for the nasal decontamination may be considered.

Health-related quality of life in haemodialysis patients suffering from chronic itch: results from GEHIS (German Epidemiology Haemodialysis Itch Study).

PURPOSE: Chronic itch (CI) is a common symptom in haemodialysis (HD) patients affecting about every 4th HD patient. Though it is known that health-related quality of life (HRQOL) is impaired in HD patients, data are lacking on how CI influences HRQOL in this group of patients, also regarding sex differences and the role of sleep and pain. METHODS: In order to investigate the itch prevalence and to investigate associated factors, GEHIS (German Epidemiology Haemodialysis Itch Study) was established as first cross-sectional study being representative for all dialysis units in Germany by considering their regional distribution and size of the located city according to population. HRQOL of 860 HD patients from a randomly selected cluster sample of 25 dialysis units was investigated using patient-reported outcomes as the Short-Form Health Survey (SF-12), the Hospital Anxiety and Depression Scale (HADS) as well as sleep and pain. Additionally, itch-specific QOL was assessed in HD patients affected by CI using the validated ItchyQoL. RESULTS: 42.8 % of HD patients were female. The mean age was 67.2 years (SD ± 13.5). Female patients showed significantly worse values in the mental component summary of the SF-12 as well as in the HADS subscale anxiety compared to male patients. Itch-specific HRQOL did not subject to sex. Patients with impairments in quality of sleep showed significantly worse values in both the SF-12 and the HADS subscales, however not in the ItchyQoL. The occurrence of pain was significantly associated with impaired SF-12, HADS and the ItchyQoL. Multivariate linear regression showed the itch-specific HRQOL to be significantly impaired with rising severity of CI. CONCLUSIONS: Impairments in HRQOL are a serious problem in HD patients. CI means an additional burden in affected patients, also impairing their HRQOL. GEHIS showed significant sex differences in HRQOL outcomes also in HD patients. CI and pain as well as sleep frequently occur combined and significantly impair HRQOL in HD patients. The care of HD patients should be complemented by psychosocial support and mental health services.

Clinical Findings and Provision of Care in Haemodialysis Patients with Chronic Itch: New Results from the German Epidemiological Haemodialysis Itch Study.

The German Epidemiological Haemodialysis Itch Study (GEHIS) has shown that more than one-third of haemodialysis (HD) patients have chronic itch (CI). As part of GEHIS, 216 patients with current CI were offered a dermatological examination, of whom 177 were investigated. According to the clinical classification of the International Forum for the Study of Itch (IFSI), 43.5% (n = 77) of the patients examined had CI with no skin lesions (IFSI II), 37.9% (n = 67) had secondary scratch lesions (IFSI III), and 18.6% (n = 33) primarily had diseased skin (IFSI I). Severity of CI and itch-related quality of life (ItchyQoL) showed a significant association only with IFSI III. Of the patients in this study, 89.8% (n = 159) had xerosis cutis. Only 40.4% (n = 80) had ever sought medical help for CI, 46.4% (n = 32) of whom were in the category IFSI III. Only 32.4% (n = 77) had ever received any treatment for CI and [AQ1] these patients had significantly more severe CI. The current analyses demonstrate that CI is a frequently disregarded symptom in HD patients.

Paraneoplastic itch: an expert position statement from the Special Interest Group (SIG) of the International Forum on the Study of Itch (IFSI).

In clinical practice, the term "paraneoplastic itch" is used to describe itch in patients with cancer. Patients with hematological or solid tumor malignancies can be affected. In general, paraneoplastic itch is considered a rare disorder. However, paraneoplastic itch in hematological malignancies such as polycythemia vera and lymphoma are relatively frequent while other forms of paraneoplastic itch are in fact extremely rare. The true frequency of this symptom is unclear, epidemiological data in this field are limited. Itch in malignant disease may additionally impair patients' quality of life. A population-based cohort study showed that chronic itch without concomitant skin changes is a risk factor for having undiagnosed hematologic and bile duct malignancies. Paraneoplastic itch is rather resistant to treatment. In 2012, an interdisciplinary interest group of physicians and researchers was founded, aiming to generate a clear definition of paraneoplastic itch. In this paper we briefly review the current knowledge and aim to define what can be summarized under the term "paraneoplastic itch".

Prevalence of chronic itch and associated factors in haemodialysis patients: a representative cross-sectional study.

Chronic itch is a common symptom in haemodialysis (HD) patients, which is often underestimated. The aim of this cross-sectional study was to investigate the prevalence and factors associated with chronic itch in HD patients. A total of 860 HD patients from a randomly selected cluster-sample of patients attending dialysis units in Germany were included. The patients' mean?±?SD age was 67.2?±?13.5 years, 57.2% were male. The point prevalence of chronic itch was 25.2% (95% CI 22.4-28.1), 12-month prevalence was 27.2% (95% CI 24.1-30.3) and lifetime prevalence was 35.2% (95% CI 31.9-38.3). Chronic itch was significantly less prevalent in patients with secondary glomerulonephritis as primary renal disease. A history of dry skin, eczema, and age

Laboratory and dialysis characteristics in hemodialysis patients suffering from chronic itch--results from a representative cross-sectional study.

BACKGROUND: A representative cross-sectional study showed that chronic itch (lasting for a minimum of 6 weeks) affects 25.2 % (point prevalence) of hemodialysis (HD) patients. Pathophysiology and etiology of chronic itch (CI) in HD are still unclear. METHODS: We investigated 860 HD patients from a representative randomly selected cluster-sample considering the regional distributions of dialysis units in Germany. The current analyses report comorbidities, laboratory values and dialysis characteristics of HD patients in relation to CI. RESULTS: Diabetes was the only comorbidity that was associated with the occurrence of itch but interestingly with less CI. Except for creatinine, phosphorus, and parathormone, there were no significant associations between the occurrence and characteristics of CI and any laboratory value. Kt/V was not associated with the presence of CI. Patients dialyzed with polyarylethersulfone-membrane showed significantly more CI in all prevalence estimates and those dialyzed with polysulfone-membrane were significantly less affected by CI. CONCLUSIONS: Long-term follow-up studies will show if the type of dialysis membrane influences the development of CI in HD patients. It is most likely that several factors e.g. elevated parathormone, origin of end stage renal disease (ESRD), type of dialysis membrane, and a neuropathic component all contribute to the occurrence of CI in HD patients. Future research should consider a multifactorial origin of itch in HD.

Role of lncRNAs in prostate cancer development and progression.

Prostate cancer (PCa) is the second most common cause of cancer-related deaths in men. Despite advances in the characterization of genomic and epigenetic aberrations contributing to PCa, the etiology of PCa is still far from being understood. Research over the past decade demonstrated the role of long non-coding RNAs (lncRNAs) in deregulation of target genes mainly through epigenetic mechanisms. In PCa, evidence accumulated that hundreds of lncRNAs are dysregulated. Functional analyses revealed their contribution to prostate carcinogenesis by targeting relevant pathways and gene regulation mechanisms including PTEN/AKT and androgen receptor signaling as well as chromatin remodeling complexes. Here we summarize our current knowledge on the roles of lncRNAs in PCa and their potential use as biomarkers for aggressive PCa and as novel therapeutic targets.

Characteristics and provision of care in patients with chronic hand eczema: updated data from the CARPE registry.

The aim of the CARPE registry is to investigate characteristics and medical care in patients affected by chronic hand eczema. Patients are assessed by dermatological examination and patient questionnaire. Socio-economic and clinical data are collected, and quality of life is measured using the Dermatology Life Quality Index (DLQI). A total of 1,163 patients with chronic hand eczema were eligible for analysis (mean age 47.0 years; 54.6% female; mean disease duration 7.6 years). At inclusion, chronic hand eczema was very severe in 23.4%, severe in 47.0%, moderate in 20.1%, and clear or almost clear in 9.6% of patients. Median DLQI was 8.0. In all, 93.8% of patients reported use of topical corticosteroids, 25.6% systemic antihistamines, 28.3% topical calcineurin-inhibitors, 38.0% ultraviolet phototherapy, and 35.3% systemic treatment (19.7% alitretinoin) prior to inclusion in the registry. A significant proportion of patients may not receive adequate treatment according to the guideline on management of hand eczema.

Body dissatisfaction in female adolescents: extent and correlates.

This study aimed to assess the extent, patterns, and predictors of feelings of body dissatisfaction experienced by female German adolescents. Using 3D-avatar software, a sample population of 144 girls between 14 and 17 years of age was asked to estimate their actual body image, their desired body image (individual ideal), and the body image they believed their parents and their best female friend considered to be the ideal body image for them. The participants estimated their actual body mass index (BMI) to be 18.82 ± 3.01. The individual ideal body shape reported was significantly thinner, with a BMI score of 16.84 ± 2.51. Given a girl who stands 1.65 m and weighs 55 kg, this corresponds to a difference in weight of about 5.5 kg. After adjustment for the participant's self-reported BMI, participating in an esthetic sport was correlated with a significantly lower body dissatisfaction. Conversely, low socio-economic status and the amount of time spent watching TV was correlated with a significantly higher body dissatisfaction. Negative body image-related comments made by parents were significantly associated with body dissatisfaction. The girls who participated in this study would like to be an average of 1.97 BMI units thinner. The findings presented here suggest that future intervention measures should focus on the risk groups of physically inactive girls, those who smoke, and those with a lower social status and high rates of TV consumption. Intervention measures would be especially effective in German schools which offer lower education levels and should include the pupils' parents, who should be informed about the negative effects weight- and diet-related comments have on their children's body images.

"The itching hand"- important differential diagnoses and treatment.

Skin diseases affecting the hands receive particular individual attention and constitute a considerable emotional burden. Many dermatoses also present with itching of the hands. Itch is often underestimated when it occurs in a comparably limited body area such as the hands. The high occupational significance of the hands in many professions must, nevertheless, be stressed. One of the most frequent diagnoses in itching of the hands is eczema. In the differential diagnosis, less common diseases such as neurological and systemic diseases and adverse drug reactions must also be taken into consideration. Itching of the hands can also be accompanied by other sensations, such as burning, stinging and pain. A thorough history regarding sensations and dysesthesias already allows for a diagnostic classification of the disease in some cases. Itching of the hands requires a careful and thorough diagnostic approach. This forms the basis of a specific and successful therapy which may be adapted stepwise, depending on the underlying cause, and also may require, in addition to causal therapy, symptomatic antipruritic therapy. Therapy should follow the current guidelines for chronic pruritus and hand eczema. This article reviews over the differential diagnosis and therapy of "itching hands".

SARS-CoV-2 Vaccine Breakthrough Infections of Omicron and Delta Variants in Healthcare Workers.

Understanding SARS-CoV-2 breakthrough infections in vaccinated healthcare workers is of key importance in mitigating the effects of the COVID-19 pandemic in healthcare facilities. An observational prospective cohort study was conducted in vaccinated employees with acute SARS-CoV-2 infection between October 2021 and February 2022. Serological and molecular testing was performed to determine SARS-CoV-2 viral load, lineage, antibody levels, and neutralizing antibody titers. A total of 571 (9.7%) employees experienced SARS-CoV-2 breakthrough infections during the enrolment period, of which 81 were included. The majority (n = 79, 97.5%) were symptomatic and most (n = 75, 92.6%) showed Ct values < 30 in RT-PCR assays. Twenty-four (30%) remained PCR-positive for > 15 days. Neutralizing antibody titers were strongest for the wildtype, intermediate for Delta, and lowest for Omicron variants. Omicron infections occurred at higher anti-RBD-IgG serum levels (p = 0.00001) and showed a trend for higher viral loads (p = 0.14, median Ct difference 4.3, 95% CI [-2.5-10.5]). For both variants, viral loads were significantly higher in participants with lower anti-RBD-IgG serum levels (p = 0.02). In conclusion, while the clinical course of infection with both the Omicron and Delta variants was predominantly mild to moderate in our study population, waning immune response over time and prolonged viral shedding were observed.

Patients' views on asthma-specific quality of life questionnaires: qualitative interview study in Germany.

OBJECTIVE: It is unclear which of the commonly used asthma-specific quality of life (QoL) questionnaires best capture the lived experience of people with asthma. The objective of this study was to explore patients' views on three asthma-specific QoL questionnaires. METHODS: Ten adult individuals with asthma were asked to complete three asthma-specific QoL questionnaires (Standardized Juniper Asthma Quality of Life Questionnaire (AQLQ-J-s), Sydney Asthma Quality of Life Questionnaire (AQLQ-S), and Fragebogen zur Lebensqualität bei Asthma (FLA)). Interviews were conducted to elicit patients' views on the questionnaires. Interviews were transcribed verbatim and thematic content analysis was performed. RESULTS: Participants spoke about response format and options, missing and redundant/similar content as well as content that was perceived to be irrelevant. A lack of specificity was named for some items, and issues concerning layout were raised. Despite the diversity of views expressed, participants mostly agreed on the ranking of the questionnaires and, overall, favored the AQLQ-S. CONCLUSIONS: Patient involvement highlights shortcomings and strengths of various asthma-specific questionnaires in terms of both format and content. The AQLQ-S was the most positively perceived questionnaire. Future research will need to explore other settings and potentially involve a larger and more diverse sample.

The impact of COVID-19 on liver transplantation programs in Austria.

BACKGROUND: Coronavirus disease of 2019 (COVID-19) has affected liver disease management. The impact of the COVID-19 pandemic on the Austrian orthotopic liver transplantation (OLT) programs, however, has not been systematically investigated. METHODS: All patients listed for OLT in Austria during 2020-2021 were studied. Data on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing, vaccinations, infections, mortality and the overall number of OLTs (vs. pre-COVID-19: 2015-2019) were analyzed. RESULTS: Overall, 490 patients (median age: 58.0 years, 70.4% men, hepatocellular carcinoma: 27.3%) were listed for OLT in Austria in 2020-2021. Alcohol-related cirrhosis (35.3%), cholestatic (16.7%) and viral liver disease (13.9%) were the main etiologies. Of the patients 61.2% underwent OLT and 8.8% died while on the waiting list. The number of OLTs performed during COVID-19 (2020: n = 150; 2021: n = 150) remained unchanged compared to pre-COVID-19 (median: n = 152). Among waiting list patients, 7.7% (n = 31/401) were diagnosed with COVID-19 and 7 (22.6%) of these patients died. By the end of 2021, 45.1% (n = 176/390; 82.8% mRNA vaccinations) and 28.8% (105/365) of patients received 2 and 3 SARS-CoV­2 vaccinations, respectively. After two SARS-CoV­2 vaccinations, antibodies more often remained undetectable in patients vaccinated post-OLT (25.6% vs. 6.5% in patients vaccinated pre-OLT; p = 0.034). Patients with three vaccinations after OLT had lower antibody titers than patients vaccinated pre-OLT (post-OLT: 513.5, IQR 44.4-2500.0 vs. pre-OLT: 2500.0, IQR 1462.0-2500.0 BAU/mL; p = 0.020). CONCLUSION: The number of OLTs in Austria remained unchanged during COVID-19. SARS-CoV­2 infections were rare but associated with high mortality in patients on the Austrian OLT waiting lists. SARS-CoV­2 vaccination rates at the end of 2021 were suboptimal, while serological response was better in patients vaccinated pre-OLT vs. post-OLT.

Intensive structured education for type 1 diabetes management using BERTIE: Long-term follow-up to assess impact on glycaemic control and quality of life indices.

AIMS: Bournemouth Type 1 Intensive Education (BERTIE) is a structured education course delivered 1 day a week for 4 weeks for self-management of type 1 diabetes. BERTIE outcomes were analysed to assess long-term effectiveness: primary outcome assessed impact of BERTIE on glycaemic control, secondary outcomes assessed impact on Problem Area in Diabetes (PAID) scale, severe hypoglycaemia and diabetic ketoacidosis incidence (DKA). METHODS: Prospectively collected outcome data from attendees included glycated haemoglobin (HbA1c), PAID, severe hypoglycaemia and DKA incidence recorded pre-course, 6 months and 1 year post-attendance, with HbA1c assessed annually at subsequent clinic visits. RESULTS: Between 1999 and 2015, 524 people attended BERTIE with 5 year follow-up in 316 (60.3%) attendees. HbA1c was reduced from 74 ±â€¯17 mmol/mol (8.9 ±â€¯1.6%) at baseline to 71 ±â€¯15 mmol/mol (8.6 ±â€¯1.4%) at 1 year and 70 ±â€¯15 mmol/mol (8.6 ±â€¯1.3%) at 5 years (p < 0.0001); severe hypoglycaemia incidence reduced from 0.8 ±â€¯2.1 to 0.4 ±â€¯2.2 episodes/person/year at 1 year (p < 0.0001); PAID scale reduced from 23 ±â€¯16 to 15 ±â€¯12 (p < 0.0001) at 1 year; DKA incidence was 0.06 ±â€¯0.34 episodes/person/year pre-course and 0.03 ±â€¯0.21 at 1 year (p = 0.5271). CONCLUSIONS: BERTIE outcome data demonstrate favorable biochemical and psychological outcomes supporting recommendations that structured education be provided to adults with type 1 diabetes.

BAZ2A (TIP5) is involved in epigenetic alterations in prostate cancer and its overexpression predicts disease recurrence.

Prostate cancer is driven by a combination of genetic and/or epigenetic alterations. Epigenetic alterations are frequently observed in all human cancers, yet how aberrant epigenetic signatures are established is poorly understood. Here we show that the gene encoding BAZ2A (TIP5), a factor previously implicated in epigenetic rRNA gene silencing, is overexpressed in prostate cancer and is paradoxically involved in maintaining prostate cancer cell growth, a feature specific to cancer cells. BAZ2A regulates numerous protein-coding genes and directly interacts with EZH2 to maintain epigenetic silencing at genes repressed in metastasis. BAZ2A overexpression is tightly associated with a molecular subtype displaying a CpG island methylator phenotype (CIMP). Finally, high BAZ2A levels serve as an independent predictor of biochemical recurrence in a cohort of 7,682 individuals with prostate cancer. This work identifies a new aberrant role for the epigenetic regulator BAZ2A, which can also serve as a useful marker for metastatic potential in prostate cancer.

Hematopoietic cell renewal as the limiting factor in low-level radiation exposure: diagnostic implications and therapeutic options.

In some radiation accidents, exposure doses are delivered over days or even months. In all cases the organ system most relevant to a patient's survival is the hematopoietic tissue. There appears to be a threshold of approximately 10 mSv per day above which hematopoietic effects become apparent and hematopoietic failure may occur. Experimental observations in dogs demonstrate that exposure to chronic gamma-irradiation may be tolerated for over a year if the daily dose does not exceed 7 mSv to 18 mSv. The pathophysiological mechanisms are being studied by hematological measures and biomathematical models. The results are in accordance with the assumption of excess cell loss and progressive diminution of the stem cell pool over time until a "turbulence region," with an increased probability of system failure, is approached. Diagnostic procedures require a thorough hematological assessment that includes the stem cell compartment. Therapeutic options include administration of hematopoietic growth factors and stem cell transplantation.

A DNA methyltransferase modulator inspired by peyssonenyne natural product structures.

A novel epigenetic modulator that displays a DNMT1 inhibition and DNMT3A activation profile was characterized (compound 8). This compound is a derivative of palmitic acid that incorporates the putative reactive functional group (diynone) of the peyssonenyne natural products. Other analogues containing the diynone or an acetoxyenediyne did not show the same biological profile. In U937 human leukemia cells, diynone 8 induced cell differentiation and apoptosis, which correlated with the expression of Fas protein. Very surprisingly, diynone 8 was toxic to normal human fibroblasts (BJ) and mouse embryo fibroblasts (MEF), but not to immortalized human fibroblasts (BJEL); this unique effect was not observed with the classical DNMT inhibitor 5-azacytidine. Therefore, compound 8 interferes in a very specific manner with signaling pathways, the activities of which differ between normal and immortalized cell types. This toxicity is reminiscent of the effects of Dnmt1 ablation on mouse fibroblasts. In fact, some of the genes deregulated by the loss of Dnmt1 are similarly deregulated by 8, but not by the DNMT inhibitor SGI-1027.