Cytokine profile and viral diversity in the early seronegative stage of community-acquired hepatitis C virus (HCV) infection.

Most Hepatitis C virus (HCV)-infected subjects develop chronic infection, whereas a minority clear the virus in the early phase of infection. We analyzed factors associated with outcome (chronicity vs clearance) during the preclinical seronegative phase of community-acquired HCV infection. Among 17.5 million blood donations in the years 2000-2016, 124 blood donors were found to be HCV RNA-positive/anti-HCV-negative. All were contacted after 0.5-12.7 years and 40 responded and provided blood sample. Hypervariable region 1 was analyzed by ultradeep pyrosequencing and cytokines in serum were quantified by Luminex (R&D Systems) multiplex immunoassay. Twenty-one (52.5%) donors were found to be HCV-RNA-positive, while 19 (47.5%) were HCV RNA negative (none received antiviral treatment). All but one seroconverted to anti-HCV. Donors with resolving hepatitis did not differ significantly from donors with chronic infection with respect to age, genotypes, IL28B polymorphisms, number of viral variants, nucleotide diversity per site or the overall number of nucleotide substitutions. However, the former group had significantly higher levels of IL-1beta, IL-1RA, IL-6, IFN-gamma and FGF-2 in serum. In our study of community-acquired acute hepatitis C approximately half of all subjects eliminated the virus spontaneously, and this clearance was associated with marked cytokine response in the early seronegative stage of infection.

Depression and Cognitive Dysfunction in Patients with Chronic Hepatitis C: Correlation with Viral Replication in the Peripheral Blood Mononuclear Cells and Cytokines in Serum.

Chronic hepatitis C virus (HCV) infection is commonly associated with depression and cognitive dysfunction, the cause of which could be related to the HCV neuroinvasion and/or state of chronic inflammation. Viral sequences and proteins were previously detected in the brain and since blood leukocytes can cross the blood-brain barrier, they could provide viral access to the CNS. Eighty chronic hepatitis C patients were tested for viral replication in PBMCs (detection of the HCV RNA-negative strand) and serum cytokines. Depression was assessed by the Beck Depression Inventory (BDI), neuroticism by the Eysenck Personality Inventory (N/EPO-R), and anxiety by the State-Trait Anxiety Inventory (STAI) while neurocognitive testing included the Wisconsin Card Sorting Test (WCST), Ruff Figural Fluency Test (RFFT), California Verbal Learning Test (CVLT), and Grooved Pegboard Test (GPT). The HCV RNA-negative strand was detected in PBMCs from 24 (30%) patients and these patients had significantly higher BDI scores (median 12.5 [IQR] 6.3-20.5 vs. median 8.00 [IQR] 3-12; p = 0.013). Both depression and anxiety correlated positively with IL-8 while cognitive flexibility, executive function, problem-solving skills, memory, and motor functioning correlated negatively with some proinflammatory cytokines. Our findings suggest that due to chronic HCV infection, the brain function is negatively affected by both viral replication in PBMCs and by the immune activation state.

Military Blood Service in Poland.

Introduction: On 24 February 2022, the Russia-Ukraine military conflict unfolded just across the eastern border of the European Union. It made everyone realize how important it is to secure blood supplies to health-care units in the event of an armed conflict. This paper presents the principles of functioning of the Military Blood Donation Service and the Military Center for Blood Donation and Hemotherapy in Poland. Methods: The study used data collected in the "Military Blood Bank" information processing system and data from annual reports (2010-2021) sent to the Minister of Health of the Republic of Poland. The reports concerned, among others: demographic data on donors, reasons of permanent disqualifications, numbers of complete and incomplete donations, etc. Results: Since 2005, the number of donors registered in military blood donation centers ranged between 15 and 35 thousand/year. The most dramatic declines in donors were observed in 2010 and 2020. Successful donations accounted for more than 98% of all donations/year (except 2015), and their number varied between 20 and 32 thousand/year. Among the blood donors, men always predominated and the dominant age group (except for 2010) was 25-44 years. The reasons for permanent disqualification have varied over time: their proportions decreased for viral hepatitis and cardiovascular disease, and increased for respiratory and endocrine/metabolic diseases. Due to the COVID-19 pandemic in 2020/2021, these proportions have sometimes been reversed. Discussion: The Military Blood Donation Service has been functioning in Poland for several decades. It is specialized in supplying blood and blood products to the Armed Forces. Unfortunately, it was not possible to refer to the functioning of similar institutions in other countries. Therefore, when evaluating the functioning of Polish military blood donation, we had to rely on numerical values (eg, number of donors/year, donor profile, etc.), which prove a very good organization of blood donation centers. However, it should be noted that, as in other countries, a more active promotion of blood donation in the media is advisable in order to encourage as many young people as possible to donate blood.

Higher platelet counts correlate to tumour progression and can be induced by intratumoural stroma in non-metastatic breast carcinomas.

BACKGROUND: Platelets support tumour progression. However, their prognostic significance and relation to circulating tumour cells (CTCs) in operable breast cancer (BrCa) are still scarcely known and, thus, merit further investigation. METHODS: Preoperative platelet counts (PCs) were compared with clinical data, CTCs, 65 serum cytokines and 770 immune-related transcripts obtained using the NanoString technology. RESULTS: High normal PC (hPC; defined by the 75th centile cut-off) correlated with an increased number of lymph node metastases and mesenchymal CTCs in the 70 operable BrCa patients. Patients with hPC and CTC presence revealed the shortest overall survival compared to those with no CTC/any PC or even CTC/normal PC. Adverse prognostic impact of hPC was observed only in the luminal subtype, when 247 BrCa patients were analysed. hPC correlated with high content of intratumoural stroma, specifically its phenotype related to CD8+ T and resting mast cells, and an increased concentration of cytokines related to platelet activation or even production in bone marrow (i.e. APRIL, ENA78/CXCL5, HGF, IL16, IL17a, MDC/CCL22, MCP3, MMP1 and SCF). CONCLUSIONS: Preoperative platelets evaluated alone and in combination with CTCs have prognostic potential in non-metastatic BrCa and define patients at the highest risk of disease progression, putatively benefiting from anti-platelet therapy.

Loneliness and mental health among the elderly in Poland during the COVID-19 pandemic.

BACKGROUND: The unexpected changes caused by the COVID-19 pandemic related to the fear of developing the disease, and the need for social distancing and isolation have had an effect on people's mental health. These drastic changes can result in the development of anxiety, depressive symptoms and sense of loneliness. Elderly and chronically ill individuals are at a particularly high risk of developing COVID-19, suffering severe illness and dying as a result of it. AIM OF THE STUDY: The aim of the study was to assess the prevalence of anxiety, depressive symptoms, irritability and loneliness in the elderly aged 60 years and older as a group exposed to the negative impact of the COVID-19 pandemic, and to analyze the relationships between loneliness and mental health of the respondents and sociodemographic variables and chronic diseases. MATERIALS AND METHODS: The study was conducted in Poland among 221 individuals aged 60+. The study material was collected using a sociodemographic questionnaire, Hospital Anxiety and Depression Scale (HADS-M) and a revised University of California Los Angeles loneliness scale (R-UCLA). Women accounted for 47.51% and men for 52.49% of study participants; the mean age was 65.18 (SD = 4.06). RESULTS: In total, according to HADS-M, depressive symptoms were present in 19.15% of the participants and borderline states in 14.18% of them. Based on R-UCLA, moderate and moderately high sense of loneliness was present in 58.83% of the participants. Sense of loneliness was significantly correlated with the prevalence of depressive symptoms (p < 0.001). CONCLUSIONS: In this study, one in five participants experienced anxiety and depressive symptoms. Two out of three participants experienced a moderate sense of loneliness. Individuals who displayed a higher level of loneliness also had a higher severity of anxiety level depressive symptoms and irritability. Elderly individuals should be under special care due to their high risk of experiencing physical and mental effects of the COVID-19 pandemic.

Human Milk Oligosaccharides Exhibit Biofilm Eradication Activity Against Matured Biofilms Formed by Different Pathogen Species.

Human milk oligosaccharides (HMOs) have been shown to exhibit plenty of benefits for infants, such as prebiotic activity shaping the gut microbiota and immunomodulatory and anti-inflammatory activity. For some pathogenic bacteria, antimicrobial activity has been proved, but most studies focus on group B streptococci. In the present study, we investigated the antimicrobial and antibiofilm activities of the total and fractionated HMOs from pooled human milk against four common human pathogenic Gram-negative species (Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Burkholderia cenocepacia) and three Gram-positive species (Staphylococcus aureus, Enterococcus faecium, and Enterococcus faecalis). The activity of HMOs against enterococci and B. cenocepacia are addressed here for the first time. We showed that HMOs exhibit a predominant activity against the Gram-positive species, with E. faecalis being the most sensitive to the HMOs, both in planktonic bacteria and in biofilms. In further tests, we could exclude fucosyllactose as the antibacterial component. The biological significance of these findings may lie in the prevention of skin infections of the mother's breast as a consequence of breastfeeding-induced skin laceration and/or protection of the infants' nasopharynx and lung from respiratory pathogens such as staphylococci.

Relationship between loneliness and blood glucose control in diabetes.

BACKGROUND: The data of the International Diabetes Federation show that about 463 million people have diabetes. Better understanding of psychosocial aspects of life with this disease has become one of healthcare priorities in this group of patients. The aim of this study was to assess the relationships between loneliness and blood glucose control in diabetic patients. METHODS: The study included 250 hospitalized patients with type 1 and 2 diabetes. The patients included in the study were those who had had diabetes for at least 1 year and received pharmacotherapy. Standardized Revised UCLA Loneliness Scale (R-UCLA) and an analysis of patient test results including 10 indicators of blood glucose control were used for data collection. Correlation analysis, i.e. Pearson's linear correlation coefficient (r, parametric method), was used for hypothesis verification. RESULTS: Less than one-fifth (16%) of the patients included in the study had higher loneliness index (based on the R-UCLA scale), and this loneliness index (total result) was significantly correlated with higher blood pressure. No significant correlations were demonstrated between loneliness and the other 9 indicators of blood glucose control. CONCLUSIONS: Systolic blood pressure was significantly correlated with loneliness in patients with diabetes. Further studies are needed to confirm these findings.

Actual and perceived knowledge of type 1 diabetes mellitus among school nurses.

BACKGROUND: In general, school nurses are aware that it is important to have knowledge of type 1 diabetes to give adequate care to children with the disease. Many studies assessing diabetes knowledge have found different deficits among nurses. To our knowledge, however, no study has assessed the knowledge of type 1 diabetes among school nurses. OBJECTIVE: To assess actual and perceived diabetes knowledge among school nurses. DESIGN: Cross-sectional studies. SETTINGS: Seventeen primary care facilities in Warsaw that employed school nurses. PARTICIPANTS: Two hundred and thirty school nurses. METHODS: With the Diabetes Knowledge Questionnaire (DKQ), we assessed actual diabetes knowledge. With the Self-Assessed Diabetes Knowledge (SADK), we assessed perceived diabetes knowledge. Both the DKQ and SADK assessed seven domains of diabetes knowledge: general diabetes knowledge; insulin and glucagon; insulin pumps; diabetes complications; nutrition; physical activity, stress, and comorbidities; and glycemia measurements. We related DKQ and SADK scores to each other and to sociodemographic and work-related factors. RESULTS: The rate of correct responses in the DKQ was 46.7%, with the lowest rate regarding knowledge of insulin pumps (36.5%), nutrition (37.4%), and insulin and glucagon (37.9%). Actual and perceived diabetes knowledge were moderately positively correlated (rho = 0.18, p =.009). In six of the seven knowledge domains examined, school nurses perceived their diabetes knowledge better compared with their actual knowledge. DKQ scores were higher in nurses with higher education (p = .024), those who had relatives or friends with diabetes (p = .032), and those who had prior diabetes training (p = .050). Interestingly, DKQ scores were higher among nurses with fewer years of experience (rho = - 0.18, p = .011). CONCLUSIONS: There is a need for additional diabetes training among nursing students and practicing nurses to provide safe and effective care for children with type 1 diabetes.

Worse survival in breast cancer in elderly may not be due to underutilization of medical procedures as observed upon changing healthcare system in Poland.

BACKGROUND: Evidence is emerging that older women may tolerate breast cancer therapies equally well as the young ones, providing that they receive good supportive care. It has also been reported that these patients remain outside the current therapeutic standards. The aim of this observational study was to assess the access of breast cancer patients to medical procedures. METHODS: We retrospectively reviewed a database of breast cancer patients registered in the National Cancer Registry in Poland, searching for the numbers of new cases and deaths in the years 2010-2015. We obtained the numbers and costs of key medical procedures provided for these patients from the National Health Fund in Poland. Breast cancer survival in the years 2010-2015 was estimated based on the mortality/incidence ratio. The t-Student test and Spearman correlation coefficient were used for the analysis of data obtained from both databases. RESULTS: There was no increase in survival throughout the years 2010-2015 in both analysed subpopulations of all breast cancer patients below and over 65 years of age, despite an unprecedented rise in healthcare funding in Poland. We noted 37% lower probability of 5-year survival in patients older than 65 years. The average number of outpatient visits and surgical procedures per person per year were slightly, yet significantly (p < 0.01), higher in younger vs. older patients (3.9 vs. 3.4 and 1.18 vs. 1.02, respectively). Outpatient chemotherapy was more common in older patients (6.0 vs. 5.25 cycles a year per person on average, p < 0.01). There were no significant differences in the average numbers of hospitalisations for chemotherapy, frequencies of radiotherapy and in the use of targeted therapy programmes (calculated per person per year), between younger and older patients. CONCLUSIONS: Older women with breast cancer are treated similarly to younger patients, but have significantly worse chances to survive breast cancer in Poland. A simple increase in healthcare financing will not improve the survival in the elderly with breast cancer without developing funded individualised care and survivorship programmes.

The pro-tumor effect of CD200 expression is not mimicked by agonistic CD200R antibodies.

Tumor-infiltrating immune cells can impact tumor growth and progression. The inhibitory CD200 receptor (CD200R) suppresses the activation of myeloid cells and lack of this pathway results in a reduction of tumor growth, conversely a tumorigenic effect of CD200R triggering was also described. Here we investigated the role of CD200R activation in syngeneic mouse tumor models. We showed that agonistic CD200R antibody reached tumors, but had no significant impact on tumor growth and minor effect on infiltration of immune myeloid cells. These effects were reproduced using two different anti-CD200R clones. In contrast, we showed that CD200-deficiency did decrease melanoma tumor burden. The presence of either endogenous or tumor-expressed CD200 restored the growth of metastatic melanoma foci. On the basis of these findings, we conclude that blockade of the endogenous ligand CD200 prevented the tumorigenic effect of CD200R-expressing myeloid cells in the tumor microenvironment, whereas agonistic anti-CD200R has no effect on tumor development.

Salivary interleukin 6, interleukin 8, interleukin 17A, and tumour necrosis factor α levels in patients with periodontitis and rheumatoid arthritis.

INTRODUCTION: Rheumatoid arthritis (RA) and periodontitis share risk factors and inflammatory pathways that could be related to cytokines, such as interleukin (IL)-6, IL-8, IL-17A, and tumour necrosis factor-α (TNF-α). The aim of this study was to compare periodontal status and salivary levels of selected cytokines between patients diagnosed with RA and periodontitis. RA patients were assessed for the potential influence of anti-rheumatic therapy. MATERIAL AND METHODS: One hundred and six patients were enrolled in a cross-sectional study. Medical assessment and periodontal examination were performed in 35 patients with chronic periodontitis, in 35 patients with RA and chronic periodontitis, and in 36 controls. Unstimulated whole saliva samples were analysed for IL-6, IL-8, IL-17A, and TNF-α. RESULTS: Significant differences in biomarkers and periodontal parameters were found among groups. Study groups exhibited higher mean pocket depth (PD), number of PD > 4 mm, and mean clinical attachment loss, when compared with controls. The RA group had lower bleeding on probing index and PD, but higher values of plaque indices than the periodontitis group. Concentration of evaluated cytokines were higher in the RA and periodontitis groups, compared with controls. The periodontitis group showed also higher levels of IL-6, IL-17A, and TNF-α in comparison to RA. RA patients were treated with disease-modifying anti-rheumatic drugs (DMARDs) and glucocorticosteroids. CONCLUSIONS: Salivary levels of IL-6, IL-8, IL-17A, and TNF-α can be affected by periodontitis, RA, and presumably DMARDs. DMARD therapy appears to reduce destructive and inflammatory processes in periodontal tissues because lower values of PD, BOP, and salivary levels of IL-6, IL-17A, and TNF-α were found in RA.

NMR spectroscopy of human eye tissues: a new insight into ocular biochemistry.

BACKGROUND: The human eye is a complex organ whose anatomy and functions has been described very well to date. Unfortunately, the knowledge of the biochemistry and metabolic properties of eye tissues varies. Our objective was to reveal the biochemical differences between main tissue components of human eyes. METHODS: Corneas, irises, ciliary bodies, lenses, and retinas were obtained from cadaver globes 0-1/2 hours postmortem of 6 male donors (age: 44-61 years). The metabolic profile of tissues was investigated with HR MAS 1H NMR spectroscopy. RESULTS: A total of 29 metabolites were assigned in the NMR spectra of the eye tissues. Significant differences between tissues were revealed in contents of the most distant eye-tissues, while irises and ciliary bodies showed minimal biochemical differences. ATP, acetate, choline, glutamate, lactate, myoinositol, and taurine were identified as the primary biochemical compounds responsible for differentiation of the eye tissues. CONCLUSIONS: In this study we showed for the first time the results of the analysis of the main human eye tissues with NMR spectroscopy. The biochemical contents of the selected tissues seemed to correspond to their primary anatomical and functional attributes, the way of the delivery of the nutrients, and the location of the tissues in the eye.

Monitoring of in vitro dynamics of Acanthamoeba strains isolated from infected eyes as a useful tool in keratitis management.

Free-living amoebae of Acanthamoeba genus are ubiquitous in various parts of the world. Some species of these amoebozoans present a serious risk to human health as the causative agents of vision-threatening diseases, Acanthamoeba keratitis. Correct diagnosis requires both a clinical examination of the cornea and amoebic form identification in affected eyes. Despite advances in pharmacotherapy, the infection is difficult to diagnose and to threat. Population dynamics of five different Acanthamoeba strains cultured in vitro under bacteria-free condition in BSC medium, was monitored in terms of diagnostic and therapeutic management. The range of protozoan number in the exponential growth phase, the morpho-physiological status of amoeba forms and their ability to multiply were evaluated. Results of the studies revealed that early and continued monitoring of the strains maintained in an axenic culture showed correlation between the dynamics of cultivated amoebae and the course of the disease, differences in response to pharmacotherapy and the surgical management efficacy. Concluding, the in vitro monitoring of dynamics of Acanthamoeba strains isolated from infected corneas may be important not only for proper diagnosis but also as a useful tool in keratitis management and therapeutic prognosis.

Impact of donor health on corneal biochemistry--an unexpected caveat from a pilot study.

BACKGROUND: To test the possibility that some chronic systemic maladies not directly related to the function of the eye may significantly and permanently disturb corneal metabolism. MATERIAL/METHODS: Contents of selected low molecular weight metabolites were compared among corneas collected from donors who died suddenly of an accident or non-poisoning suicide, or met a sudden non-accidental death from unidentified causes, or died of a chronic cardiovascular disease or of idiopathic liver cirrhosis (N=4 for each group). Corneal buttons were halved; one half was snap-frozen and stored at -80°C, and the other half was stored at +4°C in Eusol-C for 8 days and then was snap-frozen and stored at -80°C until analyzed. Metabolite contents were assessed using high-resolution magic angle spinning proton NMR spectroscopy. RESULTS: Significant between-group differences in corneal biochemical profiles were identified. Most of them were reduced or nullified by the Eusol-C storage, suggesting their link to differences in in vivo corneal environment. The corneas from donors with liver cirrhosis or cardiovascular diseases differed considerably from the remaining ones, both before and after the Eusol-C storage. CONCLUSIONS: Various chronic systemic diseases that are not directly related to the function of the eye markedly affect corneal biochemistry. Some of the alterations are likely related to a permanent aberration in corneal metabolism. A study is warranted in larger donor groups on the effect of idiopathic liver cirrhosis and cardiovascular diseases on corneal metabolism and/or a retrospective analysis of the long-term outcome of keratoplasty and other grafting procedures employing materials from these donor groups.

Metabolic profile of keratoconic cornea.

PURPOSE: To investigate the difference in metabolic profile of keratoconic and normal corneas using two different analysis methods. METHODS: Keratoconic corneas were obtained from patients (aged 19-27) during transplantation surgery. Control samples were obtained from human donors (aged 61-75) 1-8 h post-mortem. The metabolic profile of tissues was investigated with high-resolution magic angle spinning (1)H nuclear magnetic resonance (NMR) spectroscopy and high performance liquid chromatography (HPLC). RESULTS: Nine amino acids and 20 metabolites were assigned with HPLC and NMR spectroscopy, respectively. No significant biochemical difference was revealed between keratoconic and control samples, which represent distant age groups. CONCLUSIONS: It suggests that development of keratoconus might be related to the accelerated ageing of the cornea. This issue warrants further studies.

Influence of donor age, post-mortem time and cold storage on metabolic profile of human cornea.

PURPOSE: Limited knowledge exists about the influence of donor age and death-to-preservation interval (DPI) on the metabolic properties of the cornea. The aim of this study is to investigate the relationship between both factors and metabolite content of the cornea. METHODS: Corneas from 15 human donors (age: 41-78 years) were obtained within 16 hrs post-mortem and kept in cold storage for 8 days. The metabolic profiles of the samples were investigated using high-resolution, magic angle spinning (1) H nuclear magnetic resonance spectroscopy before and after 8 days of preservation. RESULTS: Twenty-two metabolites were detected and assigned in the corneal spectra. The significant metabolic differences before and after hypothermic storage were revealed between younger and older donors. DPI-related significant differences revealed before preservation of the corneas were not displayed after 8 days of cold storage. CONCLUSIONS: Age of donor as well as post-mortem time influences the biochemical properties of the cornea. Cold storage decreases the metabolite differences between the tissues collected at different post-mortem time.

Impact of organ culturing on metabolic profile of human corneas: preliminary results.

PURPOSE: It is suggested that the quality of corneal graft may depend on modifications that appear in the tissue during culturing. The aim of this study was to investigate the differences in the metabolic profile between cultured and noncultured human corneas. METHODS: Corneas from 12 donors were obtained post-mortem and cultured for 6-20 days. Control corneas were obtained from four patients with malignant melanoma of the chorioidea and were kept frozen at -80 °C until analysed. The metabolic profiles of the samples were investigated using high-resolution, magic angle spinning (1) H nuclear magnetic resonance spectroscopy and special software for: (i) analysis of complex mixtures, (ii) principal component analysis and (iii) specialized statistical analysis. RESULTS: Twenty metabolites were detected and assigned in the corneas. Significant differences in metabolic profiles between cultured and noncultured corneas were revealed. It was also shown in samples kept in culture for 9-14 days that the levels of (i) alanine, formate, lactate and (ii) acetate, alanine, arginine, lactate were elevated in comparison with the samples kept for <9 and more than 14 days, respectively. CONCLUSIONS: Corneal culturing affects the metabolic profile of the tissue. The increases in the levels of some metabolites within the second week of culturing likely result from variations in tissue metabolic or enzymatic activity caused by changed (organ culture) environment. As the mechanisms responsible for these changes are not clear, further research is indicated.

Two novel nucleoside ester derivatives of chlorambucil as potential antileukemic prodrugs: a preliminary study.

2-Chloro-2'-deoxyadenosine (cladribine) and chlorambucil are two drugs used in the treatment of lymphoid malignancies. We have synthesized 5'-O-esters of cladribine and its parental nucleoside 2'-deoxyadenosine with chlorambucil (2-chloro-2'-deoxyadenosine-chlorambucil and 2'-deoxyadenosine-chlorambucil, respectively) and compared some properties of the esters with regard to their potential use as antileukemic prodrugs. The 5'-O-ester bond showed no spontaneous hydrolysis at pH 7.4, but was susceptible to hydrolysis by porcine liver esterase and enzymes present in human lymphocyte lysate and blood plasma. Both 2-chloro-2'-deoxyadenosine-chlorambucil and 2'-deoxyadenosine-chlorambucil were taken up more avidly than their parental nucleosides by normal and malignant human lymphoid cells. 2-Chloro-2'-deoxyadenosine-chlorambucil was by an order of magnitude more toxic than 2'-deoxyadenosine-chlorambucil to human leukemic MOLT4 cells in culture. On the other hand, 2-chloro-2'-deoxyadenosine-chlorambucil cytotoxicity did not exceed that of its parental 2-chloro-2'-deoxyadenosine in MOLT4 cells, whereas 2'-deoxyadenosine-chlorambucil was considerably more cytotoxic than free chlorambucil in a variety of myeloid and lymphoid human malignant cell lines. Moreover, acute toxicity of 2'-deoxyadenosine-chlorambucil was lower than that of chlorambucil in mice. In summary, 2'-deoxyadenosine-chlorambucil, but not 2-chloro-2'-deoxyadenosine-chlorambucil, shows promise for clinical utility as a chlorambucil prodrug and thus warrants a more detailed study in vivo.