Expression of Coagulation Factor XIII Subunit A Correlates with Outcome in Childhood Acute Lymphoblastic Leukemia

Previously we identified B-cell lineage leukemic lymphoblasts as a new expression site for subunit A of blood coagulation factor XIII (FXIII-A). On the basis of FXIII-A expression, various subgroups of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) can be identified. Fifty-five children with BCP-ALL were included in the study. Bone marrow samples were obtained by aspiration and the presence of FXIII-A was detected by flow cytometry. G-banding and fluorescent in situ hybridization was performed according to standard procedures. The 10-year event-free survival (EFS) and overall survival (OS) rate of FXIII-A-positive and FXIII-A-negative patients showed significant differences (EFS: 84% vs. 61%, respectively; p = 0.031; OS: 89% vs. 61%; p = 0.008). Of all the parameters examined, there was correlation only between FXIII-A expression and ‘B-other’ genetic subgroup. Further multivariate Cox regression analysis of FXIII-subtype and genetic group or ‘B-other’ subgroup identified the FXIII-A negative characteristic as an independent factor associated with poor outcome in BCP-ALL. We found an excellent correlation between long-term survival and the FXIII-A-positive phenotype of BCP lymphoblasts at presentation. The results presented seem to be convincing enough to suggest a possible role for FXIII-A expression in the prognostic grouping of childhood BCP-ALL patients.     

Stress, cancer and circadian rhythm of melatonin

Influence of stress on immunity and pathogenesis relates to corticotropic axis: hypothalamus-hypophysis-surrenals (HHS). Its over-stimulation due to traumas during early childhood or before birth seems to generate brain abnormalities such as reduction of hippocampus volume. More typical of adult age, hypothalamus-pineal gland axis (HP), responsible for melatonin production, may be impaired because of chronic stress, mainly through sleep disturbances or addictive behaviours. Old age has been reported to produce same impairments. Circadian cycle of melatonin is closely related to immune functions and its disturbance seems to induce, among populations undergoing frequent changes of life rhythm, a significant raise of cancer incidence: night shift workers, air pilots... Stress then seems enable to increase cancer risk through its negative impact on HHS and HP axis and therefore on immunity. Immunotherapy, which was an interesting solution considering this, has not yield yet expected results. Upstream, other ways have been successfully investigated in prospective randomised trials, such as psychotherapeutic treatments, with positive effects on cellular immunity and survival. The ability to condition immune responses in animals allows thinking that hypnotherapy could also be used along with standard treatments.     

2-Amino-6-furan-2-yl-4-substituted nicotinonitriles as A2A adenosine receptor antagonists

A 2A adenosine receptor antagonists usually have bi- or tricyclic N aromatic systems with varying substitution patterns to achieve desired receptor affinity and selectivity. Using a pharmacophore model designed by overlap of nonxanthine type of previously known A 2A antagonists, we synthesized a new class of compounds having a 2-amino nicotinonitrile core moiety. From our data, we conclude that the presence of at least one furan group rather than phenyl is beneficial for high affinity on the A 2A adenosine receptor. Compounds 39 (LUF6050) and 44 (LUF6080) of the series had K i values of 1.4 and 1.0 nM, respectively, with reasonable selectivity toward the other adenosine receptor subtypes, A 1, A 2B, and A 3. The high affinity of 44 was corroborated in a cAMP second messenger assay, yielding subnanomolar potency for this compound.     

Synthesis of somatostatin analogues containing C-terminal adamantane and their antiproliferative properties

On the basis of the structure of somatostatin analogue TT-232 (1), which exhibited a highly potent antitumor activity, we synthesized small linear peptide derivatives and evaluated their antitumor and apoptotic activity. Of them, Boc-Tyr-D-Trp-1-adamantylamide (5) had the most potent cell antiproliferative activity in SW480 and A431 cell lines, which was supported in A431 cell lines by FACS analysis that demonstrated a major increase in DNA fragmentation in the subG1 fraction.     

T Cell Subset Profile and Appearance of Donor-specific Antibodies in Primary and Retransplanted Kidney Recipients

IntroductionAccelerated antibody-mediated rejection is a major challenge after kidney transplantation. While the clinical course, diagnosis, and treatment of cell-mediated acute rejection is agreed upon and has been successfully performed, the antibody-mediated rejection remains a problem. Biopsies cannot be repeated several times, are not always representative, and are refused by many patients. Analysis of T-cell subsets and donor-specific antibodies (DSAs) might be an additive diagnostic tool in the case of kidney transplantation.MethodBetween 2015 and 2017, 50 kidney transplant patients were enrolled in the study. Patients were divided into 2 clinical groups: primary transplants and regrafted patients. Serum samples were collected right before the operation, then in 1 week; 30, 60, and 180 days; and yearly. Besides routine laboratory, multicolor flow cytometry was performed for T cell subsets, and Luminex Single Antigen Bead assay for the detection on donor-specific anti-HLA antibodies. Medical data were also fixed.ResultsThe percentage of CD4+ and CD8+ cells (the CD4+/CD8+ rate) did not change much over time in either group. The percentage of CD19+ cells increased until week 1, then decreased back to its original level by day 180. CD56+/3-% was high in both groups and had no characteristic kinetics by the time. The CD4+ naïve absolute cell count increased in first-time transplants and did not decreased back to its original value until the end of year 1. This is in contrast to retransplants, where CD4+ naïve cell count rapidly dropped below its original value and remained low throughout the first year after transplantation. The CD8+ effector memory absolute cell-count was higher in first-time transplants compared to retransplanted patients in all time points. By the end of month 1, the CD19+ naïve absolute cell-count increased in first-time transplants to 170% of its original value; however, it remained or decreased in second transplants. By the end of the first year, the CD19+ naïve absolute cell count diminished to 70% in first-time transplants and 38% in second transplants. DSA was detected in 9 out of the 38 first-time transplants (23.7%) compared to 7 out of 12 (58.3%) in regrafted patients during the observational period (P = .001). It was typical for regrafted patients for DSAs to appear earlier after transplantation, and that more simultaneously different antibodies were detected against more antigens at the first time point compared to first-time transplants.DiscussionThe 2 groups were similar in demographics and there were no differences regarding the clinical course, complications, or output data. However, we found statistical differences regarding the dynamics of T cell subsets and DSAs. The parallel measurement of CD subsets and DSAs might be a sensitive and useful additive tool in diagnosing subclinical immunologic changes after transplantation.     

Optimal recall period in assessing the adherence to antihypertensive therapy: a pilot study

Objective To evaluate the validity of patient self-reported adherence, and to find the optimal length of recall period which best reflects the long-term adherence pattern of the patient. Setting Patients were recruited from a general practitioner??s practice in a Hungarian town. Method In this prospective study 30 patients, who had already been on antihypertensive treatment, were involved. The study was designed to monitor one antihypertensive medication per patient for 3 months. Patients received a 3-month supply of one antihypertensive medication in an electronic Medication Event Monitoring System (MEMS). At the end of the study period patients completed a structured questionnaire regarding their medication taking behavior during the last 7, 14 and 30 days. The results measured with MEMS were considered as the reference value, and other measures were compared using the Bland?CAltman method. Main outcome measures self-reported adherence, length of recall period, taking adherence and timing adherence measured by MEMS. Results Of the 30 patients included, 29 patients (13 males and 16 females) completed the study. The mean age of the patients was 60.6 years, ranging between 36 and 86 years. Patients were monitored for an average of 89 days (ranging between 49 and 106 days). Fifteen patients were on once daily, 9 patients were on twice daily, and 5 patients were on 3 times daily dosing schedule. The total expected number of medication taking events was 4,281. The MEMS caps recorded a total of 4,071 openings, which showed only a 3.56% deviation from the pill counts of the remaining tablets. The overall taking adherence was 95.1%, timing adherence was 75.2%. Patients?? adherence report using a visual analog scale and reporting the number of missed doses became more accurate as the length of the recall period increased. Increased number of chronically taken medications was associated with better adherence. Increased dosing frequency of the observed antihypertensive medication resulted in decreased adherence. Conclusion The results showed that the length of the recall period influences the accuracy of self-reported adherence. Patients seem to be able to report more precisely their medication taking behavior regarding a 30 day period than a 7 day period.     

Dietary, Weight, and Psychological Changes among Patients with Obesity, 8 Years after Gastric Bypass

Background and objective

Long-term data on patients with obesity outcome after bariatric surgery are lacking. The goal was to document dietary and anthropometric changes more than 5 years after surgery, as well as patients' eating behavior, psychological state, and quality of life.

Methods

A cohort of 80 women (mean age 40±10 years) who underwent a Roux-en-Y gastric bypass between 1997 and 2002 were followed in a Swiss University Hospital for an average of 8±1.2 years. The primary outcome was successful weight loss defined as excess weight loss ≥50%. Body composition was measured by bioelectrical analysis, and diet was assessed via a food diary. Eating disorders, psychological factors, and quality of life were evaluated by questionnaires. Patients' perceptions of difficulties and benefits were explored using semistructured interviewing. Results at baseline and last visit were compared using paired t test. Cofactors' means were compared between successful and unsuccessful patients with Student t tests and logistic regression.

Results

Average weight loss 8 years after surgery was 30.7±13.8 kg. Excess weight loss ≥50% was observed for 47 patients (59%). Between baseline and last visit, relative proportions of fat mass/total body weight decreased, and fat-free mass/total body weight increased. Mean energy intake was 2,355±775 kcal at baseline and 1,680±506 kcal at last visit, with 42% of energy from carbohydrates, 39% of energy from fats, and 19% of energy from protein (0.8 g/kg). At last visit, 41 patients (51%) described episodes of binge eating or night eating syndrome. Factors associated with excess weight loss ≥50% were: younger age at operation, greater number of psychological consultations before the operation, and higher scores on ineffectiveness and social insecurity scales at baseline.

Conclusions

More than half of the patients achieved successful weight loss, but disordered eating behavior was frequent. Periodic follow-up screenings and interdisciplinary care are advised. The definition of successful outcome should take into account problematic eating behaviors.