Phase I and pharmacokinetic study of tiazofurin (TCAR,NSC 286193) administered by continuous infusion

Summary Tiazofurin (2--D-ribofuranosylthiazole-4-carboxamide, TCAR) is a synthetic C-nucleoside that demonstrated significant in vivo activity against a variety of animal tumors as well as in vitro activity against human tumor-derived cell lines. Thirteen patients were treated with TCAR administered as a 5-day continuous infusion in this Phase I trial. Seventeen complete cycles were administered in three dose levels ranging from 550 to 1450 mg/M². Dose-limiting toxicities were myelosuppression and neurotoxicity including severe lethargy. Other toxicities including superficial skin peeling, myalgias, and tearing were seen at all doses. One patient had chest pain on day 4 resulting in stopping the drug, however, there was no evidence of cardiac or pericardial disease. Uric acid levels rose within one day in the absence of allopurinol treatment. There were no treatment related deaths. HPLC measurement of drug levels demonstrated steady-state plasma levels during the infusion, and a half-life following the infusion of 7.7 ± 0.6 hours. Minor abnormalities in renal function were associated with dramatic changes in pharmacokinetics and toxicity. No clinical responses were observed in this trial.Abbreviations TCAR Tiazofurin - HPLC High performance liquid chromatography - IMPD Inosine monophosphate dehydrogenase - WBC white blood cell - CPK creatine phosphokinase - C_ss steady-state concentration     

Cross-correlation of EMG reveals widespread synchronization of motor units during some slow movements in intact cats

It is commonly assumed that the motor units comprising a single mammalian muscle will be recruited asynchronously at subtetanic firing rates to produce smoothly modulated force output. However, electromyograms from certain neck muscles, recorded by implanted bipolar "patch" electrodes having large contacts, often exhibited a rhythmic clustering of spike activity whose patterns suggested that motor-unit firing was synchronized both within and across muscles. We have developed a computerized processing system that digitizes EMG activity and calculates auto- and cross-correlation products of selected segments. The presence or absence of synchronization caused by neural mechanisms can be identified and differentiated from that due to the rhythmicity of the behavior itself (e.g. shaking) or due to cross-talk, according to the shapes of the resultant correlograms. These methods have so far been applied to the study of hindlimb and neck muscle EMG during various natural motor behaviors, but they provide a general, quantitative tool for the study of an important aspect of motor control that may be overlooked by conventional sampling and smoothing techniques.     

Conductive polymers derived from iron, ruthenium, and osmium metalloporphyrins: The shish-kebab approach

The synthesis and characterization of pyrazine-bridged polymers of iron(II/III), ruthenium(II/III), and osmium(II/III) octaethylporphyrin (dubbed “shish-kebab” polymers) are presented. Optical and dc conductivity measurements reveal that the ruthenium and osmium polymers, when partially oxidized, are highly conductive. Electrochemical and ESR results are presented that indicate the existence of an interesting metal-centered conduction pathway. Unlike most of the previously reported porphyrinic molecular metals in which the conduction electrons are macrocyclic-based, electron transport in these materials proceeds exclusively along the metal-pyrazine backbone.     

Inhibition of brain acetylcholine biosynthesis by methyldopa in spontaneously hypertensive rats

The formation of 3H-acetylcholine was measured in several brain regions of spontaneously hypertensive (SH) rats following intracerebroventricular injection of 3H-choline. Endogenous acetylcholine (ACh) also was measured and specific activity-time curves for brain ACh generated for control SH rats and for SH rats pretreated with methyldopa (100-200 mg/kg, IV). The relative turnover rates for ACh in several brain regions was estimated from the specific activity-time curves. The turnover rates of ACh in rostral hypothalamus, caudal hypothalamus, medulla oblongata and pons were reduced by 34-54%. Apparently synthesis was inhibited also since methyldopa produced relatively little effect on ACh levels. More rostral brain regions, thalamus-septum, midbrain and striatum, were not significantly affected by methyldopa. Methyldopa also reduced arterial pressure by 53/28 mmHg. The ability of methyldopa to inhibit the function of cholinergic neurons in selective brain regions may be responsible for its common "anticholinergic" side effects. Since centrally-acting anticholinergic drugs reduce arterial pressure in SH rats, it is possible that inhibition of brain ACh synthesis by methyldopa also may contribute to its antihypertensive action in experimental genetic hypertension.     

Novel second-generation rexinoid induces growth arrest and reduces cancer cell stemness in human neuroblastoma patient-derived xenografts

IntroductionThe poor therapeutic efficacy seen with current treatments for neuroblastoma may be attributed to stem cell-like cancer cells (SCLCCs), a subpopulation of cancer cells associated with poor prognosis and disease recurrence. Retinoic acid (RA) is a differentiating agent used as maintenance therapy for high-risk neuroblastoma but nearly half of children treated with RA relapse. We hypothesized that 6-Methyl-UAB30 (6-Me), a second-generation rexinoid recently developed with a favorable toxicity profile compared to RA, would reduce cancer cell stemness in human neuroblastoma patient-derived xenografts (PDXs).MethodsCells from three neuroblastoma PDXs were treated with 6-Me and proliferation, viability, motility, and cell-cycle progression were assessed. CD133 expression, sphere formation, and mRNA abundance of stemness and differentiation markers were evaluated using flow cytometry, in vitro extreme limiting dilution analysis, and real-time PCR, respectively.ResultsTreatment with 6-Me decreased proliferation, viability, and motility, and induced cell-cycle arrest and differentiation in all three neuroblastoma PDXs. In addition, 6-Me treatment led to decreased CD133 expression, decreased sphere-forming ability, and decreased mRNA abundance of Oct4, Nanog, and Sox2, indicating decreased cancer cell stemness.Conclusions6-Me decreased oncogenicity and reduced cancer cell stemness of neuroblastoma PDXs, warranting further exploration of 6-Me as potential novel therapy for neuroblastoma.     

Clinical characteristics and outcomes associated with Inquilinus infection in cystic fibrosis

BackgroundMolecular diagnostics have led to the identification of a broad range of bacterial species in cystic fibrosis (CF) including Inquilinus. The clinical significance of Inquilinus in CF has not been thoroughly characterized.MethodsRetrospective, case-control study of persons with CF from two CF centers with at least one respiratory culture positive for Inquilinus spp. compared with age-matched CF controls with chronic Pseudomonas aeruginosa. Percent predicted forced expiratory volume in one second (ppFEV1) and body mass index percentile (BMI) were modeled from time of first positive culture up to 5 years later. Rates of pulmonary exacerbations were compared. Inquilinus isolates were genotyped to evaluate strain diversity.ResultsSeventeen patients with Inquilinus infection were identified with a mean age of 13 years at first positive culture. Most cases had multiple cultures positive for Inquilinus. ppFEV1 was not different between cases versus controls (80.2% vs 81.6%, p = 0.97 at baseline, 67.5% vs. 73.3%, p = 0.82 at 5 years). Patients were undernourished and BMI percentiles did not differ between groups (30.7% vs 43.4%, p = 0.32 at baseline, 37.9% vs. 37.6%, p = 0.98 at 5 years). There was no difference in the pulmonary exacerbation rate (3.0/year vs 2.5/year, p = 0.34). Genotyping showed diverse genetic strains between patients.ConclusionsInquilinus can present in childhood and is often associated with chronic infection in CF. Lung function and nutrition status at time of detection, lung function decline, and pulmonary exacerbation rates in Inquilinus cases were similar to those with chronic P. aeruginosa, a well-established CF pathogen.     

Surgical Treatment and Proposed Modified Classification for Harrington Class III Periacetabular Metastases

ObjectivesThis study aims to: (i) evaluate the outcome of patients with Harrington class III lesions who were treated according to Harrington classification; (ii) propose a modified surgical classification for Harrington class III lesions; and (iii) assess the efficiency of the proposed modified classification.MethodsThis study composes two phases. During phase 1 (2006 to 2011), the clinical data of 16 patients with Harrington class III lesions who were treated by intralesional excision followed by reconstruction of antegrade/retrograde Steinmann pins/screws with cemented total hip arthroplasty (Harrington/modified Harrington procedure) were retrospectively reviewed and further analyzed synthetically to design a modified surgical classification system. In phase 2 (2013 to 2019), 62 patients with Harrington class III lesions were classified and surgically treated according to our modified classification. Functional outcome was assessed using the Musculoskeletal Tumor Society (MSTS) 93 scoring system. The outcome of local control was described using 2‐year recurrence‐free survival (RFS). Owing to the limited sample size, we considered P < 0.1 as significant.ResultsIn phase 1, the mean surgical time was 273.1 (180 to 390) min and the mean intraoperative hemorrhage was 2425.0 (400.0 to 8000.0) mL, respectively. The mean follow‐up time was 18.5 (2 to 54) months. Recurrence was found in 4 patients and the 2‐year RFS rate was 62.4% (95% confidence interval [CI] 31.6% to 93.2%). The mean postoperative MSTS93 score was 56.5% (20% to 90%). Based on the periacetabular bone destruction, we categorized the lesions into two subgroups: with the bone destruction distal to or around the inferior border of the sacroiliac joint (IIIa) and the bone destruction extended proximal to inferior border of the sacroiliac joint (IIIb). Six patients with IIIb lesions had significant prolonged surgical time (313.3 vs 249.0 min, P = 0.022), massive intraoperative hemorrhage (3533.3 vs 1760.0 mL, P = 0.093), poor functional outcome (46.7% vs 62.3%, P = 0.093), and unfavorable local control (31.3% vs 80.0%, P = 0.037) compared to the 10 patients with IIIa lesions. We then modified the surgical strategy for two subgroup of class III lesions: Harrington/modified Harrington procedure for IIIa lesions and en bloc resection followed by modular hemipelvic endoprosthesis replacement for IIIb lesions. Using the proposed modified surgical classification, 62 patients in the phase 2 study demonstrated improved surgical time (245.3 min, P = 0.086), intraoperative hemorrhage (1466.0 mL, P = 0.092), postoperative MSTS 93 scores (65.3%, P = 0.067), and 2‐year RFS rate (91.3%, P = 0.002) during a mean follow‐up time of 19.9 (1 to 60) months compared to those in the phase 1 study.ConclusionThe Harrington surgical classification is insufficient for class III lesions. We proposed modification of the classification for Harrington class III lesions by adding two subgroups and corresponding surgical strategies according to the involvement of bone destruction. Our proposed modified classification showed significant improvement in functional outcome and local control, along with acceptable surgical complexity in surgical management for Harrington class III lesions.     

Binge-eating disorder is associated with an unfavorable body mass composition in patients with non-alcoholic fatty liver disease

The interaction between eating disorders and non-alcoholic fatty liver disease (NAFLD) remains unexplored, especially with regards to binge-eating disorder (BED). Our team conducted a service evaluation project in order to assess risk factors for the presence of BED among patients with NAFLD and the impact of BED on body mass composition. The overall prevalence of patients screening positive to BED Screener-7 (BEDS-7) was 28.4%, while a previous diagnosis of depression and marital status (as single or separated) were independently associated with positive BED. Furthermore, patients with positive BEDS-7 had higher BMI, with greater visceral component and overall lower muscle mass. There was no difference in terms of liver disease severity as assessed by noninvasive markers of fibrosis. However, as body mass composition and sarcopenia have been shown to be associated to disease progression in patients with NAFLD, further studies are required to ascertain the long-term impact of BED in these patients. Moreover, further work is warranted to identify to implement multidisciplinary approach within clinical psychology for the management of patients with BED, who may be particularly challenging in terms of achieving lifestyle modifications. As a hepatology community, we should address NAFLD with a more holistic approach.     

Autoimmunity in Alzheimer's disease: increased levels of circulating IgGs binding Abeta and RAGE peptides

Plasma samples derived from 33 Alzheimer's disease (AD) and 42 control participants were subjected to several steps to purify specific anti-(amyloid)Abeta IgGs. Affinity-purified IgGs binding the peptide Abeta1-42, a neurotoxic sequence derived from the trans-membrane amyloid precursor protein, exhibited nearly four-fold higher titers in AD patients compared with their control non-AD cohort. Affinity-purified IgGs binding a fragment of the receptor for advanced glycation end products (RAGE) likewise were increased nearly three-fold in AD individuals. Abeta and RAGE IgG titers were negatively correlated with cognitive status, i.e. the more cognitively impaired individuals tended to exhibit higher IgG titers. Abeta IgG titers were negatively correlated with age in the control group, but not with the AD group. Levels of circulating AB- and RAGE-like proteins were not different between AD and control participants, nor was there a relationship between individual IgG titers and the respective Abeta- and RAGE-like proteins. Freshly prepared leukocyte preparations were subjected to flow cytometric analysis. AD individuals exhibited significantly increased populations of cells expressing binding sites for monoclonal antibodies directed against Abeta (5.5-fold), betaAPP (3.5-fold), and RAGE (2.6-fold) relative to the control group. These findings confirm the presence of circulating IgGs specifically directed at proteins implicated in immunological processes linked to AD. The close relationship between titers for Abeta and RAGE IgGs suggests the possibility that the antibodies are being produced in response to a common mechanism or protein complex (with the respective epitopes) linked to the disease.