Factors affecting pharmacology learning in integrated PBL in diverse medical students: a mixed methods study.

INTRODUCTION: Problem-based learning (PBL) was introduced to address passive teaching limitations. However, it is not fully characterised as a teaching modality in pharmacology. The present study investigated the factors affecting pharmacology learning in an integrated PBL-based curriculum in diverse learners. METHODS: Year 1 undergraduate medical students from two cohorts at St. George's University of London and University of Nicosia, participated. Statistical analysis of pharmacology knowledge scores, at the beginning (pre-test) and end of the academic year (post-test), investigated readiness to benefit from PBL based on diverse student characteristics (educational background, age, gender, country of origin, ethnicity, native language, PBL experience). Focus groups/interviews and a survey investigated aspects of integrated PBL impacting learning in depth. RESULTS: Pre- and post-test scores were positively correlated. Students with biomedical sciences degrees performed better at the pharmacology pre- and post-tests, while post-graduate degree holders performed better only at the pre-test. Effect size was of moderate magnitude. However, progress in learning (post-test performance after controlling for pre-test scores) was unaffected. Qualitative analysis revealed three major themes: 1) PBL as a learning environment; 2) PBL as a learning environment in pharmacology; and 3) PBL as a learning environment and confidence in prescribing. Under theme one, skill development, knowledge acquisition through collaboration and self-directed learning, group dynamics and preferred teaching methods were discussed. Under theme two, contextual learning, depth of knowledge and material correctness were raised. Under theme 3, students expressed variability in prescribing confidence. They perceived that learning could be improved by better integration, further references earlier on, more lectures and PBL facilitators with greater content expertise. The survey findings were consistent with those from focus groups/interviews. CONCLUSION: Pharmacology learning in a PBL-based curriculum is facilitated by constructive, collaborative and contextual learning. While baseline pharmacology knowledge may be advantageous, the other aforementioned characteristics studied may not affect readiness to benefit from PBL. However, further instructional scaffolding is needed, for example through further resources, lectures and self-assessment. The results from our study can inform evidence-based curriculum reform to support student learning further. Addressing learning needs could ultimately contribute to reducing medication errors through effective training of future prescribers.

Nutrient Status in Patients with Frequent Episodic Tension-Type Headache: A Case-Control Study.

OBJECTIVE: To investigate the relationship between frequent episodic tension-type headache (FE-TTH) and 25-hydroxyvitamin-D (25(OH)D), folate, vitamin B12, and magnesium. DESIGN-METHODS: A prospective case-control study involving adults with FETTH and age-sex matched healthy controls (HC) was performed. Individuals under the responsibility of the three provincial Health Centres of the prefecture of Trikala (Central Greece) were recruited during their regular check-up visits. The relationship between FETTH and serum levels of 25(OH)D, vitamin B12, folate, and magnesium was investigated (primary outcomes). Demographics, daily habits, somatometrics, psychometric and sleep quality measurements, laboratory indices, cardiovascular comorbidities and medications taken were also recorded and compared (secondary outcomes). Potential associations of the above-listed parameters with headache parameters (headache frequency, severity and analgesic consumption) were also examined (secondary outcomes). RESULTS: Between September and December 2020, 30 patients with FETTH and 30 HC were successfully recruited. Demographics, comorbidities, regular medications, smoking habits, alcohol and coffee consumption, body mass index measurements, markers of systemic inflammation, folate and vitamin B12 levels were similar between the two groups (P>0.05). Lower serum 25(OH)D was both univariately (P<0.001) and multivariately [OR= 0.72, 95%CI=(0.55, 0.94) per 1ng/ml increase] associated with FETTH, while serum magnesium was found lower in FETTH only according to the univariate approach (P=0.036). Higher levels of depression (P=0.050) and anxiety (P=0.020), as well as poor quality of sleep (P=0.008), were univariately associated with FETTH. Only the effect of anxiety remained significant following the multivariate logistic regression [OR=7.90, 95%CI=(1.00, 62.47)]. Headache parameters were not associated with any one of the assessed variables. DISCUSSION: Lower serum 25(OH)D was related to the presence of FETTH. This finding could imply a potential role for vitamin D in the pathophysiology of TTH.

Identifying On-Surface Site-Selective Chemical Conversions by Theory-Aided NEXAFS Spectroscopy: The Case of Free-Base Corroles on Ag(111).

We demonstrate here that theory-assisted near-edge X-ray absorption fine-structure (NEXAFS) spectroscopy enables the site-sensitive monitoring of on-surface chemical reactions, thus, providing information not accessible by other techniques. As a prototype example, we have used free-base 5,10,15-tris(pentafluorophenyl)corroles (3H-TpFPC) adsorbed on Ag(111) and present a detailed investigation of the angle-dependent NEXAFS of this molecular species as well as of their thermally induced derivatives. For this, we have recorded experimental C and N K-edge NEXAFS spectra and interpret them based on XAS cross-section calculations by using a continuous fraction approach and core-hole including multiprojector PAW pseudopotentials within DFT. We have characterized the as-deposited low temperature (200 K) phase and unraveled the subsequent changes induced by dehydrogenation (at 330 K) and ring-closure reactions (at 430 K). By exemplarily obtaining profound insight into the on-surface chemistry of free-base corrolic species adsorbed on a noble metal this work highlights how angle-dependent XAS combined with accurate theoretical modeling can serve for the investigation of on-surface reactions, whereby even highly similar molecular structures, such as tautomers and isomers, can be distinguished.

Characterization of dissolved organic carbon in rainwater of an urban/coastal site in Mediterranean area.

Concentration and optical characteristics of dissolved organic matter were studied in rainwater in the urban/coastal city of Thessaloniki, Northern Greece for 2-yr sampling period (2014-2016). The concentration of DOC ranged from 0.33-24.5mg/L with higher values measured in spring-summer period. Higher aromaticity and fluorescence intensity was observed in winter. Chromophoric organic matter represents a significant fraction of DOC that is highly correlated with fluorescence during cold period. Three factor spectral profiles of fluorescence were elucidated, with peaks at protein-like and humic-like area at different intensities. Fluorophores at shorter wavelengths are more susceptible to changes. DOC showed negative relationship with precipitation height, particularly during autumn and spring suggesting washout effect. NMR spectra showed the dominance of aliphatic protons in rainwater. Levoglucosan, sucrose and arabitol were determined in rainwater at concentrations <0.07-2.2µg/L, <0.03-5.1µg/L and <0.03-2.1µg/L, respectively showing impact of biomass combustion and biogenic emissions.

RNA Profiling in Human and Murine Transplanted Hearts: Identification and Validation of Therapeutic Targets for Acute Cardiac and Renal Allograft Rejection.

Acute cellular rejection (ACR) is the adverse response of the recipient's immune system against the allogeneic graft. Using human surveillance endomyocardial biopsies (EMBs) manifesting ACR and murine allogeneic grafts, we profiled implicated microRNAs (miRs) and mRNAs. MiR profiling showed that miR-21, -142-3p, -142-5p, -146a, -146b, -155, -222, -223, and -494 increased during ACR in humans and mice, whereas miR-149-5p decreased. mRNA profiling revealed 70 common differentially regulated transcripts, all involved in immune signaling and immune-related diseases. Interestingly, 33 of 70 transcripts function downstream of IL-6 and its transcription factor spleen focus forming virus proviral integration oncogene (SPI1), an established target of miR-155, the most upregulated miR in human EMBs manifesting rejection. In a mouse model of cardiac transplantation, miR-155 absence and pharmacological inhibition attenuated ACR, demonstrating the causal involvement and therapeutic potential of miRs. Finally, we corroborated our miR signature in acute cellular renal allograft rejection, suggesting a nonorgan specific signature of acute rejection. We concluded that miR and mRNA profiling in human and murine ACR revealed the shared significant dysregulation of immune genes. Inflammatory miRs, for example miR-155, and transcripts, in particular those related to the IL-6 pathway, are promising therapeutic targets to prevent acute allograft rejection.

Fate of natural organic matter at a full-scale Drinking Water Treatment Plant in Greece.

The aim of this study was to investigate the fate of natural organic matter (NOM) and subsequent changes during the various treatment processes at a full-scale Drinking Water Treatment Plant (DWTP). Monthly sampling campaigns were conducted for 1 year at six sites along DWTP of Thessaloniki, Northern Greece including raw water from the Aliakmonas River that supplies DWTP and samples from various treatment processes (pre-ozonation, coagulation, sand filtration, ozonation, and granular activated carbon (GAC) filtration). The concentration of NOM and its characteristics as well as the removal efficiency of various treatment processes on the basis of dissolved organic carbon, UV absorbance, specific ultra-violet absorbance, fluorescence intensity, hydrophobicity, biodegradable dissolved organic carbon, and formation potential of chlorination by-products trihalomethanes (THMs) and haloacetic acids (HAAs) were studied. The concentration of dissolved organic carbon (DOC) in reservoir of the Aliakmonas River ranged from 1.46 to 1.84 mg/L, exhibiting variations regarding UV, fluorescence, and hydrophobic character through the year. Along DWTP, a significant reduction of aromatic, fluorophoric, and hydrophobic character of NOM was observed resulting in significant elimination of THM (63%) and HAAs (75%) precursors.

Incidence and factors predisposing to retinopathy of prematurity in inborn infants less than 32 weeks of gestation.

PURPOSE: Retinopathy of prematurity (ROP) is a visual-impairing disorder of the developing retinal vasculature in premature infants. Recent advances in neonatal care have led to an increase in the vulnerable premature population. The aim of this retrospective study was to assess the incidence of ROP and its risk factors according to degree of prematurity. METHODS: Data from a sequence of 1,562 infants <32 weeks of gestational age, admitted to the Jewish General Hospital Neonatal Intensive Care Unit, a tertiary care perinatal center in Montreal, Canada, were reviewed to determine the incidence and risk factors of ROP. Perinatal risk factors for ROP were analyzed using univariate and multivariate analyses in four consecutive gestational age (GA) groups (24-25+6/7weeks, 26-27+6/7 weeks, 28-29+6/7 weeks and 30-31+6/7 weeks). RESULTS: The overall incidence in our study was 15.6 %. Severe ROP, defined as stage 3 or plus disease was detected in 5.2 % of the neonates screened. In the univariate analyses, many risk factors in each GA group were found to have a significant association with ROP. On subsequent multivariate logistic regression analysis, birth weight, small for gestational age, the presence of patent ductus arteriosus (PDA), sepsis, necrotizing enterocolitis (NEC), and mechanical ventilation >7 days were independently associated with the development of ROP. Birth weight was consistently an independent risk factor for ROP in all GA groups. CONCLUSION: Our study confirmed the importance of birth weight as an independent ROP risk factor. Sepsis, NEC, PDA, and prolonged mechanical ventilation have been shown to be independent risk factors in the different gestational age groups. Hippokratia 2016, 20(2): 121-126.

Carbonyl compounds and dissolved organic carbon in rainwater of an urban atmosphere.

This study investigates the occurrence of carbonyl compounds in rainwater at the city of Thessaloniki, Northern Greece. The concentrations of carbonyl compounds (as sum of 14 compounds) ranged from 21.8 to 592 µg/L, mean concentration 119 µg/L. Formaldehyde, acetaldehyde, hexanal, glyoxal, and methylglyoxal were the dominant compounds. DOC concentrations in rainwater ranged from 0.46 to 21.3 mg/L. UV-Vis and fluorescence spectra characteristics showed variation among rain events. Carbonyl compounds were negatively correlated with temperature exhibited relatively higher concentrations in cold season. They also influenced by storm origin with higher concentrations under terrestrial air masses. Calm conditions enhance the concentrations of DOC. Wash out is an effective removal mechanism of DOC.

Occurrence and fate of ozonation by-products at a full-scale drinking water treatment plant.

The occurrence and fate of carbonyl compounds as ozonation by-products at a full scale drinking water treatment plant (DWTP) were studied for one year. Raw water and samples after the main treatment processes (pre-ozonation, coagulation/flocculation, sand filtration, main ozonation, filtration through granular activated carbon and chlorination) were collected on a monthly basis. Pre-ozonation led to the formation of carbonyl compounds at concentrations of 67.3 ± 43.3 µg/l as sum of 14 carbonyl compounds whereas lower concentrations were determined after the main ozonation process, 32.8 ± 22.3 µg/l. The dominant compounds were formaldehyde, acetaldehyde, glyoxal and methyl glyoxal contributing to 65% of total carbonyl content. The DOC reactivity in formation of carbonyl compounds varied through the year exhibiting the higher values in spring. Coagulation/flocculation and sand filtration significantly removed (64-80%) the carbonyl compounds formed at the pre-ozonation step. The removal efficiency of filtration through granular activated carbon showed great variation ranging from 15 to 62%. Finally, the concentrations of carbonyl compounds in finished water were low, close to detection limits, revealing the efficiency of DWTP in the removal of this class of ozonation by-products.

Obesity rather than regional fat depots marks the metabolomic pattern of adipose tissue: an untargeted metabolomic approach.

OBJECTIVE: This study compares the patterns of visceral (VIS) and subcutaneous (SC) adipose tissue (AT)-derived metabolites from non-obese (BMI 24-26 kg/m2) and obese subjects (BMI > 40 kg/m2) with no major metabolic risk factors other than BMI. METHODS: SC- and VIS- AT obtained from obese (Ob) and non-obese (NOb) subjects during surgery were incubated to obtain their metabolites. Differences related to obesity or anatomical provenances of AT were assessed using an untargeted metabolomics approach based on gas chromatography-mass spectrometry. RESULTS: The overall effect of obesity on the metabolite profile resulted more remarkable than the effect of regional AT. Only the depletion of 2-ketoisocaproic (2-KIC) acid reached statistical significance for the SC-AT alone, although it was observed in both depots. Obesity induced more significant changes in several amino acids levels of the VIS-AT metabolites. On the one hand, higher released levels of glutamine and alanine were detected in the VIS- obese AT, whereas on the other, the VIS- obese AT presented a diminished uptake of essential amino acids (methionine, threonine, lysine), BCAAs, leucine, and serine. CONCLUSION: This study shows that obesity markedly affects the amino acid metabolic signature of the AT before the clinical onset of other significant metabolic alterations aside from BMI.

Investigating the molecule-substrate interaction of prototypic tetrapyrrole compounds: adsorption and self-metalation of porphine on Cu(111).

We report on the adsorption and self-metalation of a prototypic tetrapyrrole compound, the free-base porphine (2H-P), on the Cu(111) surface. Our multitechnique study combines scanning tunneling microscopy (STM) results with near-edge X-ray absorption fine-structure (NEXAFS) and X-ray photoelectron spectroscopy (XPS) data whose interpretation is supported by density functional theory calculations. In the first layer in contact with the copper substrate the molecules adsorb coplanar with the surface as shown by angle-resolved NEXAFS measurements. The quenching of the first resonance in the magic angle spectra of both carbon and nitrogen regions indicates a substantial electron transfer from the substrate to the LUMO of the molecule. The stepwise annealing of a bilayer of 2H-P molecules sequentially transforms the XP and NEXAFS signatures of the nitrogen regions into those indicative of the coordinated nitrogen species of the metalated copper porphine (Cu-P), i.e., we observe a temperature-induced self-metalation of the system. Pre- and post-metalation species are clearly discriminable by STM, corroborating the spectroscopic results. Similar to the free-base porphine, the Cu-P adsorbs flat in the first layer without distortion of the macrocycle. Additionally, the electron transfer from the copper surface to the molecule is preserved upon metalation. This behavior contrasts the self-metalation of tetraphenylporphyrin (2H-TPP) on Cu(111), where both the molecular conformation and the interaction with the substrate are strongly affected by the metalation process.

The suppression of star formation by powerful active galactic nuclei.

The old, red stars that constitute the bulges of galaxies, and the massive black holes at their centres, are the relics of a period in cosmic history when galaxies formed stars at remarkable rates and active galactic nuclei (AGN) shone brightly as a result of accretion onto black holes. It is widely suspected, but unproved, that the tight correlation between the mass of the black hole and the mass of the stellar bulge results from the AGN quenching the surrounding star formation as it approaches its peak luminosity. X-rays trace emission from AGN unambiguously, whereas powerful star-forming galaxies are usually dust-obscured and are brightest at infrared and submillimetre wavelengths. Here we report submillimetre and X-ray observations that show that rapid star formation was common in the host galaxies of AGN when the Universe was 2-6 billion years old, but that the most vigorous star formation is not observed around black holes above an X-ray luminosity of 10(44) ergs per second. This suppression of star formation in the host galaxy of a powerful AGN is a key prediction of models in which the AGN drives an outflow, expelling the interstellar medium of its host and transforming the galaxy's properties in a brief period of cosmic time.

Dexamethasone plus octreotide regimen increases anticancer effects of docetaxel on TRAMP-C1 prostate cancer model.

AIM: The aim of this study was to evaluate whether the neoadjuvant use of the dexamethasone (DEX) plus octreotide (OCT) regimen can improve the direct anticancer effects of docetaxel (DOC) in the TRAMP-C1 prostate cancer model. MATERIALS AND METHODS: TRAMP-C1 cells were first characterized for the expression of SSTR1-5 and then were inoculated onto the femur of C57Bl mice. Investigation protocols employed TRAMP-C1 cell proliferation and invasion assays, analysis of radiographic images of the bone lesions and overall survival of the diseased animals. RESULTS: The triple combination treatment scheme showed significant anticancer effects, in both proliferation and invasion assays, compared to any single agent treatment scheme. DOC treatment following the neoadjuvant administration of DEX plus OCT regimen improved significantly the anticancer effects both on the grading of the bone lesions and on the overall survival of the diseased animals. CONCLUSION: Our data suggest that the neoadjuvant administration of DEX plus OCT regimen can improve the anticancer effects of DOC on the TRAMP-C1 model.

Prevalence of thrombophilic mutations in patients with unprovoked thromboembolic disease. A comparative analysis regarding arterial and venous disease.

BACKGROUND: Thromboembolic disease (TED) represents one of the main reasons of morbitity and mortality in Western World. Venous and arterial thrombotic disorders have long been viewed as separate pathophysiological entities. However, in recent times the separate nature of arterial and venous thrombotic events has been challenged. Although inherited thrombophilia's predominant clinical manifestation is venous thrombosis, its contribution to arterial thrombosis remains controversial. Purpose  of  the  study  was  to  evaluate  the  prevalence  of  the  most common  thrombophilic  mutations, FV Leiden G1691A-FVL and FII G20210A-PTM and to assess  the  differences between venous, arterial and mixed thrombotic events. Testing  for polymorphism MTHFR C677T and  antithrombin,  protein  C  and  protein  S was also performed. Correlations with  dyslipidemia, smoking, obesity, homocysteine and antiphospholipid antibodies were made. METHODS: 515 patients with unprovoked TED, 263 males, median age 44 years, were studied. Patients were divided into three groups: 258 with venous thrombosis (group A), 239 with arterial (group B) and 18 with mixed episodes (group C). All patients were interviewed regarding family history of TED, origin, smoking and dyslipidemia. Body mass index (BMI) had been calculated. Molecular assessment of the FVL, PTM and MTHFR C677T was performed. Antithrombin, protein C, protein S, APCR, homocysteine, antiphospholipid antibodies and lipid profile were also measured. RESULTS: The population studied was homogenous among three groups as regards age (p=0.943), lipid profile (p=0.271), BMI (p=0.506), homocysteine (p=0.177), antiphospholipid antibodies (p=0.576), and positive family history (p=0.099). There was no difference in the prevalence of FVL between venous and arterial disease (p=0.440). Significant correlation of PTM with venous TED was found (p=0.001). The number of positive and negative for MTHFR presented statistically significant difference with a support in arterial disease (p=0.05). Moreover, a 2-fold increase in the risk of venous thrombosis in FVL positive patients (odds ratio: 2.153) and a positive correlation of homocysteine levels with MTHFR C677T (p<0.001) was found. CONCLUSIONS: Correlation of PTM with venous thrombosis was established. Analysis showed no difference in prevalence of FVL between venous and arterial thrombosis, indicating that FVL might be a predisposing factor for arterial disease. A significant increase in MTHFR C677T prevalence in arterial disease was found. In conclusion, young patients with unprovoked arterial disease should undergo evaluation for thrombophilic genes. Identification of these mutations is important in the overall assessment and management of patients at high risk. Findings will influence the decisions of stratified approaches for antithrombotic therapy either primary or secondary thromboprophylaxis, the duration of therapy, the potential for avoiding clinical thrombosis by risk factor modification and the genetic counselling of family members. However, further studies are needed to clarify the nature of the association regarding venous and arterial thrombotic events.

Submillimetre galaxies reside in dark matter haloes with masses greater than 3 × 10(11) solar masses.

The extragalactic background light at far-infrared wavelengths comes from optically faint, dusty, star-forming galaxies in the Universe with star formation rates of a few hundred solar masses per year. These faint, submillimetre galaxies are challenging to study individually because of the relatively poor spatial resolution of far-infrared telescopes. Instead, their average properties can be studied using statistics such as the angular power spectrum of the background intensity variations. A previous attempt at measuring this power spectrum resulted in the suggestion that the clustering amplitude is below the level computed with a simple ansatz based on a halo model. Here we report excess clustering over the linear prediction at arcminute angular scales in the power spectrum of brightness fluctuations at 250, 350 and 500 µm. From this excess, we find that submillimetre galaxies are located in dark matter haloes with a minimum mass, M(min), such that log(10)[M(min)/M(⊙)] = 11.5(+0.7)(-0.2) at 350 µm, where M(⊙) is the solar mass. This minimum dark matter halo mass corresponds to the most efficient mass scale for star formation in the Universe, and is lower than that predicted by semi-analytical models for galaxy formation.

Effect of a plant stanol ester-containing spread, placebo spread, or Mediterranean diet on estimated cardiovascular risk and lipid, inflammatory and haemostatic factors.

BACKGROUND AND AIMS: Mediterranean diet is associated with a reduced risk for cardiovascular disease (CVD). Use of plant stanols decreases low density lipoprotein cholesterol (LDL-C) concentrations. We compared the effects of the Mediterranean diet and plant stanol esters on vascular risk factors and estimated CVD (eCVD) risk. METHODS AND RESULTS: In this prospective, randomized, placebo-controlled study, 150 mildly hypercholesterolaemic subjects were randomized to Mediterranean diet, a spread containing plant stanol esters (2 g/day) or a placebo spread. Vascular risk factors were assessed every month for 4 months and the eCVD risk was calculated using the PROspective- Cardiovascular-Munster (PROCAM), Framingham, and Reynolds risk engines. Placebo had no significant effect on risk factors or eCVD risk. Mediterranean diet gradually induced a significant reduction in total cholesterol (TC), LDL-C, triglycerides, high sensitivity C-reactive protein (hsCRP), blood pressure and eCVD risk (24-32%). The plant stanol ester spread reduced (by 1 month) TC (-14%), LDL-C (-16%), hsCRP (-17%), and estimated CVD risk (26-30%). eCVD risk reduction was sustained at 4th months when the gradual Mediterranean diet eCVD risk reduction became comparable to that of the stanol group. CONCLUSIONS: Plant stanol esters yielded an early, by 1st treatment month, reduction of eCVD risk that resulted from a TC, LDL-C, and hsCRP decrease. eCVD risk reduction on the Mediterranean diet resulted from a change in several CVD risk factors and equaled that of plant stanol at 4 months. The consumption of plant stanol esters by moderately hypercholesterolaemic patients may be a useful option to reduce CVD risk in those who do not adopt a Mediterranean diet.

Positive urinary cytology in patients with lung cancer in the absence of obvious urine tract metastases.

PURPOSE: To study the phenomenon of positive urine cytology in patients with lung cancer in the absence of obvious urothelial metastases. PATIENTS AND METHODS: 150 patients with small (SCLC) and non-small cell lung cancer (NSCLC) of all stages and 3 control groups were prospectively studied. Immunocytochemical study (cytokeratins 7-20, TTF1) in all positive urine specimens and chemokine profile (CXCR4, CCL21) study of the primary tumor in selected positive patients was performed. In experimental study, C57Bl/6 BALB/C mice injected with LLC lung and 4T1 mammary cancer cells were used for the detection of positive urine cytology. RESULTS: 11% of patients with NSCLC, 7% of patients with SCLC and none of the control group had positive urine cytology. In NSCLC, metastatic disease and high tumor burden positively correlated (p=0.01 and 0.03 respectively) with the phenomenon. In SCLC, correlation with extensive disease and multiple metastatic sites (p=0.02 and 0.04 respectively) was found. No correlation was found in either group with: age, gender, histology, performance status, line of chemotherapy, previous platinum-based chemotherapy, adrenal metastases, renal function, abnormal urinary sediment, response to chemotherapy and overall survival (p=0.9). Distinctive chemokine expression was identified in positive patients studied and was not observed in negative patients (×2 p=0.008). In the experimental study, only the LLC lung cancer cells were detected in the urine cytology of mice. CONCLUSION: This phenomenon, carrying undefined pathophysiological mechanisms, seems to characterize only patients with metastatic/extensive disease and high tumor burden. Further studies are needed to validate our preliminary chemokine expression results.

Preclinical evaluation of amiodarone for the treatment of murine leukemia P388. In vivo and in vitro investigation.

PURPOSE: The purpose of the present study was the investigation of antileukemic effect of amiodarone in leukemia P388 BDF1 bearing mice and its genotoxic and cytostatic effect in cultured normal human lymphocytes. METHODS: Leukemia P388 was used in this study. BDF1 mice were used for chemotherapy evaluation in vivo. The antitumor activity was assessed by the oncostatic parameter T/C, representing the increase of life span of drug-treated animals vs. controls. Lymphocyte cultures were used to study the genotoxic and cytostatic effect in vitro, expressed by enhanced sister chromatid exchange (SCE) and reduced proliferation rate indices (PRIS). RESULTS: Amiodarone was found to exert antileukemic potency against leukemia P388 bearing mice at all three different treatment schedules used, yielding T/C values of 155%, 163% with one cure and 230%. In the in vitro cytogenic experiments, significant increase of SCE rates by amiodarone was observed at 0.2 µM, while at the same concentration significant suppression of PRIS was achieved. CONCLUSION: According to the National Cancer Institute (NCI), a compound is characterized as potential chemotherapeutic deserving further evaluation if it produces T/C values≥125%. On the other hand the SCE assay has predictive value as a clinical assay for drugs exhibiting a strong correlation between cell killing and induction of SCEs. Further studies are warranted to clarify the structure-activity relationship of amiodarone.

Prognostic and predictive factors of invasive ductal breast carcinomas.

PURPOSE: To investigate the significance of certain immunohistochemical markers, namely estrogen (ER) and progesterone receptors (PgR), c-erbB-2 oncogene, p53 tumor suppressor gene and E-cadherin adhesion molecule, in invasive ductal breast carcinomas. METHODS: A series of 102 primary breast carcinomas of the ductal type and a standard immunohistochemical technique was used to detect the aforementioned biological markers. The findings were related to various clinical and pathological tumor characteristics, including lymph node metastases. RESULTS: ER and E-cadherin were expressed more commonly in tumors of low histological grade and small number (< or =3) of metastatic lymph nodes, whereas c-erbB-2 and the p53 gene were usually expressed in breast tumors of high histological grade and increased number (>3) of metastatic lymph nodes. PgR, on the other hand, was detected frequently in patients with early menarche and metastases in <3 lymph nodes, but this tendency was not statistically significant. CONCLUSION: The use of these biomarkers, preferably in combination, may provide additional prognostic and therapeutic information which may be proved useful in planning breast cancer treatment.

Structure-function relationships and clinical applications of L-asparaginases.

L-asparaginase (L-ASNase, EC 3.5.1.1) catalyzes the hydrolysis of the non-essential amino acid L-Asn to LAsp and ammonia and is widely used for the treatment of haematopoetic diseases such as acute lymphoblastic leukaemia (ALL) and lymphomas. Therapeutic forms of L-ASNase come from different biological sources (primarily E. coli and Erwinia chrysanthemi). It is well established that the various preparations have different biochemical pharmacology properties, and different tendency to induce side-effects. This is due to different structural, physicochemical and kinetic properties of L-ASNases from the various biological sources. Understanding these properties of various L-ASNases would allow a better decipherment of their catalytic and therapeutic features, thus enabling more accurate predictions of the behaviour of these enzymes under a variety of therapeutic conditions. In addition, detailed understanding of the catalytic mechanism of L-ASNases might permit the design of new forms of L-ASNases with optimal biochemical properties for clinical applications. In this paper we review the available biochemical and pharmacokinetic information of the therapeutic forms of bacterial L-ASNases, and focus on a detailed description of structure, function and clinical applications of these enzymes.