Most circulating tumor cells (CTC) are detected as single cells, whereas a small proportion of CTCs in multicellular clusters with stemness properties possess 20- to 100-times higher metastatic ...propensity than the single cells. Here we report that CTC dynamics in both singles and clusters in response to therapies predict overall survival for breast cancer. Chemotherapy-evasive CTC clusters are relatively quiescent with a specific loss of ST6GAL1-catalyzed α2,6-sialylation in glycoproteins. Dynamic hyposialylation in CTCs or deficiency of ST6GAL1 promotes cluster formation for metastatic seeding and enables cellular quiescence to evade paclitaxel treatment in breast cancer. Glycoproteomic analysis reveals newly identified protein substrates of ST6GAL1, such as adhesion or stemness markers PODXL, ICAM1, ECE1, ALCAM1, CD97, and CD44, contributing to CTC clustering (aggregation) and metastatic seeding. As a proof of concept, neutralizing antibodies against one newly identified contributor, PODXL, inhibit CTC cluster formation and lung metastasis associated with paclitaxel treatment for triple-negative breast cancer.
This study discovers that dynamic loss of terminal sialylation in glycoproteins of CTC clusters contributes to the fate of cellular dormancy, advantageous evasion to chemotherapy, and enhanced metastatic seeding. It identifies PODXL as a glycoprotein substrate of ST6GAL1 and a candidate target to counter chemoevasion-associated metastasis of quiescent tumor cells. This article is featured in Selected Articles from This Issue, p. 1949.
Background: High dose Melphalan (HDM) and autologous stem cell transplantation (ASCT) is a standard care for Myeloma ≤ 65 years. Studies have demonstrated that depth of response prior to ASCT does ...not impact outcome post ASCT, e.g. solely depth of response post ASCT matters. However, with improving induction regimens, the questions remains whether patients achieving a deeper response at completion of induction would not perform better post ASCT.
ASCT can only be performed in Tunisia if newly diagnosed Multiple Myeloma (NDMM) achieves at least PR; we therefore sought to report the national Tunisian experience.
Patients and Methods: NDMM aged ≤65 years received three cycles of Thalidomide (200mg daily) and Dexamethasone, followed by HDM and ASCT.52% received maintenance therapy for 12 months with Thalidomide, from 3 months post transplantation. Non responders to TD induction were salvaged with Lenalidomide or Bortezomib-based regimen. The response was assessed based on IMWG response criteria. The study is performed in ITT.
Results: 202 consecutive pts were included between April 2012 and December 2014. The median age was 56 yrs (range, 25-65), sex ratio was 1.R-ISS stage was 3 in 27.5%. 21% had high risk cytogenetic (by Conventional karyotyping and FISH). Renal failure was observed in 17%. ORR after induction was 71% with 12% CR, 17% VGPR. 22% failed to obtain PR following TD induction, and 51% of whom received salvage induction therapy (ST) with 72% that further reached ≥PR after ST. Overall, 141 pts (70%) underwent ASCT, 121 of whom had evidence of chemo-sensitive MM at completion of induction. 16% were transplanted in CR, 22% in VGPR and 62% in PR.
At 3 months post-ASCT, the ORR in induction chemo-sensitive MM was 89%: 36% CR, 20% VGPR, and 33% PR. With a median follow-up post-ASCT of 27 months, the OS, PFS and EFS at 27 months were 82%, 60.5% and 56%, respectively. Maintenance treatment was significantly associated with longer PFS only in MM who did not achieve CR (29 versus 9 months, p=0.004). MM with improved response post-ASCT had a significantly longer PFS (39 versus 21 months, p=0.003) and EFS (39 versus 20 months, p=0.002). Importantly, achieving CR before (p=0.03) and after ASCT (p<0.0001) was also predictive for prolonged EFS. Early relapses/progressions (less than 18 months) was the sole predictive factor of adverse OS in our study (p=0.01).
In multivariate analysis, ISS stage 3 was the sole independent predictor of induction failure (p=0.003). Importantly, predictive factors of achievement of CR post-ASCT comprised absence of delay farther to 4 months from completion of induction (p=0.006; OR = 4.54) and achievement of at least VGPR status before transplant (p=0,001; OR = 4.09).
Conclusion: Achievement of at least VGPR at completion of induction improved response after ASCT and consequently influenced the post-ASCT outcome. Therefore, depth of response matters before and after ASCT, and validates in some extent the concept of induction salvage therapy prior to ASCT for patient not reaching response.
Leleu:TEVA: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria.
We report on the formation of equilateral triangular clusters hollow inside with 5-6 atoms per side, self-assembled on Ni adislands grown on Rh(111). The observation of standing wave patterns on the ...Ni adislands and the Rh(111) indicates that the self-assembly is mediated by Friedel oscillations. In this context, we propose a model based on the energy of interaction between adsorbates, which explains the formation of the clusters as a result of the assembly of rows of 5-6 adatoms.
Two olfactory receptors (ORs), mouse M71 and chimpanzee OR7D4, were immobilized onto synthetic diamond transducers surfaces. 6His tagged M71 (6His-M71) was grafted using covalent attachment of ...nitriloacetic acid (NTA) as chelating agent, which could bind the 6His tagged receptor through nickel ions. OR7D4 was grafted through covalent bonding of hexanoic acid radical on diamond followed by EDC/NHS peptidic coupling to the receptor. Both grafting procedures were monitored by electrochemical impedance spectroscopy (EIS) on boron doped diamond (BDD) electrodes. Then the grafting protocols were applied to the surface of bulk diamond micro-cantilevers. The resulting sensors were assessed for odorant detection in the liquid phase using a Laser Doppler read-out system. The 6His-M71 based sensor was found to exhibit a good sensitivity to acetophenone, with a typical frequency shift near 100 Hz for 1 μM exposure, with a good selectivity against negative control 2-octanone. The OR7D4 based sensor showed a sensitivity of 200 Hz for exposures to 1 or 10 μM androstenone with a good selectivity against both non-ligands acetophenone and 2-octanone.
A novel bacteriocin, lactococcin MMFII, produced by Lactococcus lactis MMFII isolated from a Tunisian dairy product had been identified. The bacteriocin was purified to homogeneity from fresh ...overnight M17 broth culture by sulfate ammonium precipitation, cation-exchange chromatography, sep-pack chromatography and two steps of reverse-phase chromatography. The purified bacteriocin was heat stable, pH resistant and protease sensitive. Its amino acid sequence, obtained by Edman degradation, revealed a 37-amino acid peptide with two cysteine residues in positions 9 and 14 and a calculated mass of 4144.6 Da. Laser desorption mass spectrometry analysis gave a molecular mass of 4142.6, suggesting the presence of a disulfide bond within the purified bacteriocin. Lactococcin MMFII contains the N-terminal YGNGV consensus motif and is active against Listeria. Thus, it belongs to the class IIa bacteriocins figuring the first example of such a bacteriocin produced by a lactococcal strain.
BackgroundTherapeutic non-adherence is a major problem in patients with chronic kidney disease. This is the major cause of rejection in renal transplant patients.PurposeThe aim of this work was to ...evaluate the therapeutic adherence in renal transplant patients and to identify the causes of poor adherence.Material and methodsThis was a prospective study carried out on patients hospitalised in the renal transplant unit over a period of 4 months: from 1 April to 31 July 2016. All patients hospitalised during this period are included in the study. The test used to assess therapeutic adherence was Morisky’s test. Questioning was conducted for each patient to who were asked to fill inclinical information sheet. Data analysis was done by SPSS.ResultsWe studied 33 renal transplant patients. The average age of these patients was 43-years-old with extremes ranging from 20 to 59 years old. The number of male patients was 22 (66.6%) and the number of female patients was 11 (33.3%). Twenty-one patients had secondary level of education (63,3%), seven patients had primary level of education (21.2%) and four patients had university level of education (12%). Only one patient was illiterate (3.03%). Twenty patients had a minimal therapeutic adherence problem, which represents 60.6%. Twelve patients had good compliance (36.4%) and one had poor compliance (3.03%). Several reasons for non-compliance were raised. Forgetting medication represents 15.2%. The important number of drugs leads to therapeutic non-compliance and accounts for 18.2%. The ineffectiveness of the treatment represents a reason for non-compliance and represents 3.03%. The occurrence of adverse events represents 9.09%. The feeling of embarrassment and shyness when taking medication in front of others accounts for 25.7%.ConclusionSeveral causes are responsible for non-compliance such as forgetfulness, the multitude of drugs, ineffectiveness, the occurrence of adverse effects and the feeling of shyness when taking medication in front of others. A lot of these barriers are preventable just by better communication between the patient, his doctor and the care system. Therapeutic education is important in improving therapeutic adherance.References and/or AcknowledgementsM. Belrhiti, L. Benamar S. Hacib, A. Abouzoubair. Observance thérapeutique après transplantation rénale:expérience du service de néphrologie du CHU Ibn-Sina de Rabat. 2017.No conflict of interest
Introduction: Chronic myeloid leukemia (CML) accounts for 7%-15% of all leukemias affecting adults. The incidence in Algeria is 0.4/100,000 inhabitants in 2009. The aim of this study is to establish ...an Algerian-Tunisian epidemiological approach of CML and to know the characteristics of the disease in both countries.
Materials and methods: This is a retrospective, longitudinal and multicenter study, including Algerian and Tunisian patients with CML diagnosed between January 2010 and December 2014. Through a data form distributed to various hematology departments, we collected and analyzed the following information: Patient's general characteristics, profession, circumstances of discovery of the disease, clinical and para-clinical examinations outcomes at the time of diagnosis including blood count, blood smear, bone marrow aspiration, cytogenetics, molecular biology, stages of the disease and the Sokal and Eutos prognostic classification scores. Bio-statistical tests: incidence, prevalence and rate of prevalence or relative prevalence (reported to 100,000 inhabitants / year). The descriptive analysis of quantitative and qualitative variables as percentages and 95% confidence interval. The Chi2 test is used to compare two variables.
Results: We collected 1349 cases, including 325 from 06 Tunisian hematology units and 1024 from 18 Algerian units. The incidence in the Algerian-Tunisian population was 0.67/100,000 inhabitants with a prevalence rate of 2.72/100,000 inhabitants. The incidence in Tunisia was 0.50 / 100,000 inhabitants with a prevalence of 227 cases in 2014. In Algeria the incidence was 0.53/100,000 inhabitants with a prevalence of 1030 in 2014. The median age is 48 years (03-90) with a peak incidence in the age group (45-49 ans) and slight male predominance (sex ratio: 1,2). There was any notion of risk exposure. The average time between the start of the unrest and the date of diagnosis is 127 days (1-667). The circumstances of discovery: fortuitous in 30.5% (n = 355), splenomegaly in 39.7% (n = 463), asthenia in 24.6% (n = 287), a complication in 8.4% (n =95). Clinical examination includes general signs in 424 cases (36.4%): Weight loss 22.6% (n = 263), profuse sweating 13.8% (n = 13, 8%), bone pains found in 7.8%, splenomegaly in 81.7% (n = 952) with an overhang splenic average of 11.5 ± 5.3 cm (1-28), cutaneous and subcutaneous bleeding: 13.5% (n = 97), thrombosis 0.9% (n = 09). Biological characteristics: the Complete blood count (n = 1185) shows a white blood cells average rate of 171,223 G/L (34,700-984,800), hemoglobin average rate of 10.2 g/dl (4-17), platelets at 394,070 g/l (85-1340). Blood smear 96.3% (n = 1121): the average myelemia was 43.2% (10-98%). The Myelogram is practiced in 55% (n = 641), the average rate of the granular 76,5% (40-99%), erythroblasts 10.5% (0-82%), average blasts 3.6%. The karyotype 38.1% (n = 444), the Philadelphia chromosome was found in 423 cases (95, 3%); additional abnormalities were found in 17 cases (3.8%). The Fish was practiced in 281 cases (24.1%) and transcribed bcr/abl was found in 257 cases (91.4%). Molecular biology is practiced in 672 cases (57.7%) the transcript bcr/abl is found in 100%, the transcript of the type is specified in 373 cases, it is kind of b2a2 in 159 cases (42.6%), a b3a2 type in 180 cases (48.3%) and other transcribed in 34 cases (9.1%). CML chronic phase is diagnosed in 88.8% (n = 1051), acceleration phase in 9% (n = 107) acutisation phase in 3.1% (= 37). The distribution of pts according to Sokal prognostic classification (n = 948) describes a predominance of intermediate risk in 54% (n = 511), high risk in 30.3% (n = 287) and low risk in 16% (n = 152). The Eutos score is specified in 769 cases (66%), it is less than 87 in 661 cases (86%) and more than 87 in 108 cases (14%).
Conclusion: The incidence of CML in the Algerian-Tunisian population is 0.67/100,000 population with a prevalence rate of 2.72/100,000 inhabitants. The young adult is more affected with a peak incidence between 45 and 49. The average time between the onset of the disease and the diagnosis remains long and the delay probably explains the frequency of tumor forms encountered in Algeria and the prevalence of high and intermediate risk, according to Sokal prognostic classification.
No relevant conflicts of interest to declare.
Calponins are a small family of proteins that alter the interaction between actin and myosin II and mediate signal transduction. These proteins bind F-actin in a complex manner that depends on a ...variety of parameters such as stoichiometry and ionic strength. Calponin binds G-actin and F-actin, bundling the latter primarily through two distinct and adjacent binding sites (ABS1 and ABS2). Calponin binds other proteins that bind F-actin and considerable disagreements exist as to how calponin is located on the filament, especially in the presence of other proteins. A study (Galkin, V.E., Orlova, A., Fattoum, A., Walsh, M.P. and Egelman, E.H. (2006)
J. Mol. Biol. 359, 478–485.), using EM single-particle reconstruction has shown that there may be four modes of interaction, but how these occur is not yet known. We report that two distinct regions of calponin are capable of binding some of the same sites on actin (such as 18–28 and 360–372 in subdomain 1). This accounts for the finding that calponin binds the filament with different apparent geometries. We suggest that the four modes of filament binding account for differences in stoichiometry and that these, in turn, arise from differential binding of the two calponin regions to actin. It is likely that the modes of binding are reciprocally influenced by other actin-binding proteins since members of the α-actinin group also adopt different actin-binding positions and bind actin principally through a domain that is similar to calponin's ABS1.
Asthma in Tunisian elite athletes Sallaoui, R; Chamari, K; Chtara, M ...
International journal of sports medicine,
07/2007, Letnik:
28, Številka:
7
Journal Article
Recenzirano
Several studies in the past few decades have shown that very intense and repeated exercise, particularly when performed over many years, could cause respiratory health problems. The prevalence of ...exercise-induced asthma has increased in the athletic population, particularly in elite athletes and has not been published in North African athletes. The aim of this study was to determine the prevalence of exercise-induced asthma and/or exercise-induced bronchoconstriction in Tunisian elite athletes. Each participant responded to a questionnaire about respiratory symptoms and medical history and underwent a resting spirometry testing before exercise. Exercise-induced bronchoconstriction was defined as a decrease of at least 15% in pre-exercise forced expiratory volume in one second at any time point after exercise. Post-exercise spirometry revealed the presence of exercise induced bronchoconstriction in 14 out of 107 (13%) elite athletes, while only 1.8% of the subjects reported having previously diagnosed asthma. The prevalence of exercise-induced bronchoconstriction was 19% (8/42) among those athletes training outdoors and 10% (6/65) among those training indoors. In conclusion, our findings indicate that a significant number of Tunisian athletes had exercise-induced bronchoconstriction while not diagnosed before.
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