Antibacterial prophylaxis with ciprofloxacin for patients with multiple myeloma and lymphoma undergoing autologous haematopoietic cell transplantation: a quasi-experimental single-centre before-after study.

OBJECTIVES: We aimed to study whether ciprofloxacin prophylaxis reduces infectious complications in patients undergoing autologous haematopoietic cell transplantation (AHCT). METHODS: This is a quasi-experimental, retrospective, before-after study. We compared the incidence of bacterial-related complications among 356 patients with multiple myeloma (MM) (n = 202) and lymphoma (n = 154) who underwent AHCT with (n = 177) or without (n = 179) ciprofloxacin prophylaxis between 03/2007 and 10/2012 and between 10/2012 and 07/2016, respectively, at a single centre. RESULTS: Febrile neutropaenia, bacteraemia, and pneumonia were significantly more common among patients who underwent AHCT during the second study period and did not receive antibacterial prophylaxis compared with patients who underwent AHCT during the first study period and received antibacterial prophylaxis (89.9% (161/179) vs. 83.1% (147/177), difference 6.9%, 95% CI 0-14.1%, P = 0.002; 15.1% (27/179) vs. 4.5% (8/177), difference 10.6%, 95% CI 4.4-16.9%, p < 0.0001; 12.3% (22/179) vs. 6.2% (11/177), difference 6.1%, 95% CI 0-12.3%, p = 0.04, respectively). The number-needed-to-treat to prevent one episode of bacteraemia, pneumonia, and febrile neutropaenia was 8.6, 8.5, and 13.7, respectively. Patients with ciprofloxacin prophylaxis had higher rates of ciprofloxacin-resistant bacteraemia (62.5% (5/8) vs. 18.5% (5/27), difference 44%, 95% CI 7-70%, p = 0.01). In multivariate analysis, ciprofloxacin prophylaxis significantly decreased the odds of bacteraemia (OR 0.19, 95% CI 0.07-0.52; p < 0.0001) and pneumonia (OR 0.37, 95% CI 0.16-0.85, p = 0.02). CONCLUSION: According to our single-centre experience, patients with MM and lymphoma undergoing AHCT may benefit from antibacterial prophylaxis with ciprofloxacin.

Educational interventions encouraging appropriate use of blood transfusions.

BACKGROUND AND OBJECTIVES: The integration of a restrictive packed red blood cells (PRBC) transfusion strategy into daily clinical practice presents a challenge. This study describes the effect of an intervention including educational presentations and computerized alerts on PRBC utilization at a tertiary hospital. MATERIALS AND METHODS: During December 2014, lectures describing recommended PRBC transfusion indications were presented to all non-intensive care departments. Starting from January 2015, an alert was added to the electronic drug ordering system recommending transfusions at a haemoglobin (Hb) level <7 g/dl or Hb < 8 g/dl in symptomatic patients. The physician was not required to acknowledge the alert. Data regarding measured Hb preceding transfusions were collected. The primary end-point was defined as the percentage of PRBC administered at Hb ≥ 8 g/dl in 2015 compared with 2014. Secondary end-points were the percentage of PRBC administered to patients with Hb < 7 g/dl and the absolute number of PRBC transfused in 2015 compared with 2014. RESULTS: Compared to 2014, in 2015, the percentage of PRBC transfused when the Hb ≥ 8 g/dl was reduced by 18·8% (P < 0·001) and made up 29% of the total PRBC transfused. The absolute number of PRBC transfused decreased by 7·7%. The percentage of PRBC transfused when the Hb < 7 g/dl increased by 25·9% (P < 0·001). CONCLUSIONS: Following the described intervention, there was a significant improvement in the appropriateness of PRBC transfusions in our medical centre. These changes occurred despite the lack of interruption of the physician's workflow from the computerized alert. This simple strategy might be of use in implementing a restrictive PRBC transfusion strategy.

Origin and structure of polar domains in doped molecular crystals.

Doping is a primary tool for the modification of the properties of materials. Occlusion of guest molecules in crystals generally reduces their symmetry by the creation of polar domains, which engender polarization and pyroelectricity in the doped crystals. Here we describe a molecular-level determination of the structure of such polar domains, as created by low dopant concentrations (<0.5%). The approach comprises crystal engineering and pyroelectric measurements, together with dispersion-corrected density functional theory and classical molecular dynamics calculations of the doped crystals, using neutron diffraction data of the host at different temperatures. This approach is illustrated using centrosymmetric α-glycine crystals doped with minute amounts of different L-amino acids. The experimentally determined pyroelectric coefficients are explained by the structure and polarization calculations, thus providing strong support for the local and global understanding of how different dopants influence the properties of molecular crystals.

Malignancy associated SIADH: Characterization and clinical implications.

PURPOSE: To determine the distribution of etiologies for the syndrome of inappropriate antidiuretic hormone secretion (SIADH) in hospitalized patients with active malignancies and to characterize them according to the different etiologies. METHODS: A single center retrospective study including all patients with active malignancies diagnosed with SIADH in a large community hospital and tertiary center between 1 January 2007 and 1 January 2013. Two physicians reviewed every patient's medical file for predetermined relevant clinical data. RESULTS: The study cohort included 204 patients. 74.4% of those with solid tumors had metastatic disease. Most patients (149, 73%) had malignancy associated SIADH, while 55 (27%) had SIADH due to other etiologies. All of the major malignancy types were implicated in SIADH. Patients with breast cancer without lung or brain involvement were significantly less likely to be diagnosed with malignancy associated SIADH compared with other malignancies [Odds ratio (OR) 0.031, 95% CI 0.003-0.25, p < 0.001]. Patients with malignancy associated SIADH had lower serum sodium concentrations on short-term follow-up (p = 0.024) and significantly shorter median survival (58 vs. 910 days, p < 0.001). Short-term hyponatremia correction was associated with better survival. CONCLUSIONS: SIADH is associated with most malignancy types. Physicians caring for patients with breast cancer without lung or brain involvement diagnosed with SIADH without an obvious etiology should consider obtaining lung and brain imaging to rule out undiagnosed metastatic spread. Patients with malignancy associated SIADH have considerably worse outcomes compared to cancer patient with SIADH due to other etiologies. Short-term sodium concentration can be used as a prognostic marker for these patients.

Nanocrystallinity and direct cross-linkage as key-factors for the assembly of gold nanoparticle-superlattices.

We report here how the crystallinity of AuNPs and the choice of binding sites of molecular cross-linkers control their aggregation. The combination of different binding moieties (N-oxides, ArF-I) and the reactivity of the particles' facets allow control over the organization and crystallinity of the AuNP assemblies.

Secondary malignancies following high dose therapy and autologous hematopoietic cell transplantation-systematic review and meta-analysis.

We performed a systematic review and meta-analysis of randomized controlled trials comparing autologous hematopoietic cell transplantation (HCT) with other treatment modalities to analyze the risk for various secondary malignancies (SMs). Relative risks (RR) with 95% confidence intervals were estimated and pooled. Our search yielded 36 trials. The median follow-up was 55 (range 12-144) months. Overall, the RR for developing SMs was 1.23 ((0.97-1.55), I(2)=4%, 9870 patients). Subgroup analysis of trials assessing TBI-containing preparative regimens and of patients with baseline lymphoproliferative diseases, showed there was a higher risk for SMs in patients given autografts (RR=1.61 (1.05-2.48), I(2)=14%, 2218 patients and RR=1.62 (1.12-2.33), I(2)=22%, 3343 patients, respectively). Among all patients, there was a higher rate of myelodysplastic syndrome MDS/AML in patients given HCT compared with other treatments (RR=1.71 (1.18-2.48), I(2)=0%, 8778 patients). The risk of secondary solid malignancies was comparable in the short term between patients given HCT and patients given other treatments (RR=0.95 (0.67-1.32), I(2)=0%, 5925 patients). We conclude that overall the risk of secondary MDS/AML is higher in patients given autologous HCT compared with other treatments. In the subgroup of patients given a TBI-based regimen and in those with a baseline lymphoproliferative disease, there was a higher risk of overall SMs.

The effects of telomere shortening on cancer cells: a network model of proteomic and microRNA analysis.

Previously, we have shown that shortening of telomeres by telomerase inhibition sensitized cancer cells to cisplatinum, slowed their migration, increased DNA damage and impaired DNA repair. The mechanism behind these effects is not fully characterized. Its clarification could facilitate novel therapeutics development and may obviate the time consuming process of telomere shortening achieved by telomerase inhibition. Here we aimed to decipher the microRNA and proteomic profiling of cancer cells with shortened telomeres and identify the key mediators in telomere shortening-induced damage to those cells. Of 870 identified proteins, 98 were differentially expressed in shortened-telomere cells. 47 microRNAs were differentially expressed in these cells; some are implicated in growth arrest or act as oncogene repressors. The obtained data was used for a network construction, which provided us with nodal candidates that may mediate the shortened-telomere dependent features. These proteins' expression was experimentally validated, supporting their potential central role in this system.

Differential downregulation of telomerase activity by bortezomib in multiple myeloma cells-multiple regulatory pathways in vitro and ex vivo.

BACKGROUND: The importance of telomerase in multiple myeloma (MM) is well established; however, its response to bortezomib has not been addressed. METHODS: The effect of bortezomib on telomerase activity and cell proliferation was evaluated in four MM cell lines and in myeloma cells obtained from eight patients. The mechanism of telomerase regulation on epigenetic, transcriptional, and post-translational levels was further assessed in two selected cell lines: ARP-1 and CAG. Clinical data were correlated with the laboratory findings. RESULTS: Bortezomib downregulated telomerase activity and decreased proliferation in all cell lines and cells obtained from patients, albeit in two different patterns of kinetics. ARP-1 cells demonstrated higher and earlier sensitivity than CAG cells due to differential phosphorylation of hTERT by PKCα. Methylation of hTERT promoter was not affected. Transcription of hTERT was similarly inhibited in both lines by decreased binding of SP-1 and not of C-Myc and NFκB. The ex vivo results confirmed the in vitro findings and suggested existence of clinical relevance. CONCLUSION: Bortezomib downregulates telomerase activity in MM cells both transcriptionally and post-translationally. MM cells, both in vitro and in patients, exhibit different sensitivity to the drug due to different post-translational response. The effect of bortezomib on telomerase activity may correlate with resistance to bortezomib in patients, suggesting its potential utility as a pre-treatment assessment.

Racemic beta-sheets as templates of relevance to the origin of homochirality of peptides: lessons from crystal chemistry.

The origin of life is a historical event that has left no relevant fossils; therefore, it is unrealistic to reconstruct the chronology of its occurrence. Instead, by performing laboratory experiments under conditions that resemble the prebiotic world, one might validate feasible reaction pathways and reconstruct model systems of artificial life. Creating such life in a test tube should go a long way toward removing the shroud of mystery over how it began naturally. The riddle of the appearance of natural proteins and nucleic acids--that is, biopolymers wholly consisting of homochiral subunits (L-amino acids and D-sugars, respectively)--from the unanimated racemic prebiotic world is still unsolved. There are two hypotheses concerning the sequence of their emergence: one maintains that long homochiral (isotactic) peptides must have been formed after the appearance of the first living systems, whereas the other presumes that such biopolymers preceded the primeval enzymes. The latter scenario necessitates, however, the operation of nonlinear synthetic routes, because the polymerization of racemates in ideal solutions yields chains composed of residues of either handedness. In this Account, we suggest applying lessons learned from crystal chemistry, in which molecules from isotropic media are converted into crystals with three-dimensional (3D) periodic order, to understand how the generation of homochiral peptides from racemic alpha-amino acids might be achieved, despite its seemingly overwhelming complexity. We describe systems that include the self-assembly of activated alpha-amino acids either in two-dimensional (2D) or in 3D crystals, followed by a partial lattice-controlled polymerization at the crystal-aqueous solution interface. We also discuss the polymerization of mixtures of activated hydrophobic racemic alpha-amino acids in aqueous solutions, as initiated by primary amines or thiols. The distribution of the diastereomeric oligopeptides was analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and MS/MS with monomers enantioselectively tagged with deuterium. The reaction performed in aqueous solutions encompasses the following sequential steps: (i) formation of a library of short racemic peptides enriched with isotactic diastereoisomers during the early stages of the polymerization, and (ii) self-assembly of oligopeptides into racemic beta-sheet colloidal-like aggregates that are delineated by enantiotopic sites or rims; these operate as templates (nuclei) for regio-enantioselective growth in the ensuing steps of chain elongation. Desymmetrization of the racemic mixtures of peptides was achieved with enantiopure alpha-amino acid esters as initiators. The enantiomeric excess of the isotactic peptides, not including the initiator, varies with chain length, the result of a cross-enantiomeric impeding mechanism. Our results suggest a feasible scenario in which primitive homochiral peptides might have emerged early in the prebiotic world.

Combined antiproliferative activity of imatinib mesylate (STI-571) with radiation or cisplatin in vitro.

UNLABELLED: Little is known about the interaction of novel anticancer drugs with other treatment modalities. THE AIM of this study was to examine the effect of combining imatinib mesylate (STI-571) with radiation or cisplatin on the survival of two human solid tumor cell lines - SKNMC cells derived from Ewing sarcoma and breast cancer MCF-7 cells. METHODS: Cell proliferation was determined using the sulphorodamine B cytotoxicity assay. Cell cycle analysis was performed with flow cytometry. Apoptosis was determined using a commercial cell death ELISA plus kit. Phosphorylated AKT, which has been suggested to be involved in radiation resistance, was detected by Western blot analysis. RESULTS: Exposure of SKNMC cells to STI-571 resulted in a dose-dependent antiproliferative effect and a decrease in phosphorylated AKT expression. There was no evidence of apoptosis. The combination of STI-571 with radiation or cisplatin had an additive antiproliferative effect in SKNMC cells (60% reduction in cell number). A similar effect was observed in human MCF-7 breast cancer cells. CONCLUSION: STI-571 improves the outcome of cisplatin or irradiation treatment in vitro. AKT pathway may play a role in the additive effect of STI-571 and irradiation.

Clinical outcome of low-grade NHL patients with bone marrow involvement.

BACKGROUND: Bone marrow (BM) involvement in low-grade non-Hodgkin's lymphoma (NHL) has a clear impact on patients' survival. The standard practice is morphological examination of BM biopsy at diagnosis. The clinical significance of flow cytometry (FC) analysis of BM aspirates is largely unknown. MATERIALS AND METHODS: The medical charts of 70 low-grade NHL patients, who underwent BM biopsy and FC analysis between 1994 and 2004, were reviewed. RESULTS: Forty-three patients (61.4%) were BM+ by morphology, while in those without morphological involvement by lymphoma FC was positive in 9 (BM-FC+, 12.9%) and negative in 18 (BM-FC-, 25.7%). The median treatment-free period was shorter in the BM+ and BM-FC+ groups compared with the BM-FC- group (1 and 4 months vs. 31 months, respectively) (log-rank test, P = 0.0195). The median survival time was not reached for the BM-FC- patients, whereas for BM+ and BM-FC+ patients it was 129 and 89 months, respectively, with no significant difference between them [the difference between the BM-FC- and the two other groups was statistically significant (log-rank test, P = 0.029)]. CONCLUSIONS: The outcome of low grade NHL in patients who had BM involvement by FC alone or by morphology was similar. If confirmed, these findings suggest a modification in the workup and management of localized low grade NHL.

Imatinib mesylate (Gleevec) downregulates telomerase activity and inhibits proliferation in telomerase-expressing cell lines.

Imatinib mesylate (IM) is a tyrosine kinase inhibitor, which inhibits phosphorylation of downstream proteins involved in BCR-ABL signal transduction. It has proved beneficial in treating patients with chronic myeloid leukaemia (CML). In addition, IM demonstrates activity against malignant cells expressing c-kit and platelet-derived growth factor receptor (PDGF-R). The activity of IM in the blastic crisis of CML and against various myeloma cell lines suggests that this drug may also target other cellular components. In the light of the important role of telomerase in malignant transformation, we evaluated the effect of IM on telomerase activity (TA) and regulation in various malignant cell lines. Imatinib mesylate caused a dose-dependent inhibition of TA (up to 90% at a concentration of 15 microM IM) in c-kit-expressing SK-N-MC (Ewing sarcoma), SK-MEL-28 (melanoma), RPMI 8226 (myeloma), MCF-7 (breast cancer) and HSC 536/N (Fanconi anaemia) cells as well as in ba/F3 (murine pro-B cells), which do not express c-kit, BCR-ABL or PDGF-R. Imatinib mesylate did not affect the activity of other DNA polymerases. Inhibition of TA was associated with 50% inhibition of proliferation. The inhibition of proliferation was associated with a decrease in the S-phase of the cell cycle and an accumulation of cells in the G2/M phase. No apoptosis was observed. Inhibition of TA was caused mainly by post-translational modifications: dephosphorylation of AKT and, to a smaller extent, by early downregulation of hTERT (the catalytic subunit of the enzyme) transcription. Other steps of telomerase regulation were not affected by IM. This study demonstrates an additional cellular target of IM, not necessarily mediated via known tyrosine kinases, that causes inhibition of TA and cell proliferation.

Fluorouracil induces apoptosis and surface molecule modulation of peripheral blood leukocytes.

Little is known about the direct effect of chemotherapy on normal peripheral blood leukocytes (PBL) or its contribution to leukopenia. We examined 5'-fluorouracil's (5FU) effect on PBL apoptosis and adhesion molecules' expression in a single-drug solid-tumor model. Possible apoptosis mediators were examined. The study included 32 colorectal cancer patients; apoptosis was determined by annexin-V binding and light-scatter morphology before and after drug infusion. CD18, CD11a, CD11b, and CD63 membranal levels were assayed by flow cytometry. Apoptosis was increased post-5FU administration in neutrophils (PMN), monocytes and lymphocytes (P < 0.05). Levels of Fas receptor and activated caspase 3 did not vary indicating that the process was not mediated by caspase 3 in the timeframe studied. Reduced CD63 on monocytes and decreased CD18 expression on PMN and non-apoptotic monocytes were observed (P < or = 0.05). CD11a,b expression did not vary. Decreased CD18 and CD63 levels were demonstrated in apoptotic and non-apoptotic PBL implying a more direct association with the drug itself.

Lidocaine inhibits secretion of IL-8 and IL-1beta and stimulates secretion of IL-1 receptor antagonist by epithelial cells.

Lidocaine and related local anaesthetics have been shown to be effective in the treatment of ulcerative colitis (UC). However, the mechanisms underlying their therapeutic effect are poorly defined. Intestinal epithelial cells play an important role in the mucosal inflammatory response that leads to tissue damage in UC via the secretion of pro-inflammatory cytokines and chemokines. The aim of this study was to evaluate the direct immunoregulatory effect of lidocaine on pro-inflammatory cytokine and chemokine secretion from intestinal epithelial cells. HT-29 and Caco-2 cell lines were used as a model system and treated with lidocaine and related drugs. The expression of IL-8, IL-1beta and the IL-1 receptor antagonist (RA) were assessed by ELISA and quantification of mRNA. In further experiments, the effect of lidocaine on the secretion of IL-8 from freshly isolated epithelial cells stimulated with TNFalpha was tested. Lidocaine, in therapeutic concentrations, inhibited the spontaneous and TNFalpha-stimulated secretion of IL-8 and IL-1beta from HT-29 and Caco-2 cell lines in a dose-dependent manner. Similarly, suppression of IL-8 secretion was noted in the freshly isolated epithelial cells. Other local anaesthetics, bupivacaine and amethocaine, had comparable effects. Lidocaine stimulated the secretion of the anti-inflammatory molecule IL-1 RA. Both the inhibitory and the stimulatory effects of lidocaine involved regulation of transcription. The results imply that the therapeutic effect of lidocaine may be mediated, at least in part, by its direct effects on epithelial cells to inhibit the secretion of proinflammatory molecules on one hand while triggering the secretion of anti-inflammatory mediators on the other.

Imprinting of chiral molecular recognition sites in thin TiO2 films associated with field-effect transistors: novel functionalized devices for chiroselective and chirospecific analyses.

(R)- or (S)-2-Methylferrocene carboxylic acids, (R)-1 or (S)-1, (R)- or (S)-2-phenylbutanoic acid, (R)-2 or (S)-2, and (R)- or (S)-2-propanoic acid, (R)-3 or (S)-3, can be imprinted in thin TiO2 films on the gate surface of ion-sensitive field-effect transistor (ISFET) devices. The imprinting is performed by hydrolyzing the respective carboxylate TiIV butoxide complex on the gate surface, followed by washing off the acid from the resulting TiO2 film. The imprinted sites reveal chiroselectivity only towards the sensing of the imprinted enantiomer. The chiral recognition sites reveal not only chiroselectivity but also chirospecificity and, for example, the (R)-2-imprinted film is active in the sensing of (R)-2, but insensitive towards the sensing of (R)2-phenylpropanoic acid, (R)-3, which exhibits a similar chirality. Similarly, the (R)-3-imprinted film is inactive in the analysis of (R)-2. The chiroselectivity and chirospecificity of the resulting imprinted films are attributed to the need to align and fit the respective substrates in precise molecular contours generated in the cross-linked TiO2 films upon the imprinting process.