Towards multifunctional lanthanide-based metal-organic frameworks.

We report the synthesis, structure and physicochemical attributes of a new holmium(III)-based metal-organic framework whose 3D network structure gives rise to porosity; the reported structure-type can be varied using a range of different lanthanide ions to tune the photophysical properties and produce ligand-sensitised near-infrared (NIR) and visible light emitters.

Hetero-epitaxial approach by using labile coordination sites to prepare catenated metal-organic frameworks with high surface areas.

A solid-state approach that takes advantage of the ordered 3D arrangement of active secondary building units allows the preparation of new interlocked MOFs that grow hetero-epitaxially on the crystal faces of a precursor phase that acts as a "topological blueprint". The synthetic strategy is exemplified by using rigid acetylene-based ligands to produce highly augmented Cu(II) acetate-based MOFs.

Stat1 activation attenuates IL-6 induced Stat3 activity but does not alter apoptosis sensitivity in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is at present an incurable malignancy, characterized by apoptosis-resistant tumor cells. Interferon (IFN) treatment sensitizes MM cells to Fas-induced apoptosis and is associated with an increased activation of Signal transducer and activator of transcription (Stat)1. The role of Stat1 in MM has not been elucidated, but Stat1 has in several studies been ascribed a pro-apoptotic role. Conversely, IL-6 induction of Stat3 is known to confer resistance to apoptosis in MM. METHODS: To delineate the role of Stat1 in IFN mediated sensitization to apoptosis, sub-lines of the U-266-1970 MM cell line with a stable expression of the active mutant Stat1C were utilized. The influence of Stat1C constitutive transcriptional activation on endogenous Stat3 expression and activation, and the expression of apoptosis-related genes were analyzed. To determine whether Stat1 alone would be an important determinant in sensitizing MM cells to apoptosis, the U-266-1970-Stat1C cell line and control cells were exposed to high throughput compound screening (HTS). RESULTS: To explore the role of Stat1 in IFN mediated apoptosis sensitization of MM, we established sublines of the MM cell line U-266-1970 constitutively expressing the active mutant Stat1C. We found that constitutive nuclear localization and transcriptional activity of Stat1 was associated with an attenuation of IL-6-induced Stat3 activation and up-regulation of mRNA for the pro-apoptotic Bcl-2 protein family genes Harakiri, the short form of Mcl-1 and Noxa. However, Stat1 activation alone was not sufficient to sensitize cells to Fas-induced apoptosis. In a screening of > 3000 compounds including bortezomib, dexamethasone, etoposide, suberoylanilide hydroxamic acid (SAHA), geldanamycin (17-AAG), doxorubicin and thalidomide, we found that the drug response and IC50 in cells constitutively expressing active Stat1 was mainly unaltered. CONCLUSION: We conclude that Stat1 alters IL-6 induced Stat3 activity and the expression of pro-apoptotic genes. However, this shift alone is not sufficient to alter apoptosis sensitivity in MM cells, suggesting that Stat1 independent pathways are operative in IFN mediated apoptosis sensitization.

Breaking bad news: a phenomenological exploration of Irish nurses' experiences of caring for patients when a cancer diagnosis is given in an acute care facility (part 1).

BACKGROUND: The focus of this article is on the meanings attributed by nurses who worked with patients receiving a cancer diagnosis within acute care settings in Ireland. OBJECTIVE: The aim of this article was to explore the nurses' perceptions of caring for patients who receive bad news in the form of a cancer diagnosis while in an acute care setting. METHODS: The article focuses on the perceptions of 20 nurses who formed the nurse participant group in a larger phenomenological study exploring giving and receiving a cancer diagnosis. Data were collected using unstructured in-depth interviews. Analysis was conducted using Koch's analytical framework. RESULTS: The nurses' narratives provided 2 emerging themes entitled, "connectedness: journeying as professional within the everyday world" and "connectedness: exclusion of professional within the everyday world." This article focuses on the first emerging theme and highlights the experiences of nurses as they reflect on their interactions with their patients before, during, and after the giving of a cancer diagnosis. CONCLUSIONS: This study highlights the importance of professional companionship. It provides insights into the nurse-patient challenges as a result of lack of information. IMPLICATIONS FOR PRACTICE: Lack of information and involvement affects the nurse's ability to be authentically present for the recipient and results in a fracture to the nurse-patient relationship. Understanding the experiences of nurses from acute care settings where the cancer diagnosis is often given will inform and enable the nurse working in oncology settings to engage patients in a more meaningful and focused way.

Extending the family of Zn-based MOFs: synthetic approaches to chiral framework structures and MOFs with large pores and channels.

Tri- and pentanuclear, kinetically stable SBUs were exploited for the preparation of the novel MOFs [Zn(3)(BTEB)(2)(DMF)(2)] and (Me(2)NH(2))[Zn(5)(BTEB)(3)(µ(3)-OH)(2)(DMF)(2)]. The applied synthetic approach results in topologies that are stabilised by tritopic benzene-trisethynylbenzoic acid (BTEB) linkers giving rise to chiral frameworks with large pores or channels.

Detection of explosive vapors with a charge transfer molecule: self-assembly assisted morphology tuning and enhancement in sensing efficiency.

Use of a fluorescent organic molecule consisting of binaphthyl functionalized with donor-acceptor substituted stilbenes for the detection of dinitrotoluene (DNT) and trinitrotoluene (TNT) vapors and enhancement in its sensing efficiency via self-assembly assisted morphology tuning are described.

Lipoprotein lipase is differentially expressed in prognostic subsets of chronic lymphocytic leukemia but displays invariably low catalytical activity.

Lipoprotein lipase (LPL) expression has been shown to correlate with IGHV mutational status and to predict outcome in chronic lymphocytic leukemia (CLL). We here investigated the prognostic impact of LPL expression in relation to other prognostic markers including IGHV3-21 usage in 140 CLL patients. Additionally, we studied the catalytic activity of LPL in CLL cells. A significant difference in LPL mRNA expression was detected in IGHV unmutated compared to mutated CLL patients (p<0.001). However, the poor-prognostic mutated/stereotyped IGHV3-21 patients did not differ from other mutated CLL cases. Clinical outcome was significantly different in CLL cases with high versus low LPL expression (p<0.001), and LPL expression exceeded mutation status/IGHV3-21 usage as an independent prognostic marker. Finally, LPL protein expression correlated significantly with mRNA expression and was higher in IGHV unmutated versus mutated CLL (p=0.018), although the majority of synthesized protein was catalytically inactive indicating a non-catalytical function in CLL.

In vitro activity of 20 agents in different prognostic subgroups of chronic lymphocytic leukemia--rolipram and prednisolone active in cells from patients with poor prognosis.

BACKGROUND: There is a need for development of new drugs for treatment of B-cell chronic lymphocytic leukemia (CLL), especially for poor-prognostic subgroups resistant to conventional therapy. OBJECTIVE: The in vitro antileukemic activity of 20 different anticancer agents was characterized in tumor cells from CLL, aiming at identifying agents active in poor-prognostic subgroups. DESIGN AND METHODS: In tumor cells from 40 CLL patients and in peripheral blood mononuclear cells (PBMC) from three healthy controls, the activity of 20 substances was assessed using a non-clonogenic assay. The CLL samples were characterized regarding genomic aberrations by interphase fluorescence in situ hybridization and immunoglobulin heavy-chain variable (IGHV) gene mutational status. RESULTS: In line with clinical experience, cells from patients with unfavourable genomic aberrations [del(11q)/del(17p)] showed lower drug sensitivity to fludarabine and chlorambucil than cells from patients with favourable cytogenetics [del(13q)/no aberration]. Most investigated drugs demonstrated similar activity in CLL cells from patients with unmutated and mutated IGHV genes as well as in CLL cells vs. PBMC. Interestingly, prednisolone and rolipram displayed high CLL specificity, high activity in CLL cells with unmutated IGHV genes and retained the effect in several cases with 11q/17p deletion. Further studies on prednisolone and rolipram revealed a synergy when these agents were combined in CLL cells, and suggested correlation between drug sensitivity and difference in downstream signaling. CONCLUSION: Prednisolone and rolipram are interesting for further studies in CLL with inferior prognosis. The study can also be considered a basis for future efforts to find drugs active in subsets of CLL patients that are resistant to conventional therapy.

Rapamycin shows anticancer activity in primary chronic lymphocytic leukemia cells in vitro, as single agent and in drug combination.

The mammalian target of rapamycin inhibitor rapamycin and its analogues show promising anticancer activity in various experimental tumor models and are presently evaluated in clinical trials. We, here, evaluated the in vitro activity of rapamycin with regard to tumor-type specificity and possible mechanisms of drug resistance in 97 tumor cell samples from patients and in a resistance-based cell line panel, using the fluorometric microculture cytotoxicity assay. Rapamycin was dose-dependently cytotoxic in patient tumor cells and in cell lines. In primary cells, rapamycin was more active in hematological than in solid tumor samples, with chronic lymphocytic leukemia (CLL) and acute lymphocytic leukemia being the most sensitive tumor types. Considerable inter-individual differences in sensitivity were apparent among CLL samples, but no difference was observed between IGHV mutated and unmutated CLL samples, whereas a tendency to lower rapamycin sensitivity was indicated for samples displaying poor-prognostic genomic markers. Combination experiments in CLL cells indicated that rapamycin acted synergistically with vincristine, cisplatin, chlorambucil and taxotere. These results and the clinically-experienced good tolerance to rapamycin analogues encourage clinical studies of rapamycin in CLL treatment as single agent but also in combination with, e.g., vincristine and chlorambucil.

Receiving bad news: a phenomenological exploration of the lived experience of receiving a cancer diagnosis.

This article explores the process of coming to a place of knowing one's diagnosis of cancer. The study was guided by the philosophy of hermeneutic phenomenology, with data collected via unstructured in-depth interviews. This article focuses on 10 people who received a cancer diagnosis (recipients). The analysis of the recipient narratives offered an interpretation of the phenomenon of receiving bad news as a process occurring over a period of time and not as a one-off event in time. The concept of bad news as a trajectory was clearly evident in the narratives and was represented through 3 themes: "disturbance of the everyday world," "surfacing within the lived world," and "embodiment within the lived world." The findings are consistent with the literature addressing diagnosis and end-of-life issues. Understanding the phenomenon of "knowing" is crucial in helping the healthcare professional recognize the changing information and psychosocial needs of the recipient as they experience the trajectory of bad news.

A new perspective: molecular motifs on oxidized LDL, apoptotic cells, and bacteria are targets for chronic lymphocytic leukemia antibodies.

The restricted immunoglobulin (Ig) repertoire found in B-cell chronic lymphocytic leukemia (CLL) implies a role for antigen(s) in the leukemogenesis. The nature of the antigens has, however, not been characterized, although examples of autoantigens have been demonstrated. We have analyzed a panel of 28 CLL cell lines and primary cultures, producing monoclonal Ig with different Ig heavy-chain variable region gene usage and mutational status, including several complementarity determining region 3 homology subset members. Using mass-spectrometry, immunoassays, or protein macroarrays, we have discovered novel antigens binding to CLL Igs. These antigens included cytoskeletal proteins vimentin, filamin B, and cofilin-1, but also phosphorylcholine-containing antigens (eg, Streptococcus pneumoniae polysaccharides and oxidized low-density lipoprotein [oxLDL]). Additional new antigens identified were cardiolipin and proline-rich acidic protein-1. Remarkably, these antigens represent molecular motifs exposed on apoptotic cells/blebs and bacteria, and several CLL Igs bound to apoptotic Jurkat cells. In conclusion, these intriguing data, showing a limited target structure recognition, indicate that CD5+ CLL B cells are derived from a cell compartment that produces "natural antibodies," which may be instrumental in elimination and scavenging of apoptotic cells and pathogenic bacteria.

Stereotyped patterns of somatic hypermutation in subsets of patients with chronic lymphocytic leukemia: implications for the role of antigen selection in leukemogenesis.

Somatic hypermutation (SHM) features in a series of 1967 immunoglobulin heavy chain gene (IGH) rearrangements obtained from patients with chronic lymphocytic leukemia (CLL) were examined and compared with IGH sequences from non-CLL B cells available in public databases. SHM analysis was performed for all 1290 CLL sequences in this cohort with less than 100% identity to germ line. At the cohort level, SHM patterns were typical of a canonical SHM process. However, important differences emerged from the analysis of certain subgroups of CLL sequences defined by: (1) IGHV gene usage, (2) presence of stereotyped heavy chain complementarity-determining region 3 (HCDR3) sequences, and (3) mutational load. Recurrent, "stereotyped" amino acid changes occurred across the entire IGHV region in CLL subsets carrying stereotyped HCDR3 sequences, especially those expressing the IGHV3-21 and IGHV4-34 genes. These mutations are underrepresented among non-CLL sequences and thus can be considered as CLL-biased. Furthermore, it was shown that even a low level of mutations may be functionally relevant, given that stereotyped amino acid changes can be found in subsets of minimally mutated cases. The precise targeting and distinctive features of somatic hypermutation (SHM) in selected subgroups of CLL patients provide further evidence for selection by specific antigenic element(s).

The GNAS1 T393C polymorphism and lack of clinical prognostic value in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease with no known single predisposing genetic factor shown in all cases. Recently, a single nucleotide polymorphism (SNP) T393C in the GNAS1 gene has been reported to have a clinical impact on CLL progression and overall survival. In order to further investigate the T393C SNP in CLL, we have genotyped 279 CLL cases and correlated the genotypes to clinical outcome and other known prognostic factors such as the immunoglobulin heavy chain variable (IGHV) gene mutation status and CD38 expression. In the present study, no difference in overall survival or time to treatment was observed in the CLL patients with the different genotypes in contrast to the previous report. Furthermore, no correlation was observed with the T393C genotypes and IGHV mutational status, Binet stage or CD38 in this cohort. In summary, our data does not support the use of the T393C GNAS SNP as a clinical prognostic factor in CLL.

An evaluation of an attendance monitoring system for undergraduate nursing students.

Internationally the preparation and ongoing education of nurses continues to evolve in response the changing nature of both nursing and health care. The move into third level structures that has taken place in countries such as the UK and the Republic of Ireland, results in new challenges to the historical fabric of nurse education. One such challenge is monitoring of nursing students' attendance. Viewed by students as a patriarchal and draconian measure, the nursing profession historically value their ability to ensure the public and professional bodies that nursing students fully engage with educational programmes. University class sizes and the increased perception of student autonomy can negate against formalised monitoring systems. This paper reports on an evaluation of one such monitoring system. The findings revealed that attendance was recognised implicitly by nurse educators as an important learning activity within these programmes results and that current methods employed were less than reliable and so did little to appropriately control the phenomenon. Subsequent to the evaluation; a standardised approach to the measurement of absenteeism was employed. Deliberate short-term absence was a feature of this group. Reasons cited included travelling long distances, dissatisfaction with programme timetables and personal reasons. Preventative measures employed included improvement in student timetable delivery.

Thioredoxin, produced by stromal cells retrieved from the lymph node microenvironment, rescues chronic lymphocytic leukemia cells from apoptosis in vitro.

BACKGROUND AND OBJECTIVES: The redox-regulatory protein thioredoxin has several functions including transcriptional regulation, and antioxidant, cytokine, and chemokine activities. We have previously shown that extracellular thioredoxin protects B-cell chronic lymphocytic leukemia (CLL) cells from apoptosis in vitro. In this study we were interested to determine whether thioredoxin is produced by cells surrounding the CLL cells in the in vivo microenvironment and whether this cell-derived thioredoxin has any leukemia growth-promoting effect in vitro. DESIGN AND METHODS: Lymph nodes from CLL patients (n=25) were analyzed for thioredoxin expression by immunohistology. Stromal cells purified from the lymph nodes were analyzed for thioredoxin secretion at the single cell level using an ELIspot assay. The survival effect of the stromal-derived thioredoxin was tested by co-culturing stromal- and CLL cells with and without Fab-fragments of an anti-thioredoxin antibody. RESULTS: The results indicated that the thioredoxin production correlated with the amount of proliferating cells and was mainly localized to the proliferation centers (pseudofollicles) in the CLL lymph nodes. The leukemia cells per se showed minimal thioredoxin levels; in contrast, stromal cells strongly expressed thioredoxin. Purified primary stromal cells, which secreted extracellular thioredoxin, significantly protected the CLL cells from undergoing apoptosis in 72 h co-cultures. Interestingly, this anti-apoptotic effect could be abrogated by addition of Fab-fragments of an anti- thioredoxin antibody. INTERPRETATION AND CONCLUSIONS: In conclusion, we have shown that stromal cells in the lymph node microenvironment produce thioredoxin and that the thioredoxin production is localized to the proliferation centers of the CLL lymph nodes. In addition, thioredoxin produced by purified stromal cells rescued CLL cells from apoptosis in vitro.

The immunoglobulin genes: structure and specificity in chronic lymphocytic leukemia.

The rearrangement of the immunoglobulin genes (IG) provides a large diversity of B-cell receptors conformations and allows the immune system to respond differently to foreign antigens. In chronic lymphocytic leukemia (CLL), there are a restricted number of stereotyped B-cell receptors rearranged by the tumor B-cells between CLL patients. These subsets with stereotyped receptors appear to have clinical implications, for example cases that rearrange the IGHV3-21 gene display poor clinical prognosis. The number of subsets with stereotyped receptors has been reported at a frequency of over 20% of CLL cases; however, the specificities of these receptors are still not clearly defined. Reactivity to epitopes from bacterial antigen, cytoskeleton components such as vimentin, and antigens on viable and apoptotic T-cell have been proposed. The role of antigen in CLL development is currently being more clearly defined with identification of stereotyped receptors, and their antigen specificity and the continued role antigen stimulation plays in CLL disease will be an important question in the future.

Telomere length and correlation with histopathogenesis in B-cell leukemias/lymphomas.

Telomere length was recently reported to correlate with cellular origin of B-cell malignancies in relation to the germinal center (GC). In this report, we measured telomere length by quantitative-PCR in 223 B-cell lymphomas/leukemias and correlated results with immunoglobulin (Ig) mutation status and immunostainings for GC/non-GC subtypes of diffuse large B-cell lymphoma (DLBCL). Shortest telomeres were found in Ig-unmutated chronic lymphocytic leukemia (CLL) [median telomere to single copy gene value (T/S) 0.33], differing significantly to Ig-mutated CLL (0.63). Contrary to this, mantle cell lymphomas (MCLs) exhibited similar telomere lengths regardless of Ig mutation status (0.47). Telomere length differed significantly between GC-like (0.73) and non-GC-like DLBCLs (0.43), and follicular lymphomas (FLs) had shorter telomeres (0.53) than GC-DLBCL. Hairy cell leukemias, which display Ig gene intraclonal heterogeneity, had longer telomeres (0.62) than FLs and non-GC-DLBCL, but shorter than GC-DLBCL. We conclude that although DLBCL and CLL subsets can be clearly distinguished, telomere length reflects many parameters and may not simply correlate with GC-related origin.

What is the current evidence for antigen involvement in the development of chronic lymphocytic leukemia?

For many years it has been evident that B-cell chronic lymphocytic leukemia (CLL) displays preferential usage of individual immunoglobulin (Ig) variable heavy chain (V(H)) genes. The V(H)1-69 gene was the first to be reported overrepresented in a large number of CLL patients, where the V(H)1-69(+) CLL rearrangements showed characteristic molecular features, such as unmutated V(H) genes, usage of specific diversity/joining gene segments, and a longer than average complementarity determining region (CDR) 3 with certain common amino acid motifs. Also, biased usage of the V(H)3-07 and V(H)4-34 genes with specific rearrangement characteristics was reported in CLL. These findings led to the speculation that antigens could be involved during CLL development by triggering proliferation of B-cells with specific B-cell receptors (BCRs) leading to an increased risk of transforming events. Recently, we characterized a subset of CLL utilizing the V(H)3-21 gene that also displayed peculiar Ig features, e.g. very short and homologous CDR3s, predominant lambda expression and preferential V(lambda)2-14 gene usage. This V(H)3-21(+) subgroup also had poor prognosis despite the fact that two-thirds of cases carried mutated V(H) genes. Moreover, we and others have thereafter described further CLL subsets with very similar heavy and light chain gene rearrangement features. These latter findings of subsets expressing restricted BCRs have emphasized the hypothesis that antigens could play a role during the pathogenesis of CLL. Interestingly, recombinant antibodies produced from these restricted subsets showed similar cytoplasmatic reactivity within each group, thus suggesting recognition of a limited number of autoantigens. Further characterization of antigens is now necessary in order to understand their nature and exact role in CLL development.