Photocatalytic properties of graphene-supported titania clusters from density-functional theory.

Density-functional theory calculations of (TiO2 )n clusters (n = 1-5) in the gas phase and adsorbed on pristine graphene as well as graphene quantum dots are presented. The cluster adsorption is found to be dominated by van der Waals forces. The electronic structure and in particular the excitation energies of the bare clusters and the TiO2 /graphene composites are found to vary largely in dependence on the size of the respective constituents. This holds in particular for the energy and the spatial localization of the highest occupied and lowest unoccupied molecular orbitals. In addition to a substantial gap narrowing, a pronounced separation of photoexcited electrons and holes is predicted in some instances. This is expected to prolong the lifetime of photoexcited carriers. Altogether, TiO2 /graphene composites are predicted to be promising photocatalysts with improved electronic and photocatalytic properties compared to bulk TiO2 .

[Cannabis medicines in pain management : Interim analysis of the survey accompanying the prescription of cannabis-based medicines in Germany with regard to pain as primarily treated symptom]. / Cannabisarzneimittel in der Schmerztherapie : Zwischenauswertung der Cannabisbegleiterhebung hinsichtlich der primär behandelten Symptomatik Schmerz.

BACKGROUND: In Germany, physicians who prescribe cannabis-based medicines at the expense of the statutory health insurance are obliged to take part in an accompanying survey. Pain was the most commonly reported diagnosis, making an interim evaluation for the indication of pain feasible. METHODS: Patient-related data was transmitted to the German Federal Institute for Drugs and Medical Devices via an online portal. In addition to demographic data, information on the treated disease or symptoms, the course of therapy, adverse reactions and treatment success were evaluated. RESULTS: A total of 3138 data sets were evaluated for the main diagnosis of pain. Dronabinol was the most frequently (64%) prescribed cannabis-based drug. On average, patients were 57 years old and women and men were equally represented. Patients treated with cannabis flowers were significantly younger (48 years). The proportion of men in this group was 68% and 83% in the group of 18- to 40-year-olds. According to the assessment by treating physicians, pain was significantly improved in 35.5% of the patients. The most frequent side effects (fatigue, dizziness, nausea) corresponded to those already known from the product information of the cannabis-based medicinal products authorized under the pharmaceutical law. Treatment was discontinued in 1179 patients within 1 year. CONCLUSION: Physicians should comply with their legal obligation to participate in the accompanying survey. Pain is by far the most common diagnosis in cannabis drugs. For about one third of these patients, physicians reported a clear improvement in pain. Due to the amount of data hitherto and the limitations in the accompanying survey, the results should not be overinterpreted in terms of efficacy and should always be related to existing reviews. The lower age and higher proportion of men among patients treated with cannabis flowers were remarkable. At 37.6%, the overall drop-out rate was high. The most frequent side effects related to vigilance and are therefore highly relevant in terms of driving ability, work ability and risk of falling. For a differentiated evaluation of treatment success, more data needs to be available.

Efficient PAW-based bond strength analysis for understanding the In/Si(111)(8 × 2) - (4 × 1) phase transition.

A numerically efficient yet highly accurate implementation of the crystal orbital Hamilton population (COHP) scheme for plane-wave calculations is presented. It is based on the projector-augmented wave (PAW) formalism in combination with norm-conserving pseudopotentials and allows to extract chemical interactions between atoms from band-structure calculations even for large and complex systems. The potential of the present COHP implementation is demonstrated by an in-depth analysis of the intensively investigated metal-insulator transition in atomic-scale indium wires self-assembled on the Si(111) surface. Thereby bond formation between In atoms of adjacent zigzag chains is found to be instrumental for the phase change. © 2017 Wiley Periodicals, Inc.

On-Surface Site-Selective Cyclization of Corrole Radicals.

Radical cyclization is among the most powerful and versatile reactions for constructing mono- and polycyclic systems, but has, to date, remained unexplored in the context of on-surface synthesis. We report the controlled on-surface synthesis of stable corrole radicals on Ag(111) via site-specific dehydrogenation of a pyrrole N-H bond in the 5,10,15-tris(pentafluoro-phenyl)-corrole triggered by annealing at 330 K under ultrahigh-vacuum conditions. We reveal a thermally induced regioselective cyclization reaction mediated by a radical cascade and resolve the reaction mechanism of the pertaining cyclodefluorination reaction at the single-molecule level. Via intramolecularly resolved probing of the radical-related Kondo signature, we achieve real space visualization of the distribution of the unpaired electron density over specific sites within the corrole radical. Annealing to 550 K initiates intermolecular coupling reactions, producing an extended π-conjugated corrole system.

Hairy cell leukemia: short review, today's recommendations and outlook.

Hairy cell leukemia (HCL) is part of the low-grade non-Hodgkin lymphoma family and represents approximately 2% of all leukemias. Treatment with splenectomy and interferon-α historically belonged to the first steps of therapeutic options, achieving partial responses/remissions (PR) in most cases with a median survival between 4 and 6 years in the 1980s. The introduction of the purine analogs (PA) pentostatin and cladribine made HCL a well-treatable disease: overall complete response rates (CRR) range from 76 to 98%, with a median disease-free survival (DFS) of 16 years a normal lifespan can be reached and HCL-related deaths are rare. However, insufficient response to PA with poorer prognosis and relapse rates of 30-40% after 5-10 years of follow-up may require alternative strategies. Minimal residual disease can be detected by additional examinations of bone marrow specimens after treatment with PA. The use of immunotherapeutic monoclonal antibodies (mAB) like rituximab as a single agent or in combination with a PA or more recently clinical trials with recombinant immunotoxins (RIT) show promising results to restrict these problems. Recently, the identification of the possible disease-defining BRAF V600E mutation may allow the development of new therapeutic targets.

[Evaluation of 12 pilot projects to improve outpatient palliative care]. / Evaluation von 12 Pilotprojekten zur Verbesserung der ambulanten Palliativversorgung.

BACKGROUND: With a priority programme the German Cancer Aid supported the development of quality-assured outpatient palliative care to cover the whole country. The 12 regional pilot projects funded with the aim to improve outpatient palliative care in different models and different frameworks were concurrently monitored and evaluated. METHODS: The supported projects, starting and ending individually, documented all patients who were cared for using HOPE (Hospice and palliative care evaluation) and MIDOS (Minimal documentation system for palliative patients). Total data were analyzed for 3239 patients decriptively. In addition to the quantitative data the experiences of the projects were recorded in a number of workshops (2008, 2009, 2010, and 2012). In particular, the experiences reported in the final meeting in July 2012 were considered for this article as well as the final reports for the German Cancer Aid. RESULTS: In the quantitative evaluation 85.6% of 3239 palliative care patients had a cancer diagnosis. In all model projects the goal of a network with close cooperation of primary providers, social support, and outpatient and inpatient specialist services has been achieved. For all projects, the initial financing of the German Cancer Aid was extremely important, because contracts with health insurance funds were negotiated slowly, and could then be built on the experiences with the projects. CONCLUSION: The participants of the project-completion meeting emphasized the need to carry out a market analysis before starting palliative care organizations considering the different regional structures and target groups of patients. Education, training and continuing education programs contribute significantly to the network. A reliably funded coordination center/case management across all institutions is extremely important.

[Pain management in palliative care. Current aspects of medicinal therapy]. / Palliative Schmerztherapie. Aktuelle Aspekte der Arzneimitteltherapie.

Palliative care patients do not only suffer from cancer pain but also from painful muscle spasticity due to multiple sclerosis, amyotrophic lateral sclerosis, after stroke or due to dementia if damage of the pyramidal motor system is present. Centrally active muscle relaxants can be helpful also when used as coanalgesics for cancer pain. In addition to opioids other coanalgesics, such as tricyclic antidepressants or serotonin/noradrenalin reuptake inhibitors as well as anticonvulsants (sodium channel and calcium channel blockers) can be helpful if neuropathic cancer pain is present. Idiopathic Parkinsonism or multiple system atrophy leads more to a painful rigor and pain control should be supported here by optimal adjustment of L-DOPA or DOPA agonist therapy. However, pain treatment should always address the psychological, social and spiritual demands of the patient.

Vibrational properties of the LiNbO3 z-surfaces.

The existence of localized vibrational modes both at the positive and at the negative LiNbO3 (0001) surface is demonstrated by means of first-principles calculations and Raman spectroscopy measurements. First, the phonon modes of the crystal bulk and of the (0001) surface are calculated within the density functional theory. In a second step, the Raman spectra of LiNbO(3) bulk and of the two surfaces are measured. The phonon modes localized at the two surfaces are found to be substantially different, and are also found to differ from the bulk modes. The calculated and measured frequencies are in agreement within the error of the method. Raman spectroscopy is shown to be sensitive to differences between bulk and surface and between positive and negative surface. It represents therefore an alternative method to determine the surface polarity, which does not exploit the pyroelectric or piezoelectric properties of the material.

Phenanthrenequinone adsorbed on Si(001): geometries, electronic properties, and optical response.

As a prototypical case of a pi-conjugated organic overlayer on a semiconductor surface the adsorption of phenanthrenequinone (C14O2H8) on the Si(001) surface is studied by means of first principles calculations, using gradient-corrected density functional theory together with ultrasoft pseudopotentials and the projector augmented wave method. A thermodynamic phase diagram gives adsorption geometries depending on experimental conditions, the microscopically most favorable bonding configuration representing a "[4+2]-cycloaddition product". The surface electronic structure depends strongly on the respective adsorption configuration. Calculations of the surface optical signature show its sensitivity to molecular adsorption and are in agreement with experimental results. A detailed analysis illustrates that the bonding to the surface has to be taken into account accurately to unveil the molecule's contribution to the surface optical response.

Ga-rich limit of surface reconstructions on GaAs(001): atomic structure of the (4 x 6) phase.

The Ga-rich reconstruction of the GaAs(001) surface has been studied. Using scanning tunneling microscopy (STM), we have found the existence of a well-ordered (4 x 6) reconstruction under extreme Ga-rich conditions. A structure model, consisting of subsurface Ga-Ga dimers and surface Ga-As dimers, is proposed for the (4 x 6) surface. This model is found to be energetically favorable at the Ga-rich limit and agrees well with our experimental data from STM and reflection high-energy electron diffraction.

Gene therapy for hematological malignancies.

Since cancer is the result of genetic mutations, it should be well suited for correction through gene therapy. Hematological malignancies in which human gene transfer has been performed are leukemias, lymphomas, graft-versus host disease after allogeneic bone marrow transplantation in leukemia, and multiple myeloma. Gene therapy may be used to induce or enhance an antitumor immunological reaction, to correct a genetic defect in the tumor cells, to render the malignant disease more susceptible to conventional therapies, to make the normal host cells more resistant to conventional therapies, or to track cells used for therapy. Gene therapy will probably be most valuable for the eradication of minimal residual disease after the use of conventional therapies.

A genome screen for genes predisposing to bipolar affective disorder detects a new susceptibility locus on 8q.

Bipolar affective disorder (BPAD), also known as manic depressive illness, is a severe psychiatric disorder characterized by episodes of mania and depression. It has a lifetime prevalence of approximately 1% in all human populations. In order to identify chromosomal regions containing genes that play a role in determining susceptibility to this psychiatric condition, we have conducted a complete genome screen with 382 markers (average marker spacing of 9.3 cM) in a sample of 75 BPAD families which were recruited through an explicit ascertainment scheme. Pedigrees were of German, Israeli and Italian origin, respectively. Parametric and non-parametric linkage analysis was performed. The highest two-point LOD score was obtained on 8q24 (D8S514; LOD score = 3.62), in a region that has not attracted much attention in previous linkage studies of BPAD. The second best finding was seen on 10q25-q26 (D10S217; LOD score = 2.86) and has been reported in independent studies of BPAD. Other regions showing 'suggestive' evidence for linkage localized to 1p33-p36, 2q21-q33, 3p14, 3q26-q27, 6q21-q22, 8p21, 13q11 and 14q12-q13. In addition, we aimed at detecting possible susceptibility loci underlying genomic imprinting by analyzing the autosomal genotype data with the recently developed extension of the GENEHUNTER program, GENEHUNTER-IMPRINTING. Putative paternally imprinted loci were identified in chromosomal regions 2p24-p21 and 2q31-q32. Maternally imprinted susceptibility genes may be located on 14q32 and 16q21-q23.

A possible susceptibility locus for bipolar affective disorder in chromosomal region 10q25--q26.

In an attempt to identify susceptibility loci for bipolar affective disorder, we are currently conducting a systematic genome screen with highly polymorphic microsatellite markers at an average marker spacing of 10 cM in a series of 75 families, comprising 66 families from Germany, eight families from Israel, and one family from Italy. The families were ascertained through index cases with bipolar affective disorder. The distribution of diagnoses is as follows: 126 individuals with bipolar I disorder, 40 with bipolar II disorder, 14 with schizoaffective disorder of the bipolar type, 40 individuals with recurrent unipolar depression, 51 with a minor psychiatric diagnosis, and two individuals with a diagnosis of schizophrenia. One hundred and seventy-one individuals are unaffected. Here, we present results from chromosome 10. Linkage analyses using a total of 33 microsatellite markers with parametric and non-parametric methods provided evidence for linkage at chromosomal region 10q25--q26. The highest two-point LOD score (2.86, theta = 0.05) was obtained for D10S217 using a dominant genetic model and a broad definition of affection status. The GENEHUNTER program localized the putative susceptibility locus within a ca 15-cM interval between markers D10S1483 and D10S217 with a maximum NPL(all) score of 3.12 (P = 0.0013). Positive linkage findings that have been reported by two independent studies further support the hypothesis of a susceptibility gene for bipolar affective disorder on 10q25-q26.

Increase in proliferation rate and normalization of TNF-alpha secretion by blockage of gene transfer-induced apoptosis in lymphocytes using low-dose cyclosporine A.

Efficient gene transfer of lymphocytes is extremely difficult. We have shown previously that induction of apoptosis may play a role in the gene transfer resistance of lymphocytes. Anti-CD3 antibody can be used as a surrogate for receptor-mediated gene transfer in T lymphocytes. However, anti-CD3 antibody has been shown to be the causative agent of apoptosis in receptor-mediated gene transfer. In this study, we show that blockage of apoptosis by addition of low-dose cyclosporine A can lead to normalization of elevated TNF-alpha secretion and to a significant increase in the proliferation rate of transfected lymphocytes. In contrast, this had no negative effect on cytotoxic activity of immunologic effector cells called cytokine-induced killer cells. Therefore, blockage of apoptosis should have an impact on the use of lymphocytes transfected with cytokine genes as immunologic effector cells in cancer gene therapy protocols.

TNF-alpha secretion and apoptosis of lymphocytes mediated by gene transfer.

Efficient gene transfer of lymphocytes is extremely difficult. Apoptosis may play a role in this gene transfer resistance of lymphocytes. Here we show that transfection of lymphocytes via non-viral vectors leads to induction of apoptosis in a significant proportion of cells. Since apoptosis may be mediated via tumor necrosis factor d (TNF-alpha) and the TNF-alpha receptor pathway, we studied the amount of TNF-alpha secreted by lymphocytes transfected without gene insert. TNF-alpha secretion was dependent on the gene transfer method used. High amounts were detected using receptor-mediated gene transfer and lipofection. In contrast, only low amounts of TNF-alpha were detected after electroporation and retroviral gene transfer. In receptor-mediated gene transfer, TNF-alpha secretion was due to the use of anti-CD3 antibody. Transfection of lymphocytes led to selective decrease in CD120b/TNF-alpha receptor II (TNFR-2)-positive cells. Induction of apoptosis and necrosis mediated by TNF-alpha via TNFR-2 (p80) was partially blocked using a neutralizing anti-TNF-alpha antibody. Blockage of apoptosis and necrosis could be further increased by adding anti-Fas-ligand (FasL) antibody, suggesting that induction of apoptosis via FasL and Fas receptor (Apo-1/CD95) may also play a role. This blockage led to a significant increase in the proliferation rate of lymphocytes transfected with cytokine genes. In conclusion, various gene transfer techniques led to TNF-alpha secretion, apoptosis and necrosis of lymphocytes. Apoptosis and necrosis could be partially blocked using a neutralizing anti-TNF-alpha antibody.

Generation of cytokine-induced killer cells using exogenous interleukin-2, -7 or -12.

Immunologic effector cells termed cytokine-induced killer (CIK) cells are generated in vitro from peripheral blood lymphocytes by addition of interferon-gamma, interleukin (IL)-2, IL-1 and an antibody against CD3. CIK cells have been shown to eradicate established tumors in a SCID mouse/human lymphoma model. CIK cells are dependent on exogenous cytokines such as IL-2, IL-7, or IL-12. We studied the effect of these cytokines in detail. Cellular proliferation was analyzed using an MTT proliferation assay, surface antigen expression via flow cytometry, cytotoxic activity using an LDH release assay, and apoptosis via flow cytometric analysis. IL-2, IL-7 and IL-12 led to significant growth of lymphocytes. Cells grown in IL-2 and IL-7 showed higher proliferation rates than cells grown in IL-12 according to the MTT assay. Concerning surface antigen expression, exogenous IL-7 led to a decrease in IL-7 receptor expression (4.8% from 60.4%) and exogenous IL-2 to a decrease in IL-2 receptor expression (61.2% from 73.2%). CD28 expression was higher in cells grown in IL-7 (77.3%) than in cells grown in IL-2 (62.5%). IL-12 led to a decrease in ICAM-1 adhesion molecule expression (57.7% from 76.7%) and an increase in CD56 expression compared with exogenous IL-7. IL-7 led to higher number of CD4-positive cells than IL-2 (53.0% vs 49.5%). No significant difference was found between IL-2, IL-7 and IL-12 in cytotoxic activity measured in an LDH release assay. Small amounts of apoptotic cells were found with all cytokines. However, the percentage of necrotic cells was higher with exogenous IL-12 than with IL-2 or IL-7. In summary, CIK cells can be generated using exogenous IL-2, IL-7 or IL-12. No difference in cytotoxic activity was found. However, significant differences were found in cell proliferation rates, antigen expression and percentage of necrotic cells.

Activated T cells and cytokine-induced CD3+CD56+ killer cells.

Over the past two decades, attempts have been made to develop immunotherapy for patients with cancer. A significant obstacle to the development of successful adoptive immunotherapy has been the availability of appropriate cytotoxic cells. Immunologic effector cells such as lymphokine-activated killer (LAK) cells, activated T cells such as tumor-infiltrating lymphocytes (TILs), and cytokine-induced killer (CIK) cells may be suitable to remove residual tumor cells.

Cancer and gene therapy.

The authors review the current literature pertaining to gene therapy as related to human cancer, covering gene therapy strategies, techniques of gene transfer, and targeted gene delivery. Gene therapy has various applications. Many technical obstacles in gene delivery need to be overcome. The safe delivery and expression of a gene to its destination are essential for clinical use. A greater understanding of the genetic basis of cancer and tumor immunology is necessary before the goal of cancer gene therapy can be fully realized.

No linkage or association of telomeric and centromeric T-cell receptor beta-chain markers with susceptibility to type 1 insulin-dependent diabetes in HLA-DR4 multiplex families.

The T-cell receptor beta locus (TCRB) on chromosome 7q35 was studied as a candidate region for genetic susceptibility to type 1 insulin-dependent diabetes (IDDM). A highly polymorphic microsatellite marker mapping to the TCRBV6.7 gene and a TCRB C-region RFLP were used to genotype the members of a total of 21 multiplex IDDM families from two different geographical areas. There was no evidence to support linkage to either of these markers with IDDM, and conventional two-point analysis excluded linkage to the telomeric end of the TCRB complex, in the region of the highly informative TCRBV6.7 marker. There was significant linkage of IDDM to the class II HLA-D locus with significant lod scores > 3.0 obtained for the HLA-DRB1 and HLA-DQB1 genes. Affected sib-pair (ASP) and transmission disequilibrium (TDT) association tests confirmed these findings.