Optimized Xenograft Protocol for Chronic Lymphocytic Leukemia Results in High Engraftment Efficiency for All CLL Subgroups

Preclinical drug development for human chronic lymphocytic leukemia (CLL) requires robust xenograft models recapitulating the entire spectrum of the disease, including all prognostic subgroups. Current CLL xenograft models are hampered by inefficient engraftment of good prognostic CLLs, overgrowth with co-transplanted T cells, and the need for allogeneic humanization or irradiation. Therefore, we aimed to establish an effective and reproducible xenograft protocol which allows engraftment of all CLL subtypes without the need of humanization or irradiation. Unmanipulated NOD.Cg-PrkdcscidIl2rgtm1Sug/JicTac (NOG) mice in contrast to C.Cg-Rag2tm1Fwa-/- Il2rgtm1Sug/JicTac (BRG) mice allowed engraftment of all tested CLL subgroups with 100% success rate, if CLL cells were fresh, injected simultaneously intra-peritoneally and intravenously, and co-transferred with low fractions of autologous T cells (2%–4%). CLL transplanted NOG mice (24 different patients) developed CLL pseudofollicles in the spleen, which increased over 4–6 weeks, and were then limited by the expanding autologous T cells. Ibrutinib treatment studies were performed to validate our model, and recapitulated treatment responses seen in patients. In conclusion, we developed an easy-to-use CLL xenograft protocol which allows reliable engraftment for all CLL subgroups without humanization or irradiation of mice. This protocol can be widely used to study CLL biology and to explore novel drug candidates

Preferences of patients with asthma or COPD for treatments in pulmonary rehabilitation

Introduction: Pulmonary rehabilitation (PR) aims to improve disease control in patients with chronic obstructive pulmonary disease (COPD) and asthma. However, the success of PR-programs depends on the patients’ participation and willingness to cooperate. Taking the patients’ preferences into consideration might improve both of these factors. Accordingly, our study aims to analyze patients’ preferences regarding current rehabilitation approaches in order to deduce and discuss possibilities to further optimize pulmonary rehabilitation. Methods and analysis: At the end of a 3 weeks in-house PR, patients’ preferences concerning the proposed therapies were assessed during two different time slots (summer 2015 and winter 2015/2016) in three clinics using a choice-based conjoint analysis (CA). Relevant therapy attributes and their levels were identified through literature search and expert interviews. Inclusion criteria were as follows: PR-inpatient with asthma and/or COPD, confirmed diagnosis, age over 18 years, capability to write and read German, written informed consent obtained. The CA analyses comprised a generalized linear mixed-effects model and a latent class mixed logit model. Results: A total of 542 persons participated in the survey. The most important attribute was sport and exercise therapy. Rehabilitation preferences hardly differed between asthma and COPD patients. Health-related quality of life (HRQoL) as well as time since diagnosis were found to have a significant influence on patients’ rehabilitation preferences. Conclusions: Patients in pulmonary rehabilitation have preferences regarding specific program components. To increase the adherence to, and thus, the effectiveness of rehabilitation programs, these results must be considered when developing or optimizing PR-programs.Introduction: Pulmonary rehabilitation (PR) aims to improve disease control in patients with chronic obstructive pulmonary disease (COPD) and asthma. However, the success of PR-programs depends on the patients’ participation and willingness to cooperate. Taking the patients’ preferences into consideration might improve both of these factors. Accordingly, our study aims to analyze patients’ preferences regarding current rehabilitation approaches in order to deduce and discuss possibilities to further optimize pulmonary rehabilitation. Methods and analysis: At the end of a 3 weeks in-house PR, patients’ preferences concerning the proposed therapies were assessed during two different time slots (summer 2015 and winter 2015/2016) in three clinics using a choice-based conjoint analysis (CA). Relevant therapy attributes and their levels were identified through literature search and expert interviews. Inclusion criteria were as follows: PR-inpatient with asthma and/or COPD, confirmed diagnosis, age over 18 years, capability to write and read German, written informed consent obtained. The CA analyses comprised a generalized linear mixed-effects model and a latent class mixed logit model. Results: A total of 542 persons participated in the survey. The most important attribute was sport and exercise therapy. Rehabilitation preferences hardly differed between asthma and COPD patients. Health-related quality of life (HRQoL) as well as time since diagnosis were found to have a significant influence on patients’ rehabilitation preferences. Conclusions: Patients in pulmonary rehabilitation have preferences regarding specific program components. To increase the adherence to, and thus, the effectiveness of rehabilitation programs, these results must be considered when developing or optimizing PR-programs

Mechanically defined microenvironment promotes stabilization of microvasculature, which correlates with the enrichment of a novel Piezo-1+ population of circulating CD11b+/CD115+ monocytes

Vascularization is a critical step in the restoration of cellular homeostasis. Several strategies including localized growth factor delivery, endothelial progenitor cells, genetically engineered cells, gene therapy, and prevascularized implants have been explored to promote revascularization. But, long-term stabilization of newly induced vessels remains a challenge. It has been shown that fibroblasts and mesenchymal stem cells can stabilize newly induced vessels. However, whether an injected biomaterial alone can serve as an instructive environment for angiogenesis remains to be elucidated. It is reported here that appropriate vascular branching, and long-term stabilization can be promoted simply by implanting a hydrogel with stiffness matching that of fibrin clot. A unique subpopulation of circulating CD11b+ myeloid and CD11b+ /CD115+ monocytes that express the stretch activated cation channel Piezo-1, which is enriched prominently in the clot-like hydrogel, is identified. These findings offer evidence for a mechanobiology paradigm in angiogenesis involving an interplay between mechanosensitive circulating cells and mechanics of tissue microenvironment

Lactate-Dehydrogenase 5 is overexpressed in non-small cell lung cancer and correlates with the expression of the transketolase-like protein 1

<p>Abstract</p> <p>Aims</p> <p>As one of the five Lactate dehydrogenase (LDH) isoenzymes, LDH5 has the highest efficiency to catalyze pyruvate transformation to lactate. LDH5 overexpression in cancer cells induces an upregulated glycolytic metabolism and reduced dependence on the presence of oxygen. Here we analyzed LDH5 protein expression in a well characterized large cohort of primary lung cancers in correlation to clinico-pathological data and its possible impact on patient survival.</p> <p>Methods</p> <p>Primary lung cancers (n = 269) and non neoplastic lung tissue (n = 35) were tested for LDH5 expression by immunohistochemistry using a polyclonal LDH5 antibody (ab53010). The results of LDH5 expression were correlated to clinico-pathological data as well as to patient's survival. In addition, the results of the previously tested Transketolase like 1 protein (TKTL1) expression were correlated to LDH5 expression.</p> <p>Results</p> <p>89.5% (n = 238) of NSCLC revealed LDH5 expression whereas LDH5 expression was not detected in non neoplastic lung tissues (n = 34) (p < 0.0001). LDH5 overexpression was associated with histological type (adenocarcinoma = 57%, squamous cell carcinoma = 45%, large cell carcinoma = 46%, p = 0.006). No significant correlation could be detected with regard to TNM-stage, grading or survival. A two sided correlation between the expression of TKTL1 and LDH5 could be shown (p = 0.002) within the overall cohort as well as for each grading and pN group. A significant correlation between LDH5 and TKTL1 within each histologic tumortype could not be revealed.</p> <p>Conclusions</p> <p>LDH5 is overexpressed in NSCLC and could hence serve as an additional marker for malignancy. Furthermore, LDH5 correlates positively with the prognostic marker TKTL1. Our results confirm a close link between the two metabolic enzymes and indicate an alteration in the glucose metabolism in the process of malignant transformation.</p

Coulomb dissociation of O-16 into He-4 and C-12

We measured the Coulomb dissociation of O-16 into He-4 and C-12 within the FAIR Phase-0 program at GSI Helmholtzzentrum fur Schwerionenforschung Darmstadt, Germany. From this we will extract the photon dissociation cross section O-16(alpha,gamma)C-12, which is the time reversed reaction to C-12(alpha,gamma)O-16. With this indirect method, we aim to improve on the accuracy of the experimental data at lower energies than measured so far. The expected low cross section for the Coulomb dissociation reaction and close magnetic rigidity of beam and fragments demand a high precision measurement. Hence, new detector systems were built and radical changes to the (RB)-B-3 setup were necessary to cope with the high-intensity O-16 beam. All tracking detectors were designed to let the unreacted O-16 ions pass, while detecting the C-12 and He-4

Coulomb dissociation of 16O into 4He and 12C

We measured the Coulomb dissociation of 16O into 4He and 12C at the R3B setup in a first campaign within FAIR Phase 0 at GSI Helmholtzzentrum für Schwerionenforschung, Darmstadt. The goal was to improve the accuracy of the experimental data for the 12C(a,?)16O fusion reaction and to reach lower center-ofmass energies than measured so far. The experiment required beam intensities of 109 16O ions per second at an energy of 500 MeV/nucleon. The rare case of Coulomb breakup into 12C and 4He posed another challenge: The magnetic rigidities of the particles are so close because of the same mass-To-charge-number ratio A/Z = 2 for 16O, 12C and 4He. Hence, radical changes of the R3B setup were necessary. All detectors had slits to allow the passage of the unreacted 16O ions, while 4He and 12C would hit the detectors' active areas depending on the scattering angle and their relative energies. We developed and built detectors based on organic scintillators to track and identify the reaction products with sufficient precision

Villoglandular adenocarcinoma of the uterine cervix: a systematic review and meta-analysis

Purpose!#!Villoglandular adenocarcinoma (VGA) of the uterine cervix has been classified as a rare subtype of cervical adenocarcinoma with good prognosis. A conservative surgical approach is considered feasible. The main risk factor is the presence of other histologic types of cancer. In this largest systematic review to date, we assess oncological outcomes associated with conservative therapy compared to those associated with invasive management in the treatment of stage Ia and Ib!##!Methods!#!Case series and case reports identified by searching the PubMed database were eligible for inclusion in this review (stage Ia-Ib!##!Results!#!A total of 271 patients were included in our literature review. 54 (20%) patients were treated by 'conservative management' (conization, simple hysterectomy, and trachelectomy) and 217 (80%) by 'invasive management' (radical hysterectomy ± radiation, hysterectomy, and radiation). Recurrences of disease (RODs) were found in the conservative group in two (4%) cases and in the invasive group in nine (4%) cases. There was no significant difference in disease-free survival (DFS) according to conservative or invasive treatment (p = 0.75). The histology of VGA may be complex with underlying usual adenocarcinoma (UAC) combined with VGA.!##!Conclusion!#!The excellent prognosis of pure VGA and the young age of the patients may justify the management of this tumor using a less radical procedure. The histological diagnosis of VGA is a challenge, and pretreatment should not be based solely on a simple punch biopsy but rather a conization with wide tumor-free margins

Optimized xenograft protocol for chronic lymphocytic leukemia results in high engraftment efficiency for All CLL subgroups

Preclinical drug development for human chronic lymphocytic leukemia (CLL) requires robust xenograft models recapitulating the entire spectrum of the disease, including all prognostic subgroups. Current CLL xenograft models are hampered by inefficient engraftment of good prognostic CLLs, overgrowth with co-transplanted T cells, and the need for allogeneic humanization or irradiation. Therefore, we aimed to establish an effective and reproducible xenograft protocol which allows engraftment of all CLL subtypes without the need of humanization or irradiation. Unmanipulated NOD.Cg-Prkdc$^{scid}$Il2rg$^{tm1Sug}$/JicTac (NOG) mice in contrast to C.Cg-Rag2$^{tm1Fwa-/-}$Il2rg$^{tm1Sug}$/JicTac (BRG) mice allowed engraftment of all tested CLL subgroups with 100% success rate, if CLL cells were fresh, injected simultaneously intra-peritoneally and intravenously, and co-transferred with low fractions of autologous T cells (2%-4%). CLL transplanted NOG mice (24 different patients) developed CLL pseudofollicles in the spleen, which increased over 4-6 weeks, and were then limited by the expanding autologous T cells. Ibrutinib treatment studies were performed to validate our model, and recapitulated treatment responses seen in patients. In conclusion, we developed an easy-to-use CLL xenograft protocol which allows reliable engraftment for all CLL subgroups without humanization or irradiation of mice. This protocol can be widely used to study CLL biology and to explore novel drug candidates