julilili42/papers huggingface dataset:
The GERMELATOX DeCOG-trial: Attitude of German melanoma patients towards toxicity during adjuvant interferon treatment—Differences between the patient's and the physician's perspective.
2015-05-20

e20099 Background: Although trials of adjuvant interferon alfa-2b (IFNa-2b) in high-risk melanoma patients suggest improvement in disease-free survival (DFS), metaanalyses showed only a marginal overall survival benefit. Widespread use of IFNa-2b has decreased for its significant toxicity. This study addressed for the first time the attitudes and choice-based preferences of German patients and physicians for adjuvant treatment with IFNa-2b. Methods: In this multicenter trial („GERMELATOX trial“) we assessed preferences and utilities for health outcomes associated with IFN among melanoma patients (T1a, AJCC stage I, no IFN), and dermatooncologists from 10 German melanoma units using the standard gamble technique. The trial described four typical IFNa-2b side effect scenarios and three post-treatment outcomes: no relapse or melanoma recurrence (with or without IFNa-2b) leading to cancer death. We also asked patients and physicians about the improvement in 5-year DFS they would require to tolerate defined IFN side-effects. Results: Data were obtained from 150 patients and 116 physicians (median age: 53yrs/34yrs, 48.3%/66.4% female). Utilities for melanoma relapse (+/- IFN) were significantly lower than utilities for all scenarios of IFN side effects. Patients indicated a median threshold of 50% for being relapse free at 5 years after adjuvant IFN with mild-to-moderate side effects. In comparison, the median threshold for physicians was 30% indicating a higher willingness to accept side effects.. In case of severe side effects, the required chance had to be 70% for patients and 50% for physicians. Conclusions: This study demonstrated a marked variation among patients with respect to preferences on adjuvant IFN-a-2b treatment and a significant difference between the patient ́s and physician ́s attitude related to side effects and outcome. This difference might be meaningful in decision making for adjuvant treatment options and should therefore also be investigated in further trials for new adjuvant treatment modalities.
Discordance between HER2-phenotype on circulating tumor cells and primary tumor in women with advanced breast cancer.
2015-05-20

11003 Background: In the DETECT study program, women with HER2-negative metastatic breast cancer (MBC) are screened for circulating tumor cells (CTCs) to evaluate eligibility for different DETECT treatment intervention trials based on presence and HER2 phenotype of CTCs. Here we present data on the association of CTC prevalence and positive HER2-status on CTCs with patient and tumor characteristics. Methods: As of January 2015, number of CTCS using the FDA-cleared CellSearch System (Janssen Diagnostics, LLC) and their HER2 status have been evaluated in 1052 women with HER2-negative MBC screened for the DETECT Study program. Patients were defined as CTC positive if at least 1 CTC was detected in 7.5 ml of peripheral blood, and the cutoff for HER2 positivity was the presence of at least 1 CTC with a strong (+++) immunocytochemical HER2 staining intensity. Results: Overall, CTCs were detected in 661 (62.8%) of the 1052 screened patients (median 7 CTCs, range 1 – 35078). CTC prevalence was associated with a higher proportion of pN2/pN3 tumors (28.0 vs. 20.2%; p = 0.021) and a higher proportion of lobular carcinomas (22.4 vs. 9.5%; p < 0.001) compared to CTC-negative patients. Among the 661 patients with CTCs, at least one HER2-positive CTC was found in 130 patients (19.7%), indicating a discordance between primary tumor and CTCs with regard to HER2-status. Patients with HER2-positive CTCs had less often G3 tumors (27.7 vs. 39.0%; p = 0.024), and more often lobular carcinomas (39.2 vs. 18.3%; p < 0.001) compared to patients with only HER2-negative CTCs. In addition, patients with triple-negative tumors were less likely to have HER2-positive CTCs than patients with HER2-negative but hormone-receptor positive tumors (6.6 vs. 22.8%; p < 0.001). Conclusions: Our data confirm discordance in HER2-status between primary tumor and CTCs in 19.7% of patients with HER2-negative MBC. Interestingly, presence of HER2-positive CTCs was associated with hormone-receptor positive tumors. Awareness of the HER2-phenotype of CTCs may have important implications for further personalized therapy options. Clinical trial information: NCT01619111/NCT02035813.
Immunological long-term follow-up of neuroblastoma stage IV patients after anti-GD2 CH14.18 antibody treatment.
2015-05-20

3029 Background: Neuroblastoma stage IV is associated with low cure rates. Treatment with the GD2 antibody ch14.18 could improve the long-term overall survival. Apart from GD2 other tumor antigens (TA) are expressed in neuroblastoma and studies implicated that T-cell responses to TA are associated with a better outcome. For the present study we analyzed the immune response in long term neuroblastoma survivors treated with anti GD2 ch14.18. Methods: Blood and serum of 17 neuroblastoma long-term survivors after GD2 therapy with > 5 years follow up (patients group) and 17 age and gender matched healthy donors (control group) were analyzed. Serum was analyzed for antibodies binding to neuroblastoma cell lines and antibodies to a nominal antigen GD2. T cells were stimulated with overlapping peptides of the tumor antigens (TA) NY-ESO-1, WT-1, Survivin, MAGE-A1 and two mimotope peptides to GD2 for 10 days and analyzed for IFN-γ secretion in flow cytometry. Results: T-cell responses to at least one TA could be found in 82% of healthy and in 93% of patients with no significant difference in the number of TA responders between the two groups to any of these TA (Fisher ́s exact test). In contrast, T-cell responses to at least one of the GD2 mimotopes were found in 53% of neuroblastoma survivors but in 0% of healthy donors. Moreover, even priming with GD2 mimotope loaded dendritic cells did not induce a T-cell response in healthy donor cells. No differences between patient and control group could be detected in binding of antibodies to neuroblastoma cell lines and no GD2-specific antibodies were detected in patients and controls. Conclusions: Survivors of neuroblastoma treated with anti-GD2 ch14.18 demonstrated robust T-cell responses to neuroblastoma associated TA that was comparable to healthy donors. This could enable patients to attack minimal residual disease efficiently. Moreover more than half of the patients had T-cell responses to GD2 which could be an effect of the GD2 antibody therapy. Our results show that involvement of the cellular immune system might have an impact on the better outcome of this treatment in stage IV neuroblastoma patients.
Generation of specific polyclonal and polyfunctional CD4+ T-helper1 cells against WT-1, MAGE-A3, Survivin and ROR-1 for adoptive T-cell immunotherapy.
2015-05-20

e14025 Background: Adoptive T cell therapy (ACT) is a promising option to treat cancer. Th1 cells have been shown effective against viremia and cancer and are mediators of senescence in tumor cells. T cells against tumor associated antigens like cancer testis antigens can be used for adoptive T-cell transfer approaches. Methods: According to these considerations, we developed a protocol according to good manufacturing practice (GMP) to generate Th1 cells against WT-1, MAGE-A3, Survivin and ROR-1. The protocol starts with a presensitization of T cells with antigen. T cells were then enriched based on IFN-γ capture technique and expanded using autologous feeder and IL-2, IL-7 and IL-15. T-cell specificity and function was analyzed by flow cytometry. Results: Large scale generation of T cells specific to the tumor antigens was performed. The T-cell lines showed high numbers of specific IFN-γ+ and TNF-α+ CD4+ T cells but no IL-10. Both, CD4+ and CD8+T cells had an effector memory phenotype and proliferated in response to the tumor antigens. Adding PD-1 antibody to the T cells resulted in an improved proliferation in response to the antigens. Treatment of a WT-1+ leukemia patient with stem cell donor derived WT-1 specific T cells in combination with WT-1 vaccine was accompanied with WT-1 CD4+ and CD8+T cell responses and ongoing remission. Conclusions: Protocols for the generation of Survivin, WT-1-, MAGE-A3- and ROR-1-specific T cells were successfully established. T cell products mainly consisted of CD4+ T-cells with secretion of the cytokines IFN-γ and TNF. This cytokine profile enables the induction of senescence in tumor cells. Although tumor associated antigens are potential self antigens, it is possible to induce a functional Th1 response in T cells from healthy donors making T-cell transfer feasible in an allogeneic settings post stem cell transplantation. Further improvements could be achieved by combination of T-cell therapy with antibodies to PD-1.
NFAT2 to regulate anergy induction in CLL through Lck.
2015-05-20

7019 Background: NFAT2 is a highly phosphorylated transcription factor which regulates developmental and activation programs in diverse cell types. CLL constitutes a heterogeneous disease with some patients exhibiting an indolent course for many years and others progressing rapidly and requiring early treatment. A defined subgroup of patients shows enhanced responsiveness to stimulation of the B cell receptor (BCR) complex and more aggressive disease. In contrast, another subset of CLL patients with more indolent course is characterized by an anergic B cell phenotype referring to B cell unresponsiveness to IgM ligation. Here, we analyzed the role of NFAT2 in the pathogenesis of CLL and in anergy induction in CLL cells. Methods: We crossed conditional CD19-Cre NFAT2 knock out mice with the Eμ-TCL1 transgenic mice, which develop a human-like CLL. We analyzed TCL1+NFAT2 ko mice and TCL1 mice without a NFAT2 deletion served as controls. We performed a comparative gene expression analysis, Ca2+mobilization assays and Western Blots for multiple downstream signaling molecules on both CLL cells. Results: Mice with NFAT2 ko exhibited a significantly more aggressive disease course with accelerated accumulation of CLL cells and a dramatically reduced life expectancy. We detected a substantially altered expression profile of genes associated with B cell anergy in the TCL1+NFAT2 ko mice. The vast majority of these genes was expressed significantly less in the absence of NFAT2 with Lck, Pacsin1 and Cbl representing the biggest hits. While anergic CLL cells from TCL1 mice exhibited an unresponsive phenotype with respect to Ca2+ flux upon IgM ligation, TCL1+NFAT2 ko mice showed a normal capacity to mobilize Ca2+and a normal activation of the downstream signaling. IgM stimulation did not activate normal phosphotyrosine induction in TCL1 mice. However TCL1 mice showed a strong activation of the anergy regulator Lck. Conclusions: Genetic loss NFAT2 leads aggressive disease and controls the expression of several important anergy-associated genes. We identified Lck as a critical target of NFAT2 in this context. Taken together, our data demonstrate that the NFAT2-Lck axis plays an essential role in the pathogenesis of CLL and implicate it as a potential target in its treatment.
A strategy for structuring and reporting a read-across prediction of toxicity
2015-05-21

Category formation, grouping and read across methods are broadly applicable in toxicological assessments and may be used to fill data gaps for chemical safety assessment and regulatory decisions. In order to facilitate a transparent and systematic approach to aid regulatory acceptance, a strategy to evaluate chemical category membership, to support the use of read-across predictions that may be used to fill data gaps for regulatory decisions is proposed. There are two major aspects of any read-across exercise, namely assessing similarity and uncertainty. While there can be an over-arching rationale for grouping organic substances based on molecular structure and chemical properties, these similarities alone are generally not sufficient to justify a read-across prediction. Further scientific justification is normally required to justify the chemical grouping, typically including considerations of bioavailability, metabolism and biological/mechanistic plausibility. Sources of uncertainty include a variety of elements which are typically divided into two main issues: the uncertainty associated firstly with the similarity justification and secondly the completeness of the read-across argument. This article focuses on chronic toxicity, whilst acknowledging the approaches are applicable to all endpoints. Templates, developed from work to prepare for the application of new toxicological data to read-across assessment, are presented. These templates act as proposals to assist in assessing similarity in the context of chemistry, toxicokinetics and toxicodynamics as well as to guide the systematic characterisation of uncertainty both in the context of the similarity rationale, the read across data and overall approach and conclusion. Lastly, a workflow for reporting a read-across prediction is suggested.
Constraints on the tectonic and landscape evolution of the Bhutan Himalaya from thermochronometry
2015-05-21

The observed geomorphology and calculated thermal histories of the Bhutan Himalaya provide&#13;\\nan excellent platform to test ideas regarding the influence of tectonics and climate on the evolution of a&#13;\\nconvergentmountain range. However, little consensus has been reached regarding the late Cenozoic history of&#13;\\nthe Bhutan Himalaya. Some researchers have argued that observed geologic relationships show slowing&#13;\\ndeformation rates, such that the range is decaying from a geomorphic perspective, while others see the range&#13;\\nas growing and steepening. We suggest that a better understanding is possible through the integrated&#13;\\ninterpretation of geomorphic and thermochronometric data from the comparison of predictions from models&#13;\\nof landscape evolution and thermal-kinematic models of orogenic systems. New thermochronometric data&#13;\\nthroughout Bhutan aremost consistent with a significant decrease in erosion rates, from2 to 3 km/Ma down to&#13;\\n0.1–0.3 km/Ma, around 6–4Ma. We interpret this pattern as a decrease in rock uplift rates due to the activation&#13;\\nof contractional structures of the Shillong Plateau, an uplifted region approximately 100 km south of Bhutan.&#13;\\nHowever, low-relief, fluvial landscapes throughout the Bhutanese hinterland record a late pulse of surface uplift&#13;\\nlikely due to a recent increase in rock uplift rates. Constraints from our youngest thermochronometers suggest&#13;\\nthat this increase in rock uplift and surface uplift occurred within the last 1.75Ma. These results imply that&#13;\\nthe dynamics of the Bhutan Himalaya and Shillong Plateau have been linked during the late Cenozoic, with&#13;\\nstructural elements of both regions active in variable ways and times over that interval.
High β-glucosidase (GBA) activity not attributable to GBA1 and GBA2 in live normal and enzyme-deficient fibroblasts may emphasise the role of additional GBAs
2015-05-21

Abstract Beta-glucosidases (GBA) include GBA1, GBA2 and other β-glucosidases (non-GBA1-2). GBA1 is a lysosomal and GBA2 an extra-lysosomal enzyme. GBA1- and GBA2-deficient genetic conditions, with different phenotypes, are glucosylceramide (GC; the main GBA substrate) accumulating diseases. To study the activity profile of GBA, live fibroblasts were loaded with radioactive GC. The GC metabolism was measured in wild-type, GBA1-deficient (Gaucher disease) and GBA2-deficient ( Gba2 -/- mouse) cells. The differences found allowed the prediction of marked proportions of GBA1, GBA2, and particularly non-GBA1-2 (probably including GBA3, a cytosolic β-glucosidase) activity for wild-type cells. The high proportion of non-GBA1-2 suggests an important role of these enzymes.
No association between the presence of killer-cell immunoglobulin-like receptor genes and susceptibility to childhood ALL
2015-05-21

To the editor: Killer-cell immunoglobulin-like receptors (KIRs) play a pivotal role in immunosurveillance and reduction of relapse after hematopoietic stem cell transplantation in acute leukemia.[1][1],[2][2] Outside the setting of hematopoietic stem cell transplantation, it was recently reported
WIPI-Mediated Autophagy and Longevity
2015-05-22

Autophagy is a lysosomal degradation process for cytoplasmic components, including organelles, membranes, and proteins, and critically secures eukaryotic cellular homeostasis and survival. Moreover, autophagy-related (ATG) genes are considered essential for longevity control in model organisms. Central to the regulatory relationship between autophagy and longevity is the control of insulin/insulin-like growth factor receptor-driven activation of mTOR (mechanistic target of rapamycin), which inhibits WIPI (WD repeat protein interacting with phosphoinositides)-mediated autophagosome formation. Release of the inhibitory mTOR action on autophagy permits the production of PI3P (phosphatidylinositol-3 phosphate), predominantly at the endoplasmic reticulum, to function as an initiation signal for the formation of autophagosomes. WIPI proteins detect this pool of newly produced PI3P and function as essential PI3P effector proteins that recruit downstream autophagy-related (ATG) proteins. The important role of WIPI proteins in autophagy is highlighted by functional knockout of the WIPI homologues ATG-18 and EPG-6 in Caenorhabditis elegans (C. elegans). Adult lifespan is significantly reduced in ATG-18 mutant animals, demonstrating that longevity as such is crucially determined by essential autophagy factors. In this review we summarize the role of WIPI proteins and their C. elegans homologues with regard to the molecular basis of aging. As the development of strategies on how to increase health span in humans is increasingly appreciated, we speculate that targeting WIPI protein function might represent a therapeutic opportunity to fight and delay the onset of age-related human diseases.
MR Angiography at 3 T of Peripheral Arterial Disease: A Randomized Prospective Comparison of Gadoterate Meglumine and Gadobutrol
2015-05-22

Gadoterate meglumine was found to be not inferior to gadobutrol in terms of diagnostic performance in patients with PAOD undergoing 3-T contrast-enhanced MRA. No statistically significant differences were detected between the two MRA groups.
Genomic epidemiology of the current wave of artemisinin resistant malaria
2015-05-22

Abstract Artemisinin resistant Plasmodium falciparum is advancing across Southeast Asia in a soft selective sweep involving at least 20 independent kelch13 mutations. In a large global survey, we find that kelch13 mutations which cause resistance in Southeast Asia are present at low frequency in Africa. We show that African kelch13 mutations have originated locally, and that kelch13 shows a normal variation pattern relative to other genes in Africa, whereas in Southeast Asia there is a great excess of non-synonymous mutations, many of which cause radical amino-acid changes. Thus, kelch13 is not currently undergoing strong selection in Africa, despite a deep reservoir of standing variation that could potentially allow resistance to emerge rapidly. The practical implications are that public health surveillance for artemisinin resistance should not rely on kelch13 data alone, and interventions to prevent resistance must account for local evolutionary conditions, shown by genomic epidemiology to differ greatly between geographical regions.
Effect of GPIIb/IIIa inhibition with eptifibatide or tirofiban on the expression of cellular adhesion molecules on monocytes.
2015-05-22

GPIIb/IIIa inhibition with eptifibatide or tirofiban seems to have no effect on the expression of CD11b, CD54 and CD162 on monocytes during normothermia or hypothermia. Our results show that the beneficial effect induced by hypothermia on the extracorporal circulation-associated alteration of leukocyte function, with decreased expression of CD11b and CD162, seems not to be affected by additional treatment with eptifibatide or tirofiban.
10.1063/1.4921591.8
2015-05-22

X-ray crystallography requires sufficiently large crystals to obtain structural insights at atomic resolution, routinely obtained in vitro by time-consuming screening. Recently, successful data collection was reported from protein microcrystals grown within living cells using highly brilliant free-electron laser and third-generation synchrotron radiation. Here, we analyzed in vivo crystal growth of firefly luciferase and Green Fluorescent Protein-tagged reovirus μNS by live-cell imaging, showing that dimensions of living cells did not limit crystal size. The crystallization process is highly dynamic and occurs in different cellular compartments. In vivo protein crystallization offers exciting new possibilities for proteins that do not form crystals in vitro.
10.1063/1.4921591.6
2015-05-22

X-ray crystallography requires sufficiently large crystals to obtain structural insights at atomic resolution, routinely obtained in vitro by time-consuming screening. Recently, successful data collection was reported from protein microcrystals grown within living cells using highly brilliant free-electron laser and third-generation synchrotron radiation. Here, we analyzed in vivo crystal growth of firefly luciferase and Green Fluorescent Protein-tagged reovirus μNS by live-cell imaging, showing that dimensions of living cells did not limit crystal size. The crystallization process is highly dynamic and occurs in different cellular compartments. In vivo protein crystallization offers exciting new possibilities for proteins that do not form crystals in vitro.
10.1063/1.4921591.1
2015-05-22

X-ray crystallography requires sufficiently large crystals to obtain structural insights at atomic resolution, routinely obtained in vitro by time-consuming screening. Recently, successful data collection was reported from protein microcrystals grown within living cells using highly brilliant free-electron laser and third-generation synchrotron radiation. Here, we analyzed in vivo crystal growth of firefly luciferase and Green Fluorescent Protein-tagged reovirus μNS by live-cell imaging, showing that dimensions of living cells did not limit crystal size. The crystallization process is highly dynamic and occurs in different cellular compartments. In vivo protein crystallization offers exciting new possibilities for proteins that do not form crystals in vitro.
A new F‐box protein 7 gene mutation causing typical Parkinson's disease
2015-05-23

Abstract Background Recessive mutations in the F‐box protein 7 gene ( FBXO7 ; PARK15) have been identified as a cause of the parkinsonian‐pyramidal syndrome. Here, we report clinical and genetic findings in a Turkish family with novel FBXO7 mutations. Methods Whole exome and targeted Sanger sequencing were performed for genetic analysis in a family with two members affected by Parkinson's disease (PD). All family members underwent detailed clinical, mental, and neurological examination. Results The new p.L34R (c.101 T&gt;G) FBXO7 mutation was detected in a homozygous state in two Turkish sibs with typical levodopa‐responsive PD. Conclusion This is the first time a FBXO7 mutation has been identified that causes a phenotype compatible with typical idiopathic PD and presents with some of its common nonmotor features, such as rapid eye movement sleep behavior disorder, depression, and anxiety. © 2015 International Parkinson and Movement Disorder Society