julilili42/papers huggingface dataset:
Induction of NK Cell Reactivity in Breast Cancer by Fc-Engineered NKG2D-Ig Fusion Proteins
2012-11-16

Abstract Abstract 253 NK cells are cytotoxic lymphocytes that play an important role in anti-tumor immunity. Their capability to mediate Fc-receptor dependent effector functions like antibody dependent cellular cytotoxicity (ADCC) largely contributes to the clinical success of anti-tumor antibodies like Herceptin (Trastuzumab®), which is approved for treatment of breast cancer displaying HER2/neu-overexpression. Notably, only about 20% of breast cancer patients show overexpression of HER2/neu. Moreover, this antigen is also expressed on healthy cells, and application of Herceptin is associated with side effects. In contrast, ligands of the activating immunoreceptor NKG2D (NKG2DL) are widely expressed on malignant cells, but generally absent on healthy tissues. We aimed to take advantage of the tumor-restricted expression of NKG2DL by using them as tumor-antigens for Fc-optimized NKG2D-Ig fusion proteins targeting breast cancer cells for NK cell ADCC and IFN-γ production. NKG2D-Ig fusion proteins with distinct modifications in their Fc portion were generated by amino acid exchange as previously described (Lazar 2006; Armour 1999). Compared to wildtype NKG2D-Fc (NKG2D-Fc-WT) or Herceptin, our mutants (S239D/I332E and E233P/L234V/L235A/ΔG236/A327G/A330S) displayed highly enhanced (NKG2D-Fc-ADCC) and abrogated (NKG2D-Fc-KO) affinity to the NK cell FcγRIIIa receptor (CD16), respectively. This resulted in lacking (NKG2D-Fc-KO) or highly enhanced (NKG2D-Fc-ADCC) NK cell activation. In cultures of NK cells and breast cancer cells, NKG2D-Fc-KO significantly reduced NK cell reactivity due to blockade of NKG2DL-mediated activating signals, while NKG2D-Fc-WT substantially enhanced NK reactivity by induction of ADCC and cytokine production. Notably, the effect of our NKG2D-Fc-ADCC by far exceeded that of NKG2D-Fc-WT and, in case of HER2/neu low targets, also that of Herceptin, resulting in potently enhanced NK anti-tumor reactivity. Together, our results demonstrate that Fc-engineered NKG2D-Fc-ADCC fusion proteins can effectively target NKG2DL-expressing cancer cells for NK anti-tumor reactivity. In line with the hierarchically organized potential of the various activating receptors governing NK reactivity and due to its highly increased affinity to CD16 NKG2D-Fc-ADCC potently enhances NK cell reactivity despite the inevitable reduction of activating signals upon binding to NKG2DL. Due to the tumor-restricted expression of NKG2DL, NKG2D-Fc-ADCC may thus constitute an attractive means for immunotherapy, especially of HER2/neu-low or -negative breast cancer. Disclosures: No relevant conflicts of interest to declare.
Delayed Immune Reconstitution After Allogeneic Hematopoietic Cell Transplantation with Yttrium-90 Ibritumomab Tiuxetan-Based Reduced-Intensity Conditioning
2012-11-16

Abstract Abstract 4482 Introduction: Allogeneic hematopoietic cell transplantation (HCT) following reduced-intensity conditioning (RIC) including radioimmunotherapy (RIT) with yttrium-90 ibritumomab tiuxetan is a potential salvage treatment for patients with advanced high-risk B-cell lymphoma. The influence of RIT combined with RIC on immune reconstitution after allogeneic HCT has not been evaluated. Methods: We compared data on immune reconstitution of 14 patients receiving allogeneic HCT after RIT-RIC at our institution from 2006 to 2008. Yttrium-90 ibritumomab tiuxetan as RIT and RIC with either fludarabine (30 mg/m2, day −8 to −4)/melphalan (140 mg/m2, day −3)/alemtuzumab (20 mg for related donors and 30 mg for unrelated donors, day −3 and −2) (n=7, FLU/MEL/AL-RIT group) or fludarabine (30 mg/m2, day −4 to −2)/2 Gy total body irradiation (day 0) (n=7, FLU/TBI-RIT group) were used. Immunosuppression consisted of cyclosporine A alone (FLU/MEL/AL-RIT group) or cyclosporine A combined with mycophenolate mofetil (FLU/TBI-RIT group). The results were compared to 14 patients in a concurrent control group with similar conditioning regimens without RIT (n=7, FLU/MEL (without alemtuzumab); n=7, FLU/TBI). Differences in engraftment and immune reconstitution were evaluated. Results: Diagnoses in the RIT groups were high-grade NHL (n=6), low-grade NHL (n=6) and CLL (n=2). In the control groups diagnoses were high-grade NHL (n=4), acute leukemia (n=6), MDS (n=1), multiple myeloma (n=1), Hodgkin's lymphoma (n=1) and CLL (n=1). Neutrophil engraftment (&gt;500/μl) was observed after a median of 20 days (range 13–26) in the FLU/MEL/AL-RIT-group compared to 15 days (range 11–21) in the control group (p=0.11). After a median of 13 days (range 7–17) and 12 days (range 8–27) neutrophil engraftment was noted in the FLU/TBI-RIT group and control group, respectively (p=0.40). Median time to thrombocyte engraftment (&gt;20,000/μl) was 11 days (range 8–42) in the FLU/MEL/AL-RIT-group and 21 days (range 5–29) in the control group (p=0.81). After a median of 10 days (range 7–16) and 11 days (range 10–35) thrombocyte engraftment was noted in the FLU/TBI-RIT group and control group, respectively (p=0.23). Immune reconstitution in the four groups is shown in Table 1: Regeneration of CD3+8+ T-cells on day +100 and day +500 was significantly (p&lt;0.10) reduced in the FLU/MEL/AL-RIT group compared to the FLU/MEL control group (p=0.08 and p=0.09) while no difference was observed between the FLU/TBI-RIT and the FLU/TBI group. No significant long-term difference in recovery of the CD19+ B-cells was observed although early B-cell levels on day +100 were reduced in the RIT groups. Conclusion: Not the use of yttrium-90 ibritumomab tiuxetan alone but its combination with alemtuzumab leads to a significantly slower immune reconstitution after allogeneic HCT. Disclosures: Off Label Use: Off-label conditioning regimen.
Plant sterols and atherosclerosis
2012-11-17

Taken together, current evidence supports the recommendations for the use of plant sterols as LDL cholesterol-lowering agents. Nevertheless, a prospective, randomized, controlled, double-blinded, intervention trial conclusively showing that plant sterol supplementation will prevent hard cardiovascular endpoints is not available to date.
Metacarpophalangeal Joint Orientation in Anthropoid Manual Phalanges
2012-11-17

Abstract The proximal articular surface angle of orientation (AO) of proximal phalanges of the hand and foot has been used to infer the locomotor profile of extinct Miocene catarrhines and early hominins. Previous work has found that joint orientation distinguishes quadrupedal from suspensory anthropoids. The purpose of this study is to expand on previous research by examining this feature within and across several primate clades, allowing us to investigate the potential influences of locomotion, substrate usage, hand posture, and phylogeny. We also report AO measurements in human proximal hand phalanges, allowing us to examine human skeletal variation within a wide comparative context. The angle of orientation was measured on manual proximal third phalanges of 21 extant anthropoid species using a Microscribe digitizer. Comparisons were made between locomotor groups within hominoids, platyrrhines, and cercopithecoids. Proximal phalanges of quadrupedal species were characterized by greater dorsal orientation than those of suspensory taxa in hominoids and atelids. In addition, arboreal quadrupeds had greater AO values than terrestrial quadrupeds within the Cercopithecoidea. However, within the terrestrial locomotor group, mean AO values did not differ between palmigrade and digitigrade taxa. Thus, while there appears to be a functional signal related to substrate usage, differences in use of hand postures when moving on the ground were not reflected in proximal joint orientation of the proximal phalanx. Finally, we measured relatively low AO values in human phalanges, which might be related to integration with serially homologous pedal phalanges that are under strong selective pressure related to bipedalism. Anat Rec, 2012. © 2012 Wiley Periodicals, Inc.
Raman spectroscopy in biomedicine – non‐invasive in vitro analysis of cells and extracellular matrix components in tissues
2012-11-19

Abstract Raman spectroscopy is an established laser‐based technology for the quality assurance of pharmaceutical products. Over the past few years, Raman spectroscopy has become a powerful diagnostic tool in the life sciences. Raman spectra allow assessment of the overall molecular constitution of biological samples, based on specific signals from proteins, nucleic acids, lipids, carbohydrates, and inorganic crystals. Measurements are non‐invasive and do not require sample processing, making Raman spectroscopy a reliable and robust method with numerous applications in biomedicine. Moreover, Raman spectroscopy allows the highly sensitive discrimination of bacteria. Rama spectra retain information on continuous metabolic processes and kinetics such as lipid storage and recombinant protein production. Raman spectra are specific for each cell type and provide additional information on cell viability, differentiation status, and tumorigenicity. In tissues, Raman spectroscopy can detect major extracellular matrix components and their secondary structures. Furthermore, the non‐invasive characterization of healthy and pathological tissues as well as quality control and process monitoring of in vitro‐engineered matrix is possible. This review provides comprehensive insight to the current progress in expanding the applicability of Raman spectroscopy for the characterization of living cells and tissues, and serves as a good reference point for those starting in the field.
Nuclear matrix elements for neutrinoless double-beta decay and double-electron capture
2012-11-19

A new generation of neutrinoless double beta decay experiments with improved sensitivity is currently under design and construction. They will probe inverted hierarchy region of the neutrino mass pattern. There is also a revived interest to the resonant neutrinoless double-electron capture, which has also a potential to probe lepton number conservation and to investigate the neutrino nature and mass scale. The primary concern are the nuclear matrix elements. Clearly, the accuracy of the determination of the effective Majorana neutrino mass from the measured 0\\nu\\beta\\beta-decay half-life is mainly determined by our knowledge of the nuclear matrix elements. We review recent progress achieved in the calculation of 0\\nu\\beta\\beta and 0\\nu ECEC nuclear matrix elements within the quasiparticle random phase approximation. A considered self-consistent approach allow to derive the pairing, residual interactions and the two-nucleon short-range correlations from the same modern realistic nucleon-nucleon potentials. The effect of nuclear deformation is taken into account. A possibility to evaluate 0\\nu\\beta\\beta-decay matrix elements phenomenologically is discussed.
Imaging Mass Spectrometry and Genome Mining Reveal Highly Antifungal Virulence Factor of Mushroom Soft Rot Pathogen
2012-11-19

Caught in the act: imaging mass spectrometry of a button mushroom infected with the soft rot pathogen Janthinobacterium agaricidamnosum in conjunction with genome mining revealed jagaricin as a highly antifungal virulence factor that is not produced under standard cultivation conditions. The structure of jagaricin was rigorously elucidated by a combination of physicochemical analyses, chemical derivatization, and bioinformatics.
Worlds of Welfare Services: From Discovery to Exploration
2012-11-19

Abstract A recent thread of debate in social policy research has been the ‘discovery’ of welfare services. Previous comparative studies in this field have been largely erratic and have led to different results. This ambiguity is mainly due to flaws inherent in the data sets. In order to overcome these problems, this article uses an alternative approach of operationalizing welfare services. Employment patterns in the welfare sector provide a holistic picture of welfare services regarding quantity, kind, and organization. Cluster analysis leads to a four‐cluster structure that bears high resemblance to the conventional welfare regime typology by Esping‐Andersen and its subsequent advancements. These findings are set in the context of the welfare regimes literature in order to enhance our understanding of the functioning of welfare regimes. The study suggests that the ideological orientation of the welfare state is a good starting point for a holistic framework of welfare regimes combining the transfer and the service component.
Unusual Low-Vibrational C═O Mode of COOH Can Distinguish between Carboxylated Zigzag and Armchair Single-Wall Carbon Nanotubes
2012-11-19

Vibrational frequency analysis using density functional theory resolves some ambiguities in interpretation of IR spectra of carboxylated single-wall carbon nanotubes (o-SWNTs). Armchair (n,n) and zigzag (m,0) tubes, with diameter varying between 0.5 and 1.4 nm, were populated with different numbers of COOH groups at one terminus. While armchair-COOH tubes exhibit C═O stretching frequencies in the standard range of 1720–1760 cm–1, zigzag-COOH tubes display a new C═O band around 1650 cm–1 with much higher intensity, in addition to the higher-frequency C═O mode. The COOH groups exhibiting this low-frequency (lf-COOH) are displaced well off the lines of the tube walls, to the outside. This new band is in the same range as one observed experimentally, which has on occasion been attributed to quinone formation. The C═O bond length in the relevant COOH groups is longer by about 0.01 Å than regular C═O bonds. Such low-frequency C═O band is unusual and not common for any stand-alone COOH group and seems characteristic of carboxylated zigzag tubes irrespective of their diameter and the number of acid groups at the terminus. The lower frequency is not a result of H-bonding, nor can it be reproduced by small models such as benzoic acid or extended carbon networks as in graphene-COOH. Its origin is attributed instead to the curvature of the zigzag tubes in addition to their structural arrangement.
Recognition performance differentiates between elderly patients in the long term course of secondary progressive multiple sclerosis and amnestic mild cognitive impairment
2012-11-19

Background: Cognitive impairment is a common symptom of multiple sclerosis (MS), but little is known about cognitive decline in patients in the long-term course of progressive MS. Because advancing age is the most significant risk factor for Alzheimer’s Disease (AD), AD-related pathology must be considered in elderly patients with MS. Amnestic mild cognitive impairment (aMCI) represents the prodromal phase of AD with subjects showing memory impairment that does not improve with recognition testing. Objective: We sought to identify disease-dependent deterioration patterns by comparing elderly patients with secondary progressive MS (SPMS) and with aMCI using the Consortium to Establish a Registry for Alzheimer’s Disease test battery. Methods: This study included 120 age-, education- and gender-matched participants, including healthy controls ( n=40), SPMS patients ( n=40), and aMCI patients ( n=40). Results: Episodic memory deficits appeared in the long-term course of SPMS. Deficits were associated with deterioration of executive function, but not impairment of memory storage as recognition was preserved in SPMS in contrast to the patients with aMCI. Conclusion: Through neuropsychological testing, MS-related episodic memory impairment due to deteriorated executive function can be distinguished from AD-related encoding and storage deficits. Hence, neuropsychological testing may help to identify AD-related pathology in SPMS patients.
Imaging Mass Spectrometry and Genome Mining Reveal Highly Antifungal Virulence Factor of Mushroom Soft Rot Pathogen
2012-11-19

Entdeckt: Bildgebende Massenspektrometrie eines Champignons (siehe Bild), der mit dem Pathogen Janthinobacterium agaricidamnosum infiziert war, und „Genome-Mining“ führten zur Identifizierung von Jagaricin als antifungalem Virulenzfaktor, der unter Standardkultivierungsbedingungen nicht produziert wird. Die Struktur von Jagaricin wurde mithilfe physikochemischer Analysen, chemischer Derivatisierung und bioinformatischer Methoden vollständig aufgeklärt.
Optical sensing: recognition elements and devices
2012-11-19

The requirements in chemical and biochemical sensing with respect to recognition elements, avoiding non-specific interactions, and high loading of the surface for detection of low concentrations as well as optimized detection systems are discussed. Among the many detection principles the optical techniques are classified. Methods using labeled compounds like Total Internal Reflection Fluorescence (TIRF) and direct optical methods like micro reflectometry or refractometry are discussed in comparison. Reflectometric Interference Spectroscopy (RIfS) is presented as a robust simple method for biosensing. As applications, trace analysis of endocrine disruptors in water, hormones in food, detection of viruses and bacteria in food and clinical diagnostics are discussed.
Adoptive Transfer of Epstein-Barr Virus (EBV) Nuclear Antigen 1–Specific T Cells As Treatment for EBV Reactivation and Lymphoproliferative Disorders After Allogeneic Stem-Cell Transplantation
2012-11-20

Purpose Reactivation of Epstein-Barr virus (EBV) after allogeneic stem-cell transplantation (SCT) can lead to severe life-threatening infections and trigger post-transplantation lymphoproliferative disease (PTLD). Since EBV-specific T cells could prevent PTLD, cellular immunotherapy has been a promising treatment option. However, generation of antigen-specific T-cell populations has been difficult within a short time frame. Patients and Methods To improve availability in urgent clinical conditions, we developed a rapid protocol for isolation of polyclonal EBV nuclear antigen 1 (EBNA-1) –specific T cells by using an interferon gamma (IFN-γ) capture technique. Results We report on the use of adoptive transfer of EBNA-1–specific T cells in 10 pediatric and adult patients with EBV viremia and/or PTLD after SCT. No acute toxicity or graft-versus-host disease (GVHD) of more than grade 2 occurred as a result of adoptive T-cell transfer. In vivo expansion of transferred EBNA-1–specific T cells was observed in eight of 10 patients after a median of 16 days following adoptive transfer that was associated with clinical and virologic response in seven of them (70%). None of the responders had EBV-associated mortality. Within clinical responders, three patients were disease free by the day of last follow-up (2 to 36 months), three patients died of other infectious complications, and one patient died as a result of relapse of malignancy. EBV-related mortality was observed in two of 10 patients, and another patient had ongoing viremia without clinical symptoms at last follow-up. Conclusion Adoptive ex vivo transfer of EBNA-1–specific T cells is a feasible and well-tolerated therapeutic option, representing a fast and efficient procedure to achieve reconstitution of antiviral T-cell immunity after SCT.
Structural Loop Between the Cerebellum and the Superior Temporal Sulcus: Evidence from Diffusion Tensor Imaging
2012-11-20

The cerebellum is believed to play an essential role in a variety of motor and cognitive functions through reciprocal interaction with the cerebral cortex. Recent findings suggest that cerebellar involvement in the network specialized for visual body motion processing may be mediated through interaction with the right superior temporal sulcus (STS). Yet, the underlying pattern of structural connectivity between the STS and the cerebellum remains unidentified. In the present work, diffusion tensor imaging analysis on seeds derived from functional magnetic resonance imaging during a task on point-light biological motion perception uncovers a structural pathway between the right posterior STS and the left cerebellar lobule Crus I. The findings suggest existence of a structural loop underpinning bidirectional communication between the STS and cerebellum. This connection might also be of potential value for other visual social abilities.
Opposing effects of aminocoumarins and fluoroquinolones on the SOS response and adaptability in Staphylococcus aureus
2012-11-20

In summary, aminocoumarins inhibit recA expression in S. aureus and probably delay the process of developing antibiotic resistance and gene transfer. A clinical re-evaluation of these compounds as well as designing more applicable derivatives should be considered.
Serum-free culture of primary human hepatocytes in a miniaturized hollow-fibre membrane bioreactor for pharmacologicalin vitrostudies
2012-11-20

Primary human hepatocytes represent an important cell source for in vitro investigation of hepatic drug metabolism and disposition. In this study, a multi-compartment capillary membrane-based bioreactor technology for three-dimensional (3D) perfusion culture was further developed and miniaturized to a volume of less than 0.5 ml to reduce demand for cells. The miniaturized bioreactor was composed of two capillary layers, each made of alternately arranged oxygen and medium capillaries serving as a 3D culture for the cells. Metabolic activity and stability of primary human hepatocytes was studied in this bioreactor in the presence of 2.5% fetal calf serum (FCS) under serum-free conditions over a culture period of 10 days. The miniaturized bioreactor showed functions comparable to previously reported data for larger variants. Glucose and lactate metabolism, urea production, albumin synthesis and release of intracellular enzymes (AST, ALT, GLDH) showed no significant differences between serum-free and serum-supplemented bioreactors. Activities of human-relevant cytochrome P450 (CYP) isoenzymes (CYP1A2, CYP3A4/5, CYP2C9, CYP2D6, CYP2B6) analyzed by determination of product formation rates from selective probe substrates were also comparable in both groups. Gene expression analysis showed moderately higher expression in the majority of CYP enzymes, transport proteins and enzymes of Phase II metabolism in the serum-free bioreactors compared to those maintained with FCS. In conclusion, the miniaturized bioreactor maintained stable function over the investigated period and thus provides a suitable system for pharmacological studies on primary human hepatocytes under defined serum-free conditions.
Inhibition of hedgehog signaling attenuates carcinogenesis in vitro and increases necrosis of cholangiocellular carcinoma
2012-11-21

The Hedgehog signaling pathway plays a pivotal role during embryonic development, stem cell maintenance, and wound healing. Hedgehog signaling also is deregulated in many cancers. However, the role of this signaling pathway in the carcinogenesis of cholangiocarcinoma (CCC) is still unknown. In this study, we investigated the effects of Hedgehog inhibition by cyclopamine and 5E1 in cultured human CCC cell lines and in vivo using a xenograft mouse model. We also investigated the involvement of Hedgehog in epithelial to mesenchymal transition (EMT), migration, and CCC tumor growth. Sonic hedgehog (Shh) ligand was highly expressed in 89% of human CCC tissues and in CCC cell lines. Cyclopamine and 5E1 treatments effectively inhibited cell proliferation, migration, and invasion by down-regulating the Hedgehog target genes glioblastoma 1 and glioblastoma 2. In vitro and in vivo, we detected an increase in epithelial marker, E-cadherin, after Hedgehog inhibition. In addition, we saw an increase in necrotic areas and a decrease in mitotic figures in cyclopamine and 5E1-treated CCC xenograft tumors. Conclusion : This study supports the presence of autocrine Hedgehog signaling in human CCC, where CCC cells produce and respond to Shh ligand. Blocking the Hedgehog pathway inhibited EMT and decreased the viability of CCC cells. In addition, cyclopamine and 5E1 inhibited the growth of CCC xenograft tumors. (Hepatology 2013)