bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety aspects of 36 months of administration of long-acting intramuscular testosterone undecanoate for treatment of female-to-male transgender individuals
Authors: Jacobeit J W , Gooren L J , Schulte H M
Published: September 2009

Design

Testosterone treatment is essential for the induction and maintenance of virilization of female-to-male (FTM) transsexuals.

Aim

To test the safety of a novel testosterone preparation for this purpose.

Methods

Parenteral long-acting testosterone undecanoate (TU) was administered to 17 FTM transsexuals over 36 months. Observations were made while subjects received treatment.

Results

Serum testosterone rose from 0.50±0.25 to 6.2±1.3 ng/ml at 6 months and remained stable thereafter. The testosterone profiles were largely identical with those in hypogonadal receiving TU. There were no side effects. Over the 36 months of the study, there was a small but significant decrease in plasma cholesterol (from 218±47 to 188±42 mg/dl) and low-density lipoprotein-cholesterol (from 139±48 to 139±48 mg/dl), while plasma levels of high-density lipoprotein-cholesterol and triglycerides did not change significantly. Liver enzymes did not change during treatment. There was an increase of both levels in hemoglobin (from 13.6±1.2 to 16.0±1.5 g/dl) and hematocrit (from 41±4 to 46±4) upon administration but they remained almost without exception within the physiological range. No special measures were needed. Breast and gonads/internal genitalia did not show pathological changes over the observation period.

Conclusion

This study reports that TU is suited for induction of virilization in FTM transsexuals without significant side effects over a longer term.
Oestrogen receptor 1 mRNA is a prognostic factor in ovarian cancer patients treated with neo-adjuvant chemotherapy: determination by array and kinetic PCR in fresh tissue biopsies
Authors: Zamagni Claudio , Wirtz Ralph M , De Iaco Pierandrea , Rosati Marta , Veltrup Elke , Rosati Federica , Capizzi Elisa , Cacciari Nicoletta , Alboni Carlo , Bernardi Alessandra , Massari Francesco , Quercia Sara , D'Errico Grigioni Antonietta , Dietel Manfred , Sehouli Jalid , Denkert Carsten , Martoni Andrea Angelo
Published: September 2009

Oestrogen receptors (ESRs) regulate the growth and differentiation of normal ovarian epithelia. However, to date their role as biomarkers in the clinical setting of ovarian cancer remains unclear. In view of potential endocrine treatment options, we tested the role of ESR1 mRNA expression in ovarian cancer in the context of a neo-adjuvant chemotherapy trial. Study participants had epithelial ovarian or peritoneal carcinoma unsuitable for optimal upfront surgery and were treated with neo-adjuvant platinum-based chemotherapy before surgery. RNA was isolated from frozen tumour biopsies before treatment. RNA expression of ESR1 was determined by microarray and reverse transcriptase kinetic PCR technologies. The prognostic value of ESR1 was tested using univariate and multivariate Cox proportional hazards models, Kaplan–Meier survival statistics and the log-rank test. ESR1 positively correlates with proliferation markers and histopathological grading. ESR1 was a significant predictor of survival as a continuous variable in the univariate Cox regression analysis. In multivariate analysis, elevated baseline ESR1 mRNA levels predicted prolonged progression-free survival (P=0.041) and overall survival (P=0.01) after neo-adjuvant chemotherapy, independently of pathological grade and age. We conclude that pretreatment ESR1 mRNA is associated with tumour growth and is a strong prognostic factor in ovarian cancer, independent of the strongest clinical parameters used in clinical routine. We suggest that ESR1 mRNA status should be considered in order to minimize possible confounding effects in ovarian cancer clinical trials, and that early treatment with anti-hormonal agents based on reliable hormone receptor status determination is worth investigating.
Formation and Stability Study of Nano-Emulsions: BTX- Separation
Authors: M. Barad Jaydeep , Chakraborty Mousumi , Bart Hans-Jörg
Published: September 2009

The selective separation of aromatics (benzene, toluene and p-xylene, BTX) from aliphatic (n-heptane) is
investigated using simple permeation and facilitated transport emulsion liquid membrane mechanism. The separation
performances, represented by the permeation rate and separation factor, are analyzed systematically by varying the
operating parameters. One of the major obstacles to the application of emulsion liquid membranes to industrial separations
is the stability of emulsion globules. In the present study, stability of emulsion liquid membrane is studied by varying
different parameters e.g. surfactant and feed phase concentration, stirrer speed for emulsification. Dispersion
destabilisation of emulsion is detected by Turbiscan. Effects of interfacial tension on internal droplets size and size
distribution are also systematically investigated. Stable emulsions under optimal conditions are used for the separation of
aromatics (BTX) from aliphatic (n-heptane) in a synthetic feed mixture.
TNFA and IL10 Gene Polymorphisms are not Associated with Periodontitis in Brazilians
Authors: Moreira P. R , Costa J. E , Gomez R. S , Gollob K. J , Dutra W. O
Published: September 2009

IL-10 and TNF-α are cytokines that have complex and opposing roles in the inflammatory responses. G/A polymorphisms at position –1082 ofIL10and –308 ofTNFAgenes have been reported to influence the expression of IL-10 and TNF-α, respectively. The aim of this study was to investigate the association between theIL10(-1082) andTNFA(- 308) gene polymorphisms with different clinical forms or severity of periodontitis in a sample of Brazilian individuals. DNA was obtained from oral swabs of 165 Brazilian individuals, which were divided into three groups: individuals with chronic periodontitis, aggressive periodontitis and individuals without clinical evidence of periodontitis. Evaluation ofIL10andTNFApolymorphisms was performed by RFLP analysis. Statistical analysis of data was performed using the χ2likelihood ratio and Fisher`s exact test. No significant differences in the genotype and allele distribution of eitherIL10orTNFAwere observed among individuals with different clinical forms or with different degrees of severity of periodontitis. Moreover, combined analysis ofIL10andTNFApolymorphisms did not show any association with periodontal status. As conclusion, theIL10andTNFAgene promoter polymorphisms investigated are not associated with different clinical forms of periodontitis or with severity of the disease in the Brazilian population polymorphisms.
Effects of Clenbuterol, a β2-Adrenergic Agonist, on Sizes of Masseter, Temporalis, Digastric, and Tongue muscles
Authors: Ishikawa Chieko , Ogawa Takumi , Ikawa Tomoko , Yamane Akira
Published: September 2009

We compared the hypertrophic effects of clenbuterol, a β2-adrenergic agonist, on the masseter, digastric, and temporalis with those on the tongue, tibialis anterior, soleus, diaphragm, and heart. The weights of masseter, digastric and temporalis in the clenbuterol group were 36 ~ 56% greater than those in the control group, whereas those of the tibialis anterior, diaphragm, and heart weights in the clenbuterol group were 9 ~ 33% greater than those in the control group. No significant difference in the weights of the soleus and tongue was found between the control and clenbuterol groups. Taken together with our present and previously reported results, it is suggested that the hypertrophic effects of clenbuterol on the masseter, digastric, and temporalis are greater than those on the limb, trunk, and heart.
Where Should we Submit our Manuscript? An Analysis of Journal Submission Strategies
Authors: Heintzelman Martin , Nocetti Diego
Published: September 2009

In this paper, we analyze the problem faced by impatient researchers attempting to balance the considerations of journal quality, submission lags, and acceptance probabilities in choosing appropriate outlets for their work. We first study the case in which probabilities of submission outcomes are exogenous parameters and show that authors can find the optimal submission path through the use of journal 'scores' based only on the journals' characteristics and the author's degree of impatience. Then, we analyze a more realistic framework in which acceptance probability is determined by the quality of the manuscript, in which the reviewing process may be imperfect, and in which authors may not be certain of the manuscript's quality. Throughout, we illustrate our analysis with data on actual economics journals. We also consider the problem of journals facing a large number of submissions, limited space, and limited resources to review papers and, in particular, we examine the relative effectiveness of using submission fees and reviewing lags to ration article submissions.
Implication of 5-aminolevulinic acid fluorescence of the ventricular wall for postoperative communicating hydrocephalus associated with cerebrospinal fluid dissemination in patients with glioblastoma multiforme: a report of 7 cases
Authors: Hayashi Yutaka , Nakada Mitsutoshi , Tanaka Shingo , Uchiyama Naoyuki , Hayashi Yasuhiko , Kita Daisuke , Hamada Jun-ichiro
Published: September 2009

Object

Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) has been broadly recognized as a beneficial tool for the resection of glioblastoma multiforme (GBM). Fluorescence in the ventricular walls, which were apparently free of macroscopic tumor or MR imaging enhancement indicative of CSF dissemination, was detected during surgery for GBM. To evaluate the clinical significance of the 5-ALA fluorescence, the authors resected ventricle wall tissue together with the adjacent tumors for pathological examination and then followed up the clinical courses of the patients.

Methods

Seven consecutive GBMs located near the lateral ventricle were surgically treated using a fluorescence-guided technique with 5-ALA at the authors' hospital since acquiring instrumentation for the detection of 5-ALA fluorescence in 2007. All of the procedures were performed using a ventricular entry, and 5-ALA fluorescence of the ventricular wall was detected despite the absence of macroscopic tumor invasion of the wall.

Results

A pathological examination of the resected ventricular wall tissues revealed tumor cells in 6 of the 7 cases and disruption of the ependymal cell layer in all 7 cases. Delayed communicating hydrocephalus followed surgery in all 7 patients, and ventricular wall enhancements on MR imaging were demonstrated after hydrocephalus in 2 of the patients.

Conclusions

Data in this study suggest that 5-ALA fluorescence of the ventricular wall may be predictive of postoperative hydrocephalus associated with CSF dissemination even in cases without evidence of CSF dissemination on MR imaging studies before surgery. The authors also speculate that postoperative radiotherapy covering the whole ventricular system may be a better therapeutic option for these patients.
Approximate String Matching with Compressed Indexes
Authors: Russo Luís M.  S. , Navarro Gonzalo , Oliveira Arlindo  L. , Morales Pedro
Published: September 2009

A compressed full-text self-index for a text T is a data structure requiring reduced space and able to search for patterns P in T. It can also reproduce any substring of T, thus actually replacing T. Despite the recent explosion of interest on compressed indexes, there has not been much progress on functionalities beyond the basic exact search. In this paper we focus on indexed approximate string matching (ASM), which is of great interest, say, in bioinformatics. We study ASM algorithms for Lempel-Ziv compressed indexes and for compressed suffix trees/arrays. Most compressed self-indexes belong to one of these classes. We start by adapting the classical method of partitioning into exact search to self-indexes, and optimize it over a representative of either class of self-index. Then, we show that a Lempel- Ziv index can be seen as an extension of the classical q-samples index. We give new insights on this type of index, which can be of independent interest, and then apply them to a Lempel- Ziv index. Finally, we improve hierarchical verification, a successful technique for sequential searching, so as to extend the matches of pattern pieces to the left or right. Most compressed suffix trees/arrays support the required bidirectionality, thus enabling the implementation of the improved technique. In turn, the improved verification largely reduces the accesses to the text, which are expensive in self-indexes. We show experimentally that our algorithms are competitive and provide useful space-time tradeoffs compared to classical indexes.
Developmental Switch of the Expression of Ion Channels in Human Dendritic Cells
Authors: Zsiros Emese , Kis-Toth Katalin , Hajdu Peter , Gaspar Rezso , Bielanska Joanna , Felipe Antonio , Rajnavolgyi Eva , Panyi Gyorgy
Published: September 2009

Modulation of the expression and activity of plasma membrane ion channels is one of the mechanisms by which immune cells can regulate their intracellular Ca2+ signaling pathways required for proliferation and/or differentiation. Voltage-gated K+ channels, inwardly rectifying K+ channels, and Ca2+-activated K+ channels have been described to play a major role in controlling the membrane potential in lymphocytes and professional APCs, such as monocytes, macrophages, and dendritic cells (DCs). Our study aimed at the characterization and identification of ion channels expressed in the course of human DC differentiation from monocytes. We report in this study for the first time that immature monocyte-derived DCs express voltage-gated Na+ channels in their plasma membrane. The analysis of the biophysical and pharmacological properties of the current and PCR-based cloning revealed the presence of Nav1.7 channels in immature DCs. Transition from the immature to a mature differentiation state, however, was accompanied by the down-regulation of Nav1.7 expression concomitant with the up-regulation of voltage-gated Kv1.3 K+ channel expression. The presence of Kv1.3 channels seems to be common for immune cells; hence, selective Kv1.3 blockers may emerge as candidates for inhibiting various functions of mature DCs that involve their migratory, cytokine-secreting, and T cell-activating potential.
Impaired Mast Cell Activation in Gene-Targeted Mice Lacking the Serum- and Glucocorticoid-Inducible Kinase SGK1
Authors: Sobiesiak Malgorzata , Shumilina Ekaterina , Lam Rebecca S. , Wölbing Florian , Matzner Nicole , Kaesler Susanne , Zemtsova Irina M. , Lupescu Adrian , Zahir Naima , Kuhl Dietmar , Schaller Martin , Biedermann Tilo , Lang Florian
Published: September 2009

The PI3K pathway plays a pivotal role in the stimulation of mast cells. PI3K-dependent kinases include the serum- and glucocorticoid-inducible kinase 1 (SGK1). The present study explored the role of SGK1 in mast cell function. Mast cells were isolated from bone marrow (BMMC) of SGK1 knockout mice (sgk1−/−) and their wild-type littermates (sgk1+/+). The BMMC number as well as CD117, CD34, and FcεRI expression in BMCCs were similar in both genotypes. Upon Ag stimulation of the FcεRI receptor, Ca2+ entry but not Ca2+ release from intracellular stores was markedly impaired in sgk1−/− BMMCs. The currents through Ca2+-activated K+ channels induced by Ag were significantly higher in sgk1+/+ BMMCs than in sgk1−/− BMMCs. Treatment with the Ca2+ ionophore ionomycin (1 μM) led to activation of the K+ channels in both genotypes, indicating that the Ca2+-activated K+ channels are similarly expressed and sensitive to activation by Ca2+ in sgk1+/+ and sgk1−/− BMMCs, and that blunted stimulation of Ca2+-activated K+ channels was secondary to decreased Ca2+ entry. Ag-IgE-induced degranulation and early IL-6 secretion were also significantly blunted in sgk1−/− BMMCs. The decrease in body temperature following Ag treatment, which reflects an anaphylactic reaction, was substantially reduced in sgk1−/− mice, pointing to impaired mast cell function in vivo. Serum histamine levels measured 30 min after induction of an anaphylactic reaction were significantly lower in sgk1−/− than in sgk1+/+mice. The observations reveal a critical role for SGK1 in ion channel regulation and the function of mast cells, and thus disclose a completely novel player in the regulation of allergic reaction.
Killer Ig-Like Receptor Ligand Mismatch Directs NK Cell Expansion In Vitro
Authors: Rose Mingus J. J. , Brooks Andrew G. , Stewart Lisbeth A. , Nguyen Thi H. , Schwarer Anthony P.
Published: September 2009

NK cell alloreactivity is governed largely through failure to detect self-HLA class I ligands by the clonally distributed inhibitory killer Ig-like receptors (KIR) expressed on the NK cell surface. In this study, we investigated the extent to which HLA class I-KIR interactions influence human NK cell proliferation in the allogeneic setting. NK cells were cultured with feeder cells either matched or mismatched for inhibitory KIR ligands, the latter lacking one or more ligands present in the NK cell donor. In postculture cytotoxicity assays, the ability of polyclonal NK cells to kill KIR ligand-mismatched targets was enhanced by exposure to appropriately mismatched feeder cells in prior culture. This corresponded with an increased frequency of postculture donor NK cells expressing a given inhibitory KIR if the allogeneic feeder cells used in the culture lacked its ligand. Similar skewing of KIR distribution was seen in clonally expanded NK cells. Finally, a flow cytometry-based proliferation assay was used to show KIR-specific NK cell division in response to missing self. The findings demonstrate that KIR distribution among a population of alloresponding peripheral blood NK cells is shaped by the HLA class I environment.
IL-27 Regulates IL-10 and IL-17 from CD4+ Cells in Nonhealing Leishmania major Infection
Authors: Anderson Charles F. , Stumhofer Jason S. , Hunter Christopher A. , Sacks David
Published: September 2009

Control of infection caused by Leishmania major requires the development of IFN-γ+CD4+ lymphocytes for the induction of microbicidal activity in host macrophages. We recently reported on the inability of conventionally resistant C57BL/6 mice to successfully resolve infection by an isolate of L. major, despite a strong IFN-γ response by the host. Susceptibility was caused by Ag-specific IL-10 from CD4+ cells that were also producing IFN-γ. In the present studies, we have explored the role for IL-27 in the regulation of IL-10 from Th1 cells in leishmaniasis. Cytokine analysis of CD4+ cells in the lesions and draining lymph nodes of infected IL-27R-deficient (WSX-1−/−) mice revealed diminished IL-10 from IFN-γ+ CD4+ cells, which was accompanied by a reduction in total IFN-γ+CD4+ cells and an increase in IL-4. Despite the inhibition of IL-10 from CD4+ cells, no significant change in parasite numbers was observed, due both to the shift in the Th1/Th2 balance and to residual levels of IL-10. Strikingly, infected WSX-1−/− mice developed more severe lesions that were associated with the appearance of IL-17+ CD4+ cells, demonstrating a function for IL-27 in blocking the development of inappropriate Th17 cells during L. major infection. The results demonstrate the pleiotropic effects that IL-27 has on L. major-driven Th1, Th2, and Th17 development, and reinforce its function as a key regulatory cytokine that controls the balance between immunity and pathology.
Extracellular ATP Acting at the P2X7 Receptor Inhibits Secretion of Soluble HLA-G from Human Monocytes
Authors: Rizzo Roberta , Ferrari Davide , Melchiorri Loredana , Stignani Marina , Gulinelli Sara , Baricordi Olavio R. , Di Virgilio Francesco
Published: September 2009

Bacterial LPS induces the release of ATP from immune cells. Accruing evidence suggests that extracellular ATP participates in the inflammatory response as a proinflammatory mediator by activating the inflammasome complex, inducing secretion of cytokines (IL-1, IL-18) and cell damaging agents such as oxygen radicals, cationic proteins, and metalloproteases. It is not known whether ATP can also act as a proinflammatory mediator by inhibiting production of molecules down-modulating the immune response. Here, we show that extracellular ATP impairs in an IL-10-dependent fashion the expression of the tolerogenic soluble and membrane-bound HLA-G Ag in human monocytes. The effect of ATP was mimicked by BzATP (3′-O-(4-benzoyl)benzoyl-ATP) and greatly reduced by pretreatment with oATP (periodate-oxidized ATP), KN-62 (1-[N,O-bis(5-isoquinoline-sulfonyl)-N-methyl-l-tyrosyl]-4-phenylpiperazine), and an anti-P2X7 mAb, thus pointing to a specific role of the P2X7 receptor. The effect of ATP was time- and dose-dependent and was not due to a decrease in expression of IL-10 receptor. Inhibition by ATP was reverted by supplementation of culture medium with exogenous IL-10. Due to the well-known immunosuppressive activity of IL-10 and soluble HLA-G, this novel effect of ATP might be relevant for the pathophysiology and therapy of inflammatory disorders.
TLR3 Ligand Polyinosinic:Polycytidylic Acid Induces IL-17A and IL-21 Synthesis in Human Th Cells
Authors: Holm Christian K. , Petersen Charlotte C. , Hvid Malene , Petersen Line , Paludan Søren R. , Deleuran Bent , Hokland Marianne
Published: September 2009

TLR3 and TLR9 recognize the pathogen-associated microbial patterns dsRNA and unmethylated DNA, respectively. The recent discovery that these receptors also recognize endogenous ligands from necrotic material has drawn increased attention to their involvement in autoimmunity. Th cell cytokines IL-17A and IL-21 have been assigned with pivotal roles in the regulation of such autoimmune diseases. IL-17A is the hallmark cytokine of the recently discovered proinflammatory Th cell subset TH17. By contrast, the expression of IL-21 does not seem to be limited to a single distinct Th cell subset. We investigated the expression of IL-17A and IL-21 in human CD4+ T cells in response to stimulation with the TLR3 ligand polyinosinic:polycytidylic acid (poly(I:C)) and the TLR9 ligand CpG. We discovered that poly(I:C) induced synthesis of both IL-17A and IL-21. Moreover, we found that poly(I:C) was able to drive the differentiation of naive Th cells into an IL-21 but not into an IL-17A-producing phenotype and did this without affecting the levels of transcription factors T-bet, GATA-3, or retinoic acid receptor-related orphan receptor C. Finally, we found that the IL-21-producing cells that were differentiated in response to poly(I:C) expressed the chemokine receptor CXCR3, which is important in the recruitment of T cells into inflamed joints in rheumatoid arthritis. This is the first report to show that the TLR3 ligand poly(I:C) can directly induce the synthesis of IL-17A and IL-21 and drive differentiation of human naive CD4+ T cells.
Monocytes from Patients with Type 1 Diabetes Spontaneously Secrete Proinflammatory Cytokines Inducing Th17 Cells
Authors: Bradshaw Elizabeth M. , Raddassi Khadir , Elyaman Wassim , Orban Tihamer , Gottlieb Peter A. , Kent Sally C. , Hafler David A.
Published: September 2009

Autoimmune diseases including type 1 diabetes (T1D) are thought to have a Th1/Th17 bias. The underlying mechanisms driving the activation and differentiation of these proinflammatory T cells are unknown. We examined the monocytes isolated directly from the blood of T1D patients and found they spontaneously secreted the proinflammatory cytokines IL-1β and IL-6, which are known to induce and expand Th17 cells. Moreover, these in vivo-activated monocytes from T1D subjects induced more IL-17-secreting cells from memory T cells compared with monocytes from healthy control subjects. The induction of IL-17-secreting T cells by monocytes from T1D subjects was reduced in vitro with a combination of an IL-6-blocking Ab and IL-1R antagonist. In this study, we report a significant although modest increase in the frequency of IL-17-secreting cells in lymphocytes from long-term patients with T1D compared with healthy controls. These data suggest that the innate immune system in T1D may drive the adaptive immune system by expanding the Th17 population of effector T cells.
Temporal Regulation of Ig Gene Diversification Revealed by Single-Cell Imaging
Authors: Ordinario Ellen C. , Yabuki Munehisa , Larson Ryan P. , Maizels Nancy
Published: September 2009

Rearranged Ig V regions undergo activation-induced cytidine deaminase (AID)-initiated diversification in sequence to produce either nontemplated or templated mutations, in the related pathways of somatic hypermutation and gene conversion. In chicken DT40 B cells, gene conversion normally predominates, producing mutations templated by adjacent pseudo-V regions, but impairment of gene conversion switches mutagenesis to a nontemplated pathway. We recently showed that the activator, E2A, functions in cis to promote diversification, and that G1 phase of cell cycle is the critical window for E2A action. By single-cell imaging of stable AID-yellow fluorescent protein transfectants, we now demonstrate that AID-yellow fluorescent protein can stably localize to the nucleus in G1 phase, but undergoes ubiquitin-dependent proteolysis later in cell cycle. By imaging of DT40 polymerized lactose operator-λR cells, in which polymerized lactose operator tags the rearranged λR gene, we show that both the repair polymerase Polη and the multifunctional factor MRE11/RAD50/NBS1 localize to λR, and that λR/Polη colocalizations occur predominately in G1 phase, when they reflect repair of AID-initiated damage. We find no evidence of induction of γ-H2AX, the phosphorylated variant histone that is a marker of double-strand breaks, and Ig gene conversion may therefore proceed by a pathway involving templated repair at DNA nicks rather than double-strand breaks. These results lead to a model in which Ig gene conversion initiates and is completed or nearly completed in G1 phase. AID deaminates ssDNA, and restriction of mutagenesis to G1 phase would contribute to protecting the genome from off-target attack by AID when DNA replication occurs in S phase.
Defucosylated Anti-CCR4 Monoclonal Antibody Exerts Potent ADCC against Primary ATLL Cells Mediated by Autologous Human Immune Cells in NOD/Shi-scid, IL-2Rγnull Mice In Vivo
Authors: Ito Asahi , Ishida Takashi , Utsunomiya Atae , Sato Fumihiko , Mori Fumiko , Yano Hiroki , Inagaki Atsushi , Suzuki Susumu , Takino Hisashi , Ri Masaki , Kusumoto Shigeru , Komatsu Hirokazu , Iida Shinsuke , Inagaki Hiroshi , Ueda Ryuzo
Published: September 2009

There is a lack of suitable small animal models to evaluate human Ab-dependent cellular cytotoxicity (ADCC) in vivo, because of the species incompatibility between humans and animals or due to nonspecific allogeneic immune reactions. To overcome these problems, we established a human tumor-bearing mouse model, using NOD/Shi-scid, IL-2Rγnull (NOG) mice as recipients, in which autologous human immune cells are engrafted and mediate ADCC but in which endogenous murine cells are unable to mediate ADCC. In the present study, we used NOG mice bearing primary adult T cell leukemia/lymphoma (ATLL) cells and a therapeutic chimeric anti-CCR4 mAb, the Fc region of which is defucosylated to enhance ADCC. We report significant antitumor activity in vivo associated with robust ADCC mediated by autologous effector cells from the same patients. The present study is the first to report a mouse model in which a potent antitumor effect of the therapeutic mAb against primary tumor cells is mediated by autologous human immune cells. Human autologous ADCC in mice in vivo was confirmed by the depletion of human immune cells before ATLL PBMC inoculation. In addition, NOG mice bearing primary ATLL cells presented features identical with patients with ATLL. In conclusion, this approach makes it possible to model the human immune system active in Ab-based immunotherapy in vivo, and thus to perform more appropriate preclinical evaluations of novel therapeutic mAb. Furthermore, the potent ADCC mediated by defucosylated anti-CCR4 mAb, observed here in vivo in humanized mice, will be exploited in clinical trials in the near future.
Antitumor IgE Adjuvanticity: Key Role of FcεRI
Authors: Nigro Elisa A. , Brini Anna T. , Soprana Elisa , Ambrosi Alessandro , Dombrowicz David , Siccardi Antonio G. , Vangelista Luca
Published: September 2009

Working with C57BL/6 mouse tumor models, we had previously demonstrated that vaccination with IgE-coated tumor cells can protect against tumor challenge, an observation that supports the involvement of IgE in antitumor immunity. The adjuvant effect of IgE was shown to result from eosinophil-dependent priming of the T cell-mediated adaptive immune response. The protective effect is likely to be mediated by the interaction of tumor cell-bound IgE with receptors, which then trigger the release of mediators, recruitment of effector cells, cell killing and tumor Ag cross-priming. It was therefore of utmost importance to demonstrate the strict dependence of the protective effect on IgE receptor activation. First, the protective effect of IgE was confirmed in a BALB/c tumor model, in which IgE-loaded modified VV Ankara-infected tumor cells proved to be an effective cellular vaccine. However, the protective effect was lost in FcεRIα−/− (but not in CD23−/−) knockout mice, showing the IgE-FcεRI interaction to be essential. Moreover, human IgE (not effective in BALB/c mice) had a protective effect in the humanized knockin mouse (FcεRIα−/− hFcεRIα+). This finding suggests that the adjuvant effect of IgE could be exploited for human therapeutics.
Engagement of TLR2 Does not Reverse the Suppressor Function of Mouse Regulatory T Cells, but Promotes Their Survival
Authors: Chen Qian , Davidson Todd S. , Huter Eva N. , Shevach Ethan M.
Published: September 2009

TLRs are a class of conserved pattern recognition receptors that are used by cells of the innate immune system. Recent studies have demonstrated the expression of TLRs on both human and mouse T cells raising the possibility that TLRs play a direct role in adaptive immunity. TLR2 is activated primarily by bacterial wall components including peptidoglycan and lipoproteins. Several studies have shown that mouse regulatory T (Treg) cells express TLR2 and claimed that engagement of TLR2 by synthetic ligands reversed their suppressive function. In contrary, enhancement of Treg function was observed following engagement of TLR2 on human Treg. We have reexamined the expression and function of TLR2 on mouse Treg purified from Foxp3-GFP knock-in mice. TLR2 ligation by TLR2 agonist, the synthetic bacterial lipoprotein Pam3CSK4, enhanced the proliferative responses of both conventional T cells and Treg in response to TLR stimulation in the absence of APC. Treatment of Foxp3+ Treg with Pam3CSK4 did not alter their suppressive function in vitro or in vivo and did not reduce their level of Foxp3 expression. An additional effect of TLR2 stimulation of Treg was induction of Bcl-xL resulting in enhanced survival in vitro. Treatment of mice with the TLR2 agonist enhanced the Ag-driven proliferation of Treg in vivo, but did not abolish their ability to suppress the development of experimental autoimmune encephalomyelitis. Development of methods to selectively stimulate TLR2 on Treg may lead to a novel approaches for the treatment of autoimmune diseases.
Chicken IgY Binds Its Receptor at the CH3/CH4 Interface Similarly as the Human IgA:FcαRI Interaction
Authors: Pürzel Jana , Schmitt Ramona , Viertlboeck Birgit C. , Göbel Thomas W.
Published: September 2009

Chicken IgY, the ancestral form of mammalian IgE and IgG, is recognized by the high-affinity FcY receptor CHIR-AB1, a member of the leukocyte receptor family. In this study, we have characterized the receptor ligand interaction site by consecutive truncations of the Fcυ IgY domains and mutational analyses of selected residues. Using several fusion proteins that linked the human Cγ2 and Cγ3 domains with the Fcυ IgY domains, a binding assay revealed that both the Fcυ3 and Fcυ4 domains were essential for the IgY CHIR-AB1 interaction. Sequence comparisons of chicken IgY with human IgA demonstrated that 11 of the 19 contact residues important for the IgA FcαRI interaction have been conserved in chicken IgY, although the overall amino acid identity is only 34%. Among the 19 amino acids at respective positions in IgY, the mutation of two residues in the Fcυ3 and two in the Fcυ4 domain completely abolished the IgY to CHIR-AB1 binding revealed by two independent assays. Three further mutations substantially altered the interaction. Molecular modeling on the Cυ3 to Cυ4 crystal structure revealed that all critical residues, although on two domains, are in close proximity. The importance of N-linked carbohydrates was demonstrated by the failure of the CHIR-AB1 interaction after mutation of the glycosylation site. The identification of the IgY Cυ3/Cυ4 interdomain region as critical for binding to CHIR-AB1 significantly enhances our understanding of the IgY receptor interaction and allows further conclusions regarding the FcR phylogeny.
Discontinued Postnatal Thymocyte Development in Sphingosine 1-Phosphate-Lyase-Deficient Mice
Authors: Weber Claudia , Krueger Andreas , Münk Anika , Bode Constantin , Van Veldhoven Paul P. , Gräler Markus H.
Published: September 2009

Circulation of lymphocytes through peripheral lymphoid tissues as well as progenitor entry into the thymus and its output of mature T cells are critical for normal immune function. Egress of lymphocytes from both peripheral lymphoid organs and thymus is dependent on sphingosine 1-phosphate (S1P) gradients. S1P-lyase 1 (SGPL1) deficiency leads to accumulation of S1P in lymphoid tissues, which blocks lymphocyte egress and induces thymus atrophy. In this study, we investigated thymocyte development in SGPL1-deficient mice (SGPL1−/−), which exhibited postnatal discontinuation of early thymocytopoiesis starting at 2 wk after birth. SGPL−/− thymi showed a loss of developing thymocytes in the thymic cortex between 2 and 4 wk of age, whereas mature thymocytes accumulated in the medulla. Detailed analysis demonstrated a deficit in thymic early T cell progenitors (ETP) as the principal reason for discontinued thymocyte development. This developmental block was accompanied by accumulation of ceramides, resulting in enhanced apoptosis of developing T cells. Lack of immigration or settlement of ETP completely halted thymocyte development. We conclude that increased ceramide levels in the thymus of SGPL1−/− mice abrogate thymic development postnatally by enhanced thymocyte apoptosis and depletion of thymic ETP. Our findings indicate that potentially therapeutic immunosuppression by SGPL1 inhibition should benefit from monitoring ceramides to prevent their increase to apoptosis- inducing levels.
Heat Shock Protein-90 Inhibitors Increase MHC Class I-Related Chain A and B Ligand Expression on Multiple Myeloma Cells and Their Ability to Trigger NK Cell Degranulation
Authors: Fionda Cinzia , Soriani Alessandra , Malgarini Giulia , Iannitto Maria Luisa , Santoni Angela , Cippitelli Marco
Published: September 2009

Modulation of the host immune system represents a promising therapeutic approach against cancer, including multiple myeloma. Recent findings indicate that the NK group 2D (NKG2D)- and DNAX accessory molecule-1 (DNAM-1)-activating receptors play a prominent role in tumor recognition and elimination by cytotoxic lymphocytes, suggesting that the levels of NKG2D and DNAM-1 ligand expression on tumor cells may be a critical factor to improve the immune response against cancer. In this study, we tested the effect of 17-allylaminogeldanamycin and radicicol, drugs targeting the heat shock protein-90 (HSP-90) chaperone protein and displaying antimyeloma activity, on the expression of NKG2D and DNAM-1 ligands in human myeloma cell lines. We demonstrate that HSP-90 inhibitors are able to up-regulate both MHC class I chain-related (MIC) A and MICB protein surface and mRNA expression in human myeloma cell lines, without any significant effect on the basal expression of the DNAM-1 ligand poliovirus receptor CD155, or induction of nectin-2 and UL16-binding proteins. Activation of the transcription factor heat shock factor-1 by HSP-90 inhibitors is essential for the up-regulation of MICA/MICB expression and knockdown of heat shock factor-1 using small hairpin RNA interference blocks this effect. Moreover, in vitro and in vivo binding of heat shock factor-1 to MICA and MICB promoters indicates that it may enhance NKG2D ligand expression at the transcriptional level. Finally, exposure to HSP-90 inhibitors renders myeloma cells more efficient to activate NK cell degranulation and a blocking Ab specific for NKG2D significantly reduces this effect. Thus, these results provide evidence that targeting NKG2D ligands expression may be an additional mechanism supporting the antimyeloma activity of HSP-90 inhibitors and suggest their possible immunotherapeutic value.
Increased Density of the Liver and Amiodarone-Associated Phospholipidosis
Authors: Kojima Sunao , Kojima Shinobu , Ueno Hirofumi , Takeya Motohiro , Ogawa Hisao
Published: September 2009

This is a case report in which a 60-year-old man who suffered from ventricular tachycardia with dilated cardiomyopathy was prescribed amiodarone. After taking amiodarone, liver enzymes were increased and computed tomographic (CT) scanning of the abdomen showed a significant increase in the density of the liver without contrast medium. He was suspected as hemochromatosis and liver biopsy was performed. An abnormal high density of liver tissue may be observed in an unenhanced CT in patients treated with amiodarone and we suggest that periodic monitoring of liver function and/or liver biopsy is warranted before an irreversible stage is reached.
Applying the Burke–Litwin model as a diagnostic framework for assessing organisational effectiveness
Authors: Martins Nico , Coetzee Melinde
Published: September 2009

This exploratory study investigated the utility of the Burke–Litwin model as a diagnostic framework for assessing the factors affecting organisational effectiveness. The research setting consisted of an international company, with a population comprising representatives of more than 17 different nationalities. The purposive sampling method was used to  involve employee participants (N = 147)  in  focus groups  and  executive managers  (N =  11)  in semi- structured probing  interviews. The  factors identified related  to both  the  transformational and  transactional dimensions of  the Burke–Litwin model. The f ndings add to the existing literature on factors causing organisational effectiveness and ineffectiveness in cross-cultural organisational contexts.
Screening for Breast Cancer
Authors: Henderson Jillian T. , Webber Elizabeth M. , Weyrich Meghan S. , Miller Marykate , Melnikow Joy
Published: April 2024

Importance

Breast cancer is a leading cause of cancer mortality for US women. Trials have established that screening mammography can reduce mortality risk, but optimal screening ages, intervals, and modalities for population screening guidelines remain unclear.

Objective

To review studies comparing different breast cancer screening strategies for the US Preventive Services Task Force.

Data Sources

MEDLINE, Cochrane Library through August 22, 2022; literature surveillance through March 2024.

Study Selection

English-language publications; randomized clinical trials and nonrandomized studies comparing screening strategies; expanded criteria for screening harms.

Data Extraction and Synthesis

Two reviewers independently assessed study eligibility and quality; data extracted from fair- and good-quality studies.

Main Outcomes and Measures

Mortality, morbidity, progression to advanced cancer, interval cancers, screening harms.

Results

Seven randomized clinical trials and 13 nonrandomized studies were included; 2 nonrandomized studies reported mortality outcomes. A nonrandomized trial emulation study estimated no mortality difference for screening beyond age 74 years (adjusted hazard ratio, 1.00 [95% CI, 0.83 to 1.19]). Advanced cancer detection did not differ following annual or biennial screening intervals in a nonrandomized study. Three trials compared digital breast tomosynthesis (DBT) mammography screening with digital mammography alone. With DBT, more invasive cancers were detected at the first screening round than with digital mammography, but there were no statistically significant differences in interval cancers (pooled relative risk, 0.87 [95% CI, 0.64-1.17]; 3 studies [n = 130 196]; I2 = 0%). Risk of advanced cancer (stage II or higher) at the subsequent screening round was not statistically significant for DBT vs digital mammography in the individual trials. Limited evidence from trials and nonrandomized studies suggested lower recall rates with DBT. An RCT randomizing individuals with dense breasts to invitations for supplemental screening with magnetic resonance imaging reported reduced interval cancer risk (relative risk, 0.47 [95% CI, 0.29-0.77]) and additional false-positive recalls and biopsy results with the intervention; no longer-term advanced breast cancer incidence or morbidity and mortality outcomes were available. One RCT and 1 nonrandomized study of supplemental ultrasound screening reported additional false-positives and no differences in interval cancers.

Conclusions and Relevance

Evidence comparing the effectiveness of different breast cancer screening strategies is inconclusive because key studies have not yet been completed and few studies have reported the stage shift or mortality outcomes necessary to assess relative benefits.
Primary Care Physicians’ Experiences With and Adaptations to Time Constraints
Authors: Nguyen Michelle-Linh T. , Honcharov Vlad , Ballard Dawna , Satterwhite Shannon , McDermott Aoife M. , Sarkar Urmimala
Published: April 2024

Importance

The primary care workforce shortage is significant and persistent, with organizational and policy leaders urgently seeking interventions to enhance retention and recruitment. Time constraints are a valuable focus for action; however, designing effective interventions requires deeper understanding of how time constraints shape employees’ experiences and outcomes of work.

Objective

To examine how time constraints affect primary care physicians’ work experiences and careers.

Design, Setting, and Participants

Between May 1, 2021, and September 31, 2022, US-based primary care physicians who trained in family or internal medicine were interviewed. Using qualitative analysis of in-depth interviews, this study examined how participants experience and adapt to time constraints during a typical clinic day, taking account of their professional and personal responsibilities. It also incorporates physicians’ reflections on implications for their careers.

Main Outcomes and Measures

Thematic analysis of in-depth interviews and a measure of well-being (American Medical Association Mini-Z survey).

Results

Interviews with 25 primary care physicians (14 [56%] female and 11 [44%] male; median [range] age, 43 [34-63] years) practicing in 11 US states were analyzed. Two physicians owned their own practice, whereas the rest worked as employees. The participants represented a wide range of years in practice (range, 1 to ≥21), with 11 participants (44%) in their first 5 years. Physicians described that the structure of their work hours did not match the work that was expected of them. This structural mismatch between time allocation and work expectations created a constant experience of time scarcity. Physicians described having to make tradeoffs between maintaining high-quality patient care and having their work overflow into their personal lives. These experiences led to feelings of guilt, disillusionment, and dissatisfaction. To attempt to sustain long-term careers in primary care, many sought ways to see fewer patients.

Conclusions and Relevance

These findings suggest that organizational leaders must align schedules with work expectations for primary care physicians to mitigate physicians’ withdrawal from work as a coping mechanism. Specific strategies are needed to achieve this realignment, including incorporating more slack into schedules and establishing realistic work expectations for physicians.
Preview controller synthesis for a class of linear parameter periodic systems
Authors: Li Li , Liao Yonglong , Zhang Yaofeng
Published: April 2024

In this study, the problem of preview tracking control (PTC) was considered with regard to the linear parameter periodic systems (LPPSs) subject to previewed signals. First, the difference operator approach was extended to derive an augmented error system (AES). As a result, the PTC problem was transformed into a stabilization problem via state/output feedback. Second, sufficient conditions guaranteeing the closed‐loop stability of the augmented error systems were derived, and the design of a periodic controller with preview actions was proposed through the approach of linear matrix inequalities (LMIs). Finally, a numerical simulation was performed to illustrate the effectiveness of the proposed periodic controller.
The Biological Role of Macrophage in Lung and Its Implications in Lung Cancer Immunotherapy
Authors: Wang Chenyang , Gao Qing , Wu Jinghong , Lu Mingjun , Wang Jinghui , Ma Teng
Published: April 2024

The lungs are the largest surface of the body and the most important organ in the respiratory system, which are constantly exposed to the external environment. Tissue Resident Macrophages in lung constitutes the important defense against external pathogens. Macrophages connects the innate and adaptive immune system, and also plays important roles in carcinogenesis and cancer immunotherapy. Lung cancer is the leading cause of cancer‐related death worldwide, with an overall five‐year survival rate of only 21%. Macrophages that infiltrate or aggregate in lung tumor microenvironment are defined as tumor‐associated macrophages (TAMs). TAMs are the main components of immune cells in the lung tumor microenvironment. The differentiation and maturation process of TAMs can be roughly divided into two different types: classical activation pathway produces M1 tumor‐associated macrophages, and bypass activation pathway produces M2 tumor‐associated macrophages. Studies have found that TAMs are related to tumor invasion, metastasis, and treatment resistance, and show potential as a new target for tumor immunotherapy. Therefore, the biological function of macrophages in lung and the role of TAMs in the occurrence, development, and treatment of lung cancer are discussed in this paper.
Enhanced Silicon Anodes with Robust SEI Formation Enabled by Functional Conductive Binder
Authors: Chen Benqiang , Xu Dongmin , Chai Simin , Chang Zhi , Pan Anqiang
Published: April 2024

The application of silicon (Si) anode is limited by the drastic volume change of silicon in the lithiation/delithiation process, the repeated formation of the solid electrolyte interface (SEI), and the low intrinsic conductivity. In this work, a small amount of poly (3,4‐ethylenedioxythiophene):poly (styrene sulfonic acid) (PEDOT:PSS) (PP), citric acid (CA), isopropyl alcohol (IPA), and silicon nanoparticles (SiNPs) are mixed and vacuum treated at a specific temperature to obtain silicon‐based anode electrode composite Si@PP@CA. The interphase forms a robust elastic network with hydrogen and chemical bonds, which have good mechanical properties and self‐repairing characteristics. The modified PEDOT:PSS as the conductive medium significantly improves the charge transfer rate. Moreover, the rapid formation of SEI by CA on the surface of SiNPs enhances the structural stability of the material. The electrochemical results show that the capacity of Si@PP@CA composite electrode canretain more than 2200 mAh g−1 after 200 cycles at 0.2 A g−1. It still shows a high capacity retention of 89% even at the current density of 1.0 A g−1 after 2000 cycles. More importantly, such excellent performance can be obtained using an electrode with an active material content of up to 90 wt%, which is essential for practical applications.