bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthetic Prodiginine Obatoclax (GX15‐070) and Related Analogues: Anion Binding, Transmembrane Transport, and Cytotoxicity Properties
Authors: Díaz de Greñu Borja , Hernández Paulina Iglesias , Espona Margarita , Quiñonero David , Light Mark E. , Torroba Tomás , Pérez‐Tomás Ricardo , Quesada Roberto
Published: November 2011

Synthetic prodiginine obatoclax shows promise as a potential anticancer drug. This compound promotes apoptosis of cancer cells, although the mechanism of action is unclear. To date, only the inhibition of BCL‐2 proteins has been proposed as a mechanism of action. To gain insight into other possible modes of action, we have studied the anion‐binding properties of obatoclax and related analogues in solution, in the solid state, and by means of density functional theory calculations. These compounds are well suited to interact with anions such as chloride and bicarbonate. The anion‐transport properties of the compounds synthesized were assayed in model phospholipid liposomes by using a chloride‐selective‐electrode technique and 13C NMR spectroscopy. The results demonstrated that these compounds are efficient anion exchangers that promote chloride, bicarbonate, and nitrate transport through lipid bilayers at very low concentrations. In vitro studies on small‐cell lung carcinoma cell line GLC4 showed that active ionophores are able to discharge pH gradients in living cells and the cytotoxicity of these compounds correlates well with ionophoric activity.
Meißener Klausurtagung: Positionierung des Fachausschusses Kristallisation zu Zukunftsthemen
Authors: Lorenz Heike , Ulrich Joachim
Published: November 2011

Im April 2011 fand die Klausurtagung des ProcessNet‐Fachausschusses Kristallisation statt. Basierend auf den Beiträgen von Teilnehmern aus Industrie und universitärer Forschung sowie den anschließenden Diskussionen wurden potenzielle Zukunftsthemen und die damit verbundenen Herausforderungen auf dem Gebiet der Kristallisation abgeleitet. Diese Orientierung ist notwendig, um künftige Trends und Schnittstellen mit anderen Fachdisziplinen frühzeitig zu erkennen und entsprechende Kooperations‐ und Fördermöglichkeiten zu gewährleisten. Im Ergebnis hat sich herausgestellt, dass insbesondere drei wesentliche Bereiche in der Zukunft gezielte Forschungsaktivitäten erfordern: die Vorhersage und Ermittlung thermodynamischer und kinetischer Größen, das Aufklären der Kristallisationsmechanismen auf der Ebene der Gitterbausteine (und damit der Struktur‐Eigenschaftsbeziehungen beim Produktdesign) und die Sensorentwickung zur Überwachung von Kristallisationsprozessen.
Dielectric Radio‐Frequency Heating of Zeolites – Selectivity, Thermo‐Chromatographic Pulse and Drying by Water
Authors: Roland Ulf , Kraus Markus , Trommler Ulf , Holzer Frank , Kopinke Frank‐Dieter
Published: November 2011

Die dielektrische Erwärmung mittels Radiowellen ist für ein breites Spektrum von Zeolithen sowohl im trockenen als auch im feuchten Zustand anwendbar. Dabei ist es auch möglich, Schüttbetten im technischen Maßstab homogen aufzuheizen. Die Energieabsorption variiert stark für die einzelnen Zeolithtypen, was eine selektive Erwärmung in Schüttanordnungen unterschiedlicher Materialien ermöglicht. Die spezifische Wirkung des Wassers in Wechselwirkung mit den strukturellen Kationen erlaubt es, ausgeprägte Temperaturgradienten in Festbetten mit variierender Feuchte zu realisieren. Für bestimmte Materialien wie für den Zeolith NaY kann dabei ein gekoppelter Wasser‐Temperatur‐Puls entstehen, der das Festbett durchläuft. Anwendungsoptionen für diesen sogenannten thermo‐chromatographischen Puls reichen von der adsorptiv‐katalytischen Abluftreinigung bis hin zur thermischen Regeneration von Zeolithen im Zusammenhang mit der Trocknung von Gasen.
A multicenter, randomized, phase 2 clinical trial to evaluate the efficacy and safety of combination docetaxel and carboplatin and sequential therapy with docetaxel then carboplatin in patients with recurrent platinum‐sensitive ovarian cancer
Authors: Secord Angeles Alvarez , Berchuck Andrew , Higgins Robert V. , Nycum Lawrence R. , Kohler Matthew F. , Puls Larry E. , Holloway Robert W. , Lewandowski George S. , Valea Fidel A. , Havrilesky Laura J.
Published: November 2011

BACKGROUND:

The aim of this randomized clinical trial was to evaluate the efficacy and safety of combination (cDC) and sequential (sDC) weekly docetaxel and carboplatin in women with recurrent platinum‐sensitive epithelial ovarian cancer (EOC).

METHODS:

Participants were randomized to either weekly docetaxel 30 mg/m2 on days 1 and 8 and carboplatin area under the curve (AUC) = 6 on day 1, every 3 weeks or docetaxel 30 mg/m2 on days 1 and 8, every 3 weeks for 6 cycles followed by carboplatin AUC = 6 on day 1, every 3 weeks for 6 cycles or until disease progression. The primary endpoint was measurable progression‐free survival (PFS).

RESULTS:

Between January 2004 and March 2007, 150 participants were enrolled. The response rate was 55.4% and 43.2% for those treated with cDC and sDC, respectively. The median PFS was 13.7 months (95% confidence interval [CI], 9.9‐16.8) for cDC and 8.4 months (95% CI, 7.1‐11.0) for sDC. On the basis of an exploratory analysis, patients treated with sDC were at a 62% increased risk of disease progression compared to those treated with cDC (hazard ratio = 1.62; 95% CI, 1.08‐2.45; P = .02). The median overall survival time was similar in both groups (33.2 and 30.1 months, P = .2). The incidence of grade 2 or 3 neurotoxicity and grade 3 or 4 neutropenia was higher with cDC than with sDC (11.7% vs 8.5%; 36.8% vs 11.3%). The sDC group demonstrated significant improvements in the Functional Assessment for Cancer Therapy–Ovarian, Quality of Life Trial Outcome Index scores compared with the combination cohort (P = .013).

CONCLUSIONS:

Both cDC and sDC regimens have activity in recurrent platinum‐sensitive EOC with acceptable toxicity profiles. The cDC regimen may provide a PFS advantage over sDC. Cancer 2011. © 2011 American Cancer Society.
Reclassification of serous ovarian carcinoma by a 2‐tier system
Authors: Bodurka Diane C. , Deavers Michael T. , Tian Chunqiao , Sun Charlotte C. , Malpica Anais , Coleman Robert L. , Lu Karen H. , Sood Anil K. , Birrer Michael J. , Ozols Robert , Baergen Rebecca , Emerson Robert E. , Steinhoff Margaret , Behmaram Behnaz , Rasty Golnar , Gershenson David M.
Published: November 2011

BACKGROUND:

A study was undertaken to use the 2‐tier system to reclassify the grade of serous ovarian tumors previously classified using the International Federation of Gynecology and Obstetrics (FIGO) 3‐tier system and determine the progression‐free survival (PFS) and overall survival (OS) of patients treated on Gynecologic Oncology Group (GOG) Protocol 158.

METHODS:

The authors retrospectively reviewed demographic, pathologic, and survival data of 290 patients with stage III serous ovarian carcinoma treated with surgery and chemotherapy on GOG Protocol 158, a cooperative multicenter group trial. A blinded pathology review was performed by a panel of 6 gynecologic pathologists to verify histology and regrade tumors using the 2‐tier system. The association of tumor grade with PFS and OS was assessed.

RESULTS:

Of 241 cases, both systems demonstrated substantial agreement when combining FIGO grades 2 and 3 (overall agreement, 95%; kappa statistic, 0.68). By using the 2‐tier system, patients with low‐grade versus high‐grade tumors had significantly longer PFS (45.0 vs 19.8 months, respectively; P = .01). By using FIGO criteria, median PFS for patients with grade 1, 2, and 3 tumors was 37.5, 19.8, and 20.1 months, respectively (P = .07). There was no difference in clinical outcome in patients with grade 2 or 3 tumors in multivariate analysis. Woman with high‐grade versus low‐grade tumors demonstrated significantly higher risk of death (hazard ratio, 2.43; 95% confidence interval, 1.17‐5.04; P = .02).

CONCLUSIONS:

Women with high‐grade versus low‐grade serous carcinoma of the ovary are 2 distinct patient populations. Adoption of the 2‐tier grading system provides a simple yet precise framework for predicting clinical outcomes. Cancer 2012;118: 3087–94. © 2011 American Cancer Society.
Reasons for underuse of recommended therapies for colorectal and lung cancer in the Veterans Health Administration
Authors: Landrum Mary Beth , Keating Nancy L. , Lamont Elizabeth B. , Bozeman Samuel R. , McNeil Barbara J.
Published: November 2011

BACKGROUND:

Many studies have documented low rates of effective cancer therapies, particularly in older or minority populations. However, little is known about why effective therapies are underused in these populations.

METHODS:

The authors examined medical records of 584 patients with cancer diagnosed or treated in Department of Veterans Affairs facilities to assess reasons for lack of 1) surgery for stage I/II nonsmall cell lung cancer, 2) surgery for stage I/II/III rectal cancer, 3) adjuvant radiation therapy for stage II/III rectal cancer, and 4) adjuvant chemotherapy for stage III colon cancer. They also assessed differences in reasons for underuse by patient age and race.

RESULTS:

Across the 4 guideline‐recommended treatments, 92% to 99% of eligible patients were referred to the appropriate cancer specialist; however, therapy was recommended in only 74% to 92% of eligible cases. Poor health was cited in the medical record as the reason for lack of therapy in 15% to 61% of underuse cases; patient refusal explained 26% to 58% of underuse cases. African American patients were more likely to refuse surgery. Older patients were more likely to refuse treatments.

CONCLUSIONS:

Recommendation against therapy was a primary factor in underuse of effective therapies in older and sicker patients. Patients' refusal of therapy contributed to age and racial disparities in care. Improved data on the effectiveness of cancer therapies in community populations and interventions aimed at improved communication of known risks and benefits of therapy to cancer patients could be effective tools to reduce underuse and lingering disparities in care. Cancer 2011. © 2011 American Cancer Society.
Whole‐gland salvage high‐intensity focused ultrasound therapy for localized prostate cancer recurrence after external beam radiation therapy
Authors: Uddin Ahmed Hashim , Cathcart Paul , Chalasani Venu , Williams Andrew , McCartan Neil , Freeman Alex , Kirkham Alex , Allen Clare , Chin Joseph , Emberton Mark
Published: November 2011

BACKGROUND:

Whole‐gland high‐intensity focused ultrasound (HIFU) has been used as salvage therapy for local recurrence following external beam radiation therapy for decades. This article describes the use of the Sonablate 500 HIFU system in the salvage setting.

METHODS:

An evaluation was performed of a consecutive group of men with biochemical failure after external beam radiation therapy with histologically proven local recurrence and bone‐scan and pelvic magnetic resonance imaging to exclude macroscopic metastases, and who chose to have whole‐gland salvage HIFU (Sonablate 500) at 2 centers (3 expert HIFU surgeons at each center). The modified Clavien system was used to categorize adverse events and validated questionnaires for functional outcomes. Progression following HIFU treatment was defined as ASTRO‐Phoenix criteria (prostate serum antigen [PSA] >nadir+2 ng/mL) and/or a positive biopsy and/or start of hormone therapy.

RESULTS:

Eighty‐four men underwent whole‐gland salvage HIFU (2004‐2009). Median age, pretreatment serum PSA, and biopsy Gleason score was 68 years (range, 64‐72 years), 4.3 ng/mL (range, 1.9‐7.9 ng/mL), and 7 (range, 6‐7), respectively. Mean follow‐up was 19.8 months (range, 3.0‐35.1 months). After salvage HIFU, 62% of the men were pad‐free and leak‐free. Mean International Index of Erectile Function‐5 point score fell from 8.8 to 4.7 (P < .001). International Prostate Symptoms Score and RAND‐SF36 scores were not affected. Two men developed rectourethral fistulae after 1 salvage procedure. A further 2 fistulae occurred in the 6 men undergoing a second salvage HIFU. Intervention for bladder outlet obstruction was needed in 20% (17 of 84 patients). If PSA nonresponders were included, 1‐ and 2‐year progression‐free survival rates were 59% (50 of 84 patients) and 43% (36 of 84 patients), respectively. If PSA nonresponders were excluded, 1‐ and 2‐year progression‐free survival rates were 62% (48 of 77 patients) and 48% (37 of 77 patients), respectively.

CONCLUSIONS:

Salvage whole‐gland HIFU is a high‐risk procedure. Although its use in early cancer control is promising, strategies to better identify metastatic disease prior to salvage therapy and reduce local toxicity are needed to improve on this. Cancer 2012;118: 3071–78. © 2011 American Cancer Society.
Therapeutic efficacy of combination therapy with intra‐arterial 5‐fluorouracil and systemic pegylated interferon α‐2b for advanced hepatocellular carcinoma with portal venous invasion
Authors: Kasai Kazuhiro , Ushio Akira , Kasai Yukiho , Sawara Kei , Miyamoto Yasuhiro , Oikawa Kanta , Kuroda Hidekatsu , Takikawa Yasuhiro , Suzuki Kazuyuki
Published: November 2011

BACKGROUND:

The prognosis of advanced hepatocellular carcinoma (HCC) remains poor, particularly among patients with portal vein tumor thrombosis (PVTT). This study evaluated the efficacy of combined 5‐fluorouracil and pegylated interferon (PEG‐IFN) α‐2b in patients with advanced HCC.

METHODS:

Subjects comprised 59 HCC patients with PVTT treated using subcutaneous administration of PEG‐IFNα‐2b (50‐100 μg on day 1 of each week for 4 weeks) and intra‐arterial infusion of 5‐fluorouracil (250 mg/d for 5 hours on days 1‐5 of each week for 4 weeks). One treatment cycle lasted 4 weeks. The current therapy was discontinued in patients with progressive disease (PD). For responses other than PD, treatment was repeated for ≥1 cycle. The primary efficacy endpoint was the objective early response rate. Secondary efficacy endpoints were progression‐free survival (PFS) and overall survival.

RESULTS:

Objective early response rate was 73.0%. Cumulative PFS rates were 67.4% at 6 months, 30.2% at 12 months, 25.9% at 18 months, and 20.7% at 24 months. Median PFS was 9.7 months. Cumulative survival rates were 82.4% at 6 months, 73.6% at 12 months, 52.8% at 24 months, and 44.0% at 36 months. Median survival time was 29.9 months. All adverse reactions were controllable by temporary suspension of treatment. Serious complications and treatment‐related deaths were not observed.

CONCLUSIONS:

Although a prospective randomized controlled trial using a larger population of patients with advanced HCC is needed to evaluate combination therapy with 5‐fluorouracil and PEG‐IFNα‐2b, this new combination therapy may be useful for patients with advanced HCC. Cancer 2011. © 2011 American Cancer Society.
Photodissociation Dynamics of ClCN at Different Wavelengths
Authors: Lutz Stephan , Meuwly Markus
Published: November 2011

The photodissociation dynamics of small molecules in the gas and condensed phase is an important source of information for better characterizing intermolecular interactions. Herein, classical molecular dynamics simulations with provisions to follow reactive processes between different electronic states are used to probe the wavelength dependence of product state distributions after laser excitation of ClCN. It is found that the maximum of the rotational excitation distribution P(j) of the CN product shifts to lower j‐values with increasing wavelength and the width of the distribution narrows. Both observations are in accord with earlier experiments and provide improvements over previous theoretical treatments of the process with the same interaction potentials. For the reaction in a water droplet, strong quenching of rotational excitation is found.
Ca‐Rich Ca–Al‐Oxide, High‐Temperature‐Stable Sorbents Prepared from Hydrotalcite Precursors: Synthesis, Characterization, and CO2 Capture Capacity
Authors: Chang Po‐Hsueh , Chang Yen‐Po , Chen San‐Yuan , Yu Ching‐Tsung , Chyou Yau‐Pin
Published: November 2011

We present the design and synthesis of Ca‐rich Ca–Al–O oxides, with Ca2+/Al3+ ratios of 1:1, 3:1, 5:1, and 7:1, which were prepared by hydrothermal decomposition of coprecipitated hydrotalcite‐like Ca–Al–CO3 precursors, for high‐temperature CO2 adsorption at 500–700 °C. In situ X‐ray diffraction measurements indicate that the coprecipitated, Ca‐rich, hydrotalcite‐like powders with Ca2+/Al3+ ratios of 5:1 and 7:1 contained Ca(OH)2 and layered double hydroxide (LDH) phases. Upon annealing, LDH was first destroyed at approximately 200 °C to form an amorphous matrix, and then at 450–550 °C, the Ca(OH)2 phase was converted into a CaO matrix with incorporated Al3+ to form a homogeneous solid solution without a disrupted lattice structure. CaO nanocrystals were grown by thermal treatment of the weakly crystalline Ca–Al–O oxide matrix. Thermogravimetric analysis indicates that a CO2 adsorption capacity of approximately 51 wt. % can be obtained from Ca‐rich Ca–Al–O oxides prepared by calcination of 7:1 Ca–Al–CO3 LDH phases at 600–700 °C. Furthermore, a relatively high CO2 capture capability can be achieved, even with gas flows containing very low CO2 concentrations (CO2/N2=10 %). Approximately 95.6 % of the initial CO2 adsorption capacity of the adsorbent is retained after 30 cycles of carbonation–calcination. TEM analysis indicates that carbonation‐promoted CaCO3 formation in the Ca–Al–O oxide matrix at 600 °C, but a subsequent desorption in N2 at 700 °C, caused the formation CaO nanocrystals of approximately 10 nm. The CaO nanocrystals are widely distributed in the weakly crystalline Ca–Al–O oxide matrix and are present during the carbonation–calcination cycles. This demonstrates that Ca–Al–O sorbents that developed through the synthesis and calcination of Ca‐rich Ca–Al LDH phases are suitable for long‐term cyclic operation in severe temperature environments.
Fulminant type 1 diabetes—an important subtype in East Asia
Authors: Imagawa Akihisa , Hanafusa Toshiaki
Published: November 2011

Fulminant type 1 diabetes is defined as a subtype of type 1 diabetes with a remarkably acute onset. A nationwide survey identified that this variant accounts for approximately 20% of acute‐onset type 1 diabetic patients in Japan. Recent studies indicate that this is not a minor subtype in other East Asian countries. As genetic factors, we revealed association of HLA‐DR‐DQ, HLA‐B and CTLA‐4 to fulminant type 1 diabetes. As an environmental factor, viral infection would contribute to the development of this subtype. Cellular infiltration to islets was detected soon after the onset but not observed 1 month after the onset. Macrophages and T cells were the main components of the infiltrates. Enterovirus RNA and Toll‐like receptor‐3 expression, a signature of viral infection, was also observed. These findings suggest that viral infection in the susceptible individual might trigger anti‐viral immune response and that pancreatic beta cells are rapidly destroyed through the accelerated immune reaction. Copyright © 2011 John Wiley & Sons, Ltd.
Heterogeneity among patients with latent autoimmune diabetes in adults
Authors: Maruyama Taro , Nakagawa Terumichi , Kasuga Akira , Murata Mitsuru
Published: November 2011

Background

Some type 1 diabetic patients do not require insulin at diagnosis of diabetes, and they progress to insulin dependence only after several years (latent autoimmune diabetes in adults). However, not all patients with latent autoimmune diabetes in adults progress to insulin dependence. We compared the characteristics of patients with high glutamic acid decarboxylase antibodies (GADA) titres (≥10 U/mL) to those of patients with low titres and examined other factors possibly associated with the progression to insulin dependence.

Methods

We began registering diabetic patients in 1993 and have since followed them prospectively. Among these patients, we analysed clinical characteristics and progression to insulin dependence in those followed for more than 5 years.

Results

Patients with high GADA titres were younger and had lower body mass index, shorter disease durations and lower serum C‐peptide (s‐CPR) levels than the patients with low GADA titre and GADA negative type 2 diabetes. Frequencies of other islet‐related autoantibodies were significantly higher in patients with high GADA titre than in those with low GADA titres. Disease protective HLA class II genotypes were less frequent in patients with high titre. The positive predictive value of being GADA positive was only 42.7%. The positive predictive value increased to 78.6% when the cut‐off was set at the relatively high level of 10 U/mL. Combining GADA with other islet‐related autoantibodies or HLA class II genotype increased positive predictive value but decreased sensitivity.

Conclusions

Our results suggest that latent autoimmune diabetes in adults constitutes a heterogeneous group and that the majority of patients with high GADA titres (≥10 U/mL) will ultimately develop type 1 diabetes while those with low titres include patients with type 1 and type 2 diabetes. Copyright © 2011 John Wiley & Sons, Ltd.
Immunology of Diabetes Society T‐Cell Workshop: HLA class I tetramer‐directed epitope validation initiative T‐Cell Workshop Report—HLA Class I Tetramer Validation Initiative
Authors: Mallone R. , Scotto M. , Janicki C. N. , James E. A. , Fitzgerald‐Miller L. , Wagner R. , Gottlieb P. , Thorpe J. , Jospe N. , Durinovic‐Bellò I. , Boitard C. , Lou O. , Dayan C. M. , Wong F. S. ,   T‐Cell Workshop Committee, Immunology of Diabetes Society
Published: November 2011

Background

Identification of T‐cell reactivity to β‐cell antigen epitopes is an important goal for studying pathogenesis and for designing and monitoring of immunotherapeutic interventions in type 1 diabetes (T1D).

Methods

We performed a multicentre validation of known human leukocyte antigen (HLA) class I CD8+ T‐cell epitopes. To this end, peripheral blood T‐cell responses were measured in 35 recently (<2 years) diagnosed HLA‐A*02:01+ T1D patients using blind‐coded HLA‐A2 tetramers (TMrs) and pentamers (PMrs), encompassing two epitopes of preproinsulin (PPI; PPI$\def\endash{\hbox{--}} _{\rm{A12\endash 20}}$ and PPI$\def\endash{\hbox{--}} _{\rm{B10\endash 18}}$) and two epitopes of glutamic acid decarboxylase (GAD; GAD114–122 and GAD536–545). We also compared the readout of TMrs and PMrs with a CD8+ T‐cell interferon‐γ enzyme‐linked immunospot assay.

Results

Despite the minute frequencies of autoreactive cells detected by TMrs/PMrs, most (73–77%) T1D patients had responses to one or more of the epitopes used. All four epitopes were recognized by T1D patients, with a prevalence ranging from 5 to 25%. TMrs and PMrs detected more positive responses to the β‐cell epitopes than CD8+ T‐cell interferon‐γ enzyme‐linked immunospot. However, concordance between positive responses to TMrs and PMrs was limited.

Conclusions

Using a multicentre blind‐coded setup and three different T‐cell assays, we have validated PPI and GAD epitopes as commonly recognized CD8+ T‐cell targets in recently diagnosed T1D patients. Both TMrs and PMrs showed higher detection sensitivity than the CD8+ T‐cell interferon‐γ enzyme‐linked immunospot assay. However, there are some important methodological issues that need to be addressed in using these sensitive techniques for detecting low frequency responses. Copyright © 2011 John Wiley & Sons, Ltd.
Immunology of Diabetes Society T‐Cell Workshop: HLA class II tetramer‐directed epitope validation initiative
Authors: James E. A. , Mallone R. , Schloot N. C. , Gagnerault M. C. , Thorpe J. , Fitzgerald‐Miller L. , Reichow J. , Wagner R. , Pham M. N. , Jospe N. , Lou O. , Gottlieb P. A. , Brooks‐Worrell B. M. , Durinovic‐Belló Ivana ,   T‐Cell Workshop Committee, Immunology of Diabetes Society
Published: November 2011

Background

Islet‐antigen‐specific CD4+ T cells are known to promote auto‐immune destruction in T1D. Measuring T‐cell number and function provides an important biomarker. In response to this need, we evaluated responses to proinsulin and GAD epitopes in a multicentre study.

Methods

A tetramer‐based assay was used in five participating centres to measure T‐cell reactivities to DR0401‐restricted epitopes. Three participating centres concurrently performed ELISPOT or immunoblot assays. Each centre used blind‐coded, centrally distributed peptide and tetramer reagents.

Results

All participating centres detected responses to auto‐antigens and the positive control antigen, and in some cases cloned the corresponding T cells. However, response rates varied among centres. In total, 74% of patients were positive for at least one islet epitope. The most commonly recognized epitope was GAD270–285. Only a minority of the patients tested by tetramer and ELISPOT were concordant for both assays.

Conclusions

This study successfully detected GAD and proinsulin responses using centrally distributed blind‐coded reagents. Centres with little previous experience using class II tetramer reagents implemented the assay. The variability in response rates observed for different centres suggests technical difficulties and/or heterogeneity within the local patient populations tested. Dual analysis by tetramer and ELISPOT or immunoblot assays was frequently discordant, suggesting that these assays detect distinct cell populations. Future efforts should investigate shared blood samples to evaluate assay reproducibility and longitudinal samples to identify changes in T‐cell phenotype that correlate with changes in disease course. Copyright © 2011 John Wiley & Sons, Ltd.
Imaging of pancreatic islet cells
Authors: Arifin Dian R. , Bulte Jeff W.M.
Published: November 2011

At present, the onset and progress of diabetes, and the efficacy of potential treatments, can only be assessed through indirect means, i.e. blood glucose, insulin, or C‐peptide measurements. The development of non‐invasive and reliable methods for (1) quantification of pancreatic beta islet cell mass in vivo, (2) determining endogenous islet function and survival, and (3) visualizing the biodistribution, survival, and function of transplanted exogenous islets are critical to further advance both basic science research and islet cell therapy in diabetes. Islet cell imaging using magnetic resonance, bioluminescence, positron emission tomography, or single photon emission computed tomography may provide us with a direct means to interrogate islet cell distribution, survival, and function. Current state‐of‐the‐art strategies for beta‐cell imaging are discussed and reviewed here in context of their clinical relevance. Copyright © 2011 John Wiley & Sons, Ltd.
Insulin as a key autoantigen in the development of type 1 diabetes
Authors: Nakayama Maki
Published: November 2011

Type 1 diabetes is a T‐cell‐mediated autoimmune disease against pancreatic beta cells. T cells target various antigens such as insulin, chromogranin A, glutamic acid decarboxylase and islet‐specific glucose‐6‐phosphatase catalytic subunit‐related protein. Elimination of insulin dramatically prevents diabetes in the non‐obese diabetic (NOD) mouse model and response to insulin occurs prior to that to other antigens. These findings suggest that insulin is a target antigen at the early stage of the disease and is likely to be essential to cause anti‐islet autoimmunity in NOD mice. In this review, we discuss whether insulin is truly essential and is only the single essential autoantigen for NOD mice and potentially for man. Although the ultimate principle is still being addressed, it is certain that T‐cell response to insulin is a major check point to develop type 1 diabetes in NOD mice. Given multiple similarities between diabetes of NOD mice and man, targeting insulin and insulin‐reactive T cells may provide opportunities to develop robust immunotherapies. Copyright © 2011 John Wiley & Sons, Ltd.
Immunization with an insulin peptide–MHC complex to prevent type 1 diabetes of NOD mice
Authors: Zhang Li , Stadinski Brian D. , Michels Aaron , Kappler John W. , Eisenbarth George S.
Published: November 2011

Background

Mutating the insulin B:9–23 peptide prevents diabetes in NOD mice. Thus, the trimolecular complex of I‐A$^{\rm{g7}}$‐insulin B:9–23 peptide‐TCR may be essential for the development of spontaneous diabetes. Pathogenic T cells recognize the B:9–23 peptide presented by I‐A$^{\rm{g7}}$ in what is termed register 3, with the B22 basic amino acid (arginine) of the peptide bound in pocket 9 of I‐A$^{\rm{g7}}$. Our hypothesis is that immunization with an insulin B:12–22 peptide linked to I‐A$^{\rm{g7}}$ in register 3 (I‐A$^{\rm{g7}}$‐B:RE#3 complex) can induce specific antibodies to the complex, block pathogenic TCRs, and thus prevent diabetes.

Methods

We immunized young NOD mice with recombinant I‐A$^{\rm{g7}}$‐B:RE#3 protein, in which two amino acids of the peptide were mutated to fix the peptide in register 3, and investigated the induced antibodies targeted to the peptide in register 3.

Results

Specific antibodies targeting I‐A$^{\rm{g7}}$‐B:RE#3 but not I‐A$^{\rm{g7}}$‐HEL were identified in the sera of I‐A$^{\rm{g7}}$‐B:RE#3 immunized mice. The sera inhibited B:9–23‐induced T‐cell responses in vitro. I‐A$^{\rm{g7}}$‐B:RE#3 immunization delayed progression to diabetes (versus PBS, p = 0.0005), while immunization with I‐A$^{\rm{g7}}$‐HEL control complex did not.

Conclusions

Immunization with I‐A$^{\rm{g7}}$‐B:RE#3 complex significantly delays the development of insulin autoantibodies and the onset of diabetes in NOD mice, which is associated with the induction of I‐A$^{\rm{g7}}$‐B:RE#3 antibodies. Copyright © 2011 John Wiley & Sons, Ltd.
Innate immunity in type 1 diabetes
Authors: Zipris Danny
Published: November 2011

Background

Rat models of diabetes have emerged as a powerful experimental tool for addressing the role of microbial pathogens in the mechanism of autoimmune diabetes. We have used the biobreeding diabetes resistant and LEW1.WR1 rat models to identify the role of virus‐induced innate immunity in the mechanism of type 1 diabetes.

Methods

Groups of rats 21–25 days of age were left untreated, injected i.p. with 1 × 107PFU of Kilham rat virus (KRV) only, or with 1–3 µg/g body‐weight‐purified toll‐like receptor agonists on three consecutive days and infected with 1 × 107PFU of KRV on the following day. Spleens and pancreatic lymph nodes were recovered 5 days after infection and used for gene array analysis. To test the role of inflammation in diabetes, rats injected with KRV only or Poly(I:C) plus KRV were also administered with 2 or 0.2 µg/g body weight of dexamethasone and followed for diabetes for 40 days.

Results

KRV induced the expression of a vast array of proinflammatory genes in pancreatic lymph nodes on day 5 following infection. Brief dexamethasone therapy downmodulated inflammation and completely blocked diabetes.

Conclusions

Our data suggest a strong association between early virus‐induced proinflammatory responses and islet destruction and raise the possibility that targeting innate immune pathways in the early stages of diabetes may be a useful strategy for disease prevention. Copyright © 2011 John Wiley & Sons, Ltd.
Genetic association analyses of atopic illness and proinflammatory cytokine genes with type 1 diabetes
Authors: Saleh Nada M. , Raj Srilakshmi M. , Smyth Deborah J. , Wallace Chris , Howson Joanna M. M. , Bell Louise , Walker Neil M. , Stevens Helen E. , Todd John A.
Published: November 2011

Background

The genetic basis of the autoimmune disease type 1 diabetes (T1D) has now been largely determined, so now we can compare these findings with emerging genetic knowledge of disorders and phenotypes that have been negatively or positively associated with T1D historically. Here, we assessed the role in T1D of variants previously reported to be associated with atopic diseases and epithelial barrier function, profilaggrin (), and those that affect the expression levels of the proinflammatory cytokines tumour necrosis factor (TNF)‐α, interleukin (IL)‐1β, interferon (IFN)γ and IL‐18.

Methods

We genotyped single nucleotide polymorphisms (SNPs): − 105/rs28665122 in SELS or SEPS1 (selenoprotein), three single nucleotide polymorphisms in IL18 (−105/rs360717, + 183/rs5744292 and + 1467/rs574456) and R501X/rs61816761 in FLG, the major locus associated with atopic dermatitis and predisposing to asthma, in a minimum of 6743 T1D cases and 7864 controls.

Results

No evidence of T1D association was found for any of the SNPs we genotyped at FLG, SELS or IL18 (p ≥ 0.03), nor with haplotypes of IL18 (p = 0.82). Review of previous T1D genome‐wide association results revealed that four (human leucocyte antigen (HLA), gasdermin B/ORM1 (Saccharomyces cerevisiae)‐like/gasdermin B/, GSDMB/ORMDL3/GSDMA and IL2RB) of ten loci recently reported to be associated with asthma were associated with T1D (p⩽0.005).

Conclusions

These results show that there are shared genetic associations for atopy‐related traits and T1D, and this might help in the future to understand the mechanisms, pathways and environmental factors that underpin the rapid rise in incidence of both disorders in children. Copyright © 2011 John Wiley & Sons, Ltd.
Role of genetics in resistance to type 1 diabetes
Authors: Chen Jing , Gusdon Aaron M. , Mathews Clayton E.
Published: November 2011

Background

A single nucleotide polymorphism in the mitochondrial gene encoding NADH dehydrogenase subunit 2 (mt‐ND2) has been associated with reduced incidence of human type 1 diabetes (T1D). We identified the orthologue of this mitochondrial single nucleotide polymorphism in mouse and using NOD mouse models linked this genetic polymorphism to T1D resistance. The mechanism how this single nucleotide polymorphism affects the development of diabetes is studied using mouse models and beta cell lines.

Methods

The impact of this single nucleotide polymorphism on mitochondrial function and resistance to reactive oxygen species was assessed. For these studies we measured oxygen consumption by isolated mitochondria under different doses of nitric oxide. In addition, alloxan sensitivity of beta cell lines was tested using the MTT method to measure cell survival.

Results

mt‐Nd2a is associated with protection against mouse T1D and alloxan‐induced diabetes. Mice with mt‐Nd2a exhibited resistance to transfer of diabetes by single clone of diabetogenic CD4+ or CD8+ T cells. Beta cell line with mt‐Nd2a resist in vitro attack of diabetogenic CD8+ cytotoxic T cells, as well as free radicals generated by alloxan; isolated mitochondria with mt‐Nd2a showed lower reactive oxygen species production and were more resistant to nitric oxide.

Conclusion

mt‐Nd2a protects against T1D in mouse models. The protection is at beta cell level and is associated with resistance against reactive oxygen species‐mediated damage and death. Copyright © 2011 John Wiley & Sons, Ltd.
Characterization of the regulatory roles of the SUMO
Authors: Hwang Kwang Woo , Won Tae Joon , Kim Hyunok , Chun Ha‐Jung , Chun Taehoon , Park Yongsoo
Published: November 2011

Background

Type 1 diabetes is a multi‐factorial autoimmune disease that results from the destruction of insulin‐producing β cells of the pancreas; both genetic and environmental factors are thought to contribute to its development. Recently, a novel gene encoding small ubiquitin‐like modifier protein 4 (SUMO4) was cloned and a single nucleotide substitution (M55V) was found to be strongly associated with type 1 diabetes. SUMO4 was shown to interact with IκBα and inhibit NFκB transcriptional activity. The M55V substitution of SUMO4 may affect its ability to modify IκBα by sumoylation, and so lead to activation of NFκB and transcription of genes implicated in the development of type 1 diabetes. However, the effects of sumoylation on immune cells are poorly understood.

Methods

Human SUMO1, 2, 3, 4 and mouse SUMO2 (mSUMO2) were cloned and overexpressed in dendritic, T and B cells using retroviral transduction. We then investigated whether SUMO overexpression affected their functions in vitro. To study the function of mSUMO2 in vivo, we made transgenic mice overexpressing mSUMO2 in T cells and pancreatic β cells and compared them with transgenic mice expressing a super‐repressor of NFκB (a dominant negative form of NFκB, IκBαΔN) in T cells. Diabetes was induced in the two groups of mice by i.p. injection of streptozotocin.

Results

Human SUMO1, 2, 3, 4 and mSUMO2 were all found to negatively regulate the transcriptional activity of T, B and dendritic cells. Although mSUMO2 overexpression in dendritic cells did not alter the expression of major histocompatibility complex class II proteins or B7, IL‐1, IL‐6 and IL‐7, IL‐12 expression decreased, switching Th1‐directed immune responses into Th2 responses. Unlike T cells from the IκBαΔN mice, mSUMO2 overexpression in T cells suppressed the production of both Th1 and Th2 cytokines. Whereas the mice overexpressing IκBαΔN were completely protected against diabetes, those expressing mSUMO2 had the same susceptibility to diabetes as wild type.

Conclusion

These results indicate that at least in T cells, whereas NFκB has pro‐apoptotic activity, mSUMO2 plays a more complex role in the development of autoimmune diabetes. The relative influence of NFκB and sumoylation on the development of autoimmune diabetes in vivo may vary depending on the developmental stage and cell type. Copyright © 2011 John Wiley & Sons, Ltd.
Evidence for the role of STAT4 as a general autoimmunity locus in the Korean population
Authors: Park Yongsoo , Lee Hye‐Soon , Park Youngjoo , Min Dongsoo , Yang Seiwon , Kim Dukhee , Cho Boyoun
Published: November 2011

Background

Recently, the association of a common STAT4 haplotype with type 1 diabetes (T1D) as well as rheumatoid arthritis has been documented in Caucasians and Koreans. STAT4 is involved in the signalling of interleukin‐12 and γIFN, as well as interleukin‐23. To discover genes affecting the susceptibility of common autoimmune diseases, we studied the association of polymorphisms in STAT4 with autoimmune thyroid disease (AITD) as well as T1D in the Korean population.

Subjects and methods

Four single‐nucleotide polymorphisms on the chromosome 2q (rs11889341, rs7574865, rs8179673, and rs10181656), which were found to associate with rheumatoid arthritis were examined for association in a Korean sample of 428 AITD, 418 T1D patients, and 1060 controls.

Results

The minor alleles of all four single‐nucleotide polymorphisms and the reconstructed STAT4 haplotypes conferred significant degree of risk for AITD (p = 10−2 to 10−4). Although we found a weak association of rs11889341 with T1D (p < 0.05), the same haplotypes were not associated with T1D susceptibility. When we stratified T1D patients according to the age of onset, the minor alleles of all four single‐nucleotide polymorphisms and the same haplotypes showed significant association with the susceptibility of T1D in the early‐onset subgroup (p < 0.01), not in the late‐onset subgroup.

Conclusion

STAT4 alleles and the same haplotypes might influence cytokine signalling, and therefore the development of AITD as well as T1D. These results reinforce the influence of STAT4 gene as a general autoimmune gene. Copyright © 2011 John Wiley & Sons, Ltd.
Discordant association of islet autoantibodies with high‐risk HLA genes in Chinese type 1 diabetes
Authors: Gu Yong , Zhang Mei , Chen Heng , Wang Zhixiao , Xing Chunyan , Yang Hui , Xu Xinyu , Liu Yu , Zhou Zhiguang , Yu Liping , Hutton John , Eisenbarth George , Yang Tao
Published: November 2011

Background

To reveal the aetiology of diabetes, the relationships between the islet autoantibodies, human leukocyte antigen (HLA)‐A and DRB1 genotypes in the Chinese patients with type l diabetes (T1D) were investigated in our study.

Methods

In the cross‐sectional and case‐control study, peripheral blood samples were collected from 600 T1D patients and 102 healthy controls. The genetic polymorphisms of HLA‐A and DRB1 are examined with polymerase chain reaction‐sequence oligonucleotide probe method. The zinc transporter 8 antibody (ZnT8A), glutamic acid decarboxylase antibody (GADA) and protein‐tyrosine‐phosphatase‐2 autoantibody (IA2A) were detected by radioligand assay.

Results

The A*2402, DRB1*0301, DRB1*0405 and DRB1*0901 alleles, and A*1101‐DRB1*0901, A*2402‐DRB1*0405 and A*2402‐DRB1*0901 haplotypes were associated with T1D (all p < 0.05). The positive rates of ZnT8A in patients carried DRB1*0901, IA2A in patients carried DRB1*0405 and A*1101‐DRB1*0901 and GADA in patients carried DRB1*0901 and A*2402‐DRB1*0901 were significantly higher than those not carried (p < 0.05). HLA‐DRB1*0901 was the independent risk factor of positive antibody in T1D patients. In addition, higher body mass index is also related with the loss of islet function besides high‐risk HLA gene and islet autoantibody (p < 0.05).

Conclusions

The discordant association of autoantibodies with high‐risk HLA gene may indicate the different immunology mechanisms of those autoantibodies. And metabolic burden resulting from overweight may accelerate apoptosis of beta cells. Copyright © 2011 John Wiley & Sons, Ltd.
Encapsulated pancreatic progenitors derived from human embryonic stem cells as a therapy for insulin‐dependent diabetes
Authors: Tuch Bernard E. , Hughes Timothy C. , Evans Margaret D. M.
Published: November 2011

Background

Cellular‐based therapies for insulin‐dependent diabetes are potential means of achieving and maintaining normal blood glucose levels (BGL) without the need for insulin administration. Islets isolated from donor pancreases have been the most common tissue used to date, but supply is a limiting factor. The use of human embryonic stem cells (hESC) as a therapy became a possibility with the report that these cells could be differentiated to pancreatic progenitors (PP) over 12 days in vitro. Conversion of PP to glucose‐responsive insulin‐secreting cells can be achieved by transplanting the progenitors in vivo where cell maturation occurs. To date this step has not been shown under in vitro conditions.

Methods

Prior to transplanting, cells are encapsulated in alginate to prevent the immune cells of recipient attacking the graft. The alginate capsules have pores with a molecular weight cut‐off of 250 kDa. These are too small to allow entry of immune cells, but large enough for passage of nutrients and insulin.

Results

Encapsulated insulin‐producing cells survive and function when transplanted, and have been shown to normalize BGL when allografted into diabetic mice. As few as 750 encapsulated human islets are sufficient to normalize BGL of diabetic non‐obese diabetic severe combined immunodeficient (NOD/SCID) recipient mice for at least 2 months. The safety of transplanting encapsulated human islets as demonstrated by the lack of major adverse events and infection was recently shown in a first‐in‐human clinical trial. Finally, fetal porcine islet‐like cell clusters, which are akin to PP derived from ESC, mature and normalize BGL of diabetic recipient mice with the same efficiency as non‐encapsulated clusters placed under the kidney capsule.

Conclusion

Transplanting encapsulated PP, derived from hESCs, into diabetic recipients is the strategy that is now being explored in the Australia Diabetes Therapy Project. Copyright © 2011 John Wiley & Sons, Ltd.
MicroCT for molecular imaging: Quantitative visualization of complete three‐dimensional distributions of gene products in embryonic limbs
Authors: Metscher Brian D. , Müller Gerd B.
Published: November 2011

MicroCT volume image of acetylated alpha‐tubulin immunostaining in a stage 23 chick embryo, immunostaining shown in yellow within the intact embryo. From Metscher and Müller, Developmental Dynamics 240:2301–2308, 2011.
Ecohydrological interactions in a degraded two‐phase mosaic dryland: implications for regime shifts, resilience, and restoration
Authors: King Elizabeth G. , Franz Trenton E. , Caylor Kelly K.
Published: November 2011

In the semi‐arid rangelands of north central Kenya, the abundance of grasses has declined over recent decades. Concomitantly, the native succulent herb Sansevieria volkensii has greatly proliferated in many areas. Landscape structure has thus shifted from contiguous herbaceous cover to large, dense stands of S. volkensii with interpatches of bare or sparsely vegetated ground. Local pastoralists view this transition as highly undesirable; understanding the mechanisms and reversibility of the transition is necessary to develop management options. Because water availability is a key driver in this dryland ecosystem, we assessed the ecohydrological dynamics that may govern the vegetative spread of S. volkensii patches in a communal landholding in Laikipia District, Kenya. We assessed surface water flow patterns, soil moisture, S. volkensii proliferation, and adjacent vegetation density along the margins of dense patches of S. volkensii. We found that run‐on zones along patch margins had greater soil moisture than runoff zones following a rain event. These run‐on zones also had significantly higher S. volkensii ramet density, more new ramets, and greater leaf water content. New ramet density was negatively affected by the density of adjacent interpatch vegetation. We interpret these findings in the context of scale‐dependent feedbacks and the cusp catastrophe model of ecosystem transitions. We hypothesize that the amount and spatial heterogeneity of plant available moisture governs the reversibility of transitions in this system and discuss the implications of this finding for management and restoration. Copyright © 2011 John Wiley & Sons, Ltd.
A Series of 3D Rare‐Earth‐Metal–Organic Frameworks with Isolated Guest Keggin Silicotungstate Fragments as Anion Templates
Authors: Li Suzhi , Zhang Dongdi , Guo Yuanyuan , Ma Pengtao , Zhao Junwei , Wang Jingping , Niu Jingyang
Published: November 2011

Six rare‐earth (RE) metal constructed 3D metal–organic frameworks, [RE(pydc)(H2O)n]4[SiW12O40]·4H2O [RE = TmIII (1), YIII (2), PrIII (3), LaIII (4), SmIII (5), EuIII (6); n = 3 (1, 2), 4 (3–6); H2pydc = pyridine‐2,6‐dicarboxylic acid], have been synthesized and characterized by elemental analyses, inductively coupled plasma techniques, IR and UV spectroscopy, thermogravimetric analyses (for 1 and 3), X‐ray powder diffraction, and single‐crystal X‐ray diffraction. The structural analyses indicate that 1–6 are basically isostructural and show a rare host 3D framework that contains [SiW12O40]4– Keggin polyoxoanions as templates. Photoluminescence measurements reveal that 1–5 show the luminescence of pydc ligands, whereas 6 displays a unique red luminescence.