bluuebunny/crossref_metadata_2025 huggingface dataset:
Serotonin induces the expression of tissue factor and plasminogen activator inhibitor-1 in cultured rat aortic endothelial cells
Authors: Kawano Hidehiko , Tsuji Hajime , Nishimura Hiromi , Kimura Shinzo , Yano Shingo , Ukimura Naoki , Kunieda Yasufumi , Yoshizumi Masami , Sugano Tatsuya , Nakagawa Katsumi , Masuda Haruchika , Sawada Shohei , Nakagawa Masao
Published: July 2002

Serotonin (5-hydroxytryptamine, or 5-HT), released from activated platelets, not only accelerates aggregation of platelets but also is known to promote mitosis, migration, and contraction of vascular smooth muscle cells (VSMCs). These effects are considered to contribute to thrombus formation and atherosclerosis. The aim of this study was to investigate the effects of 5-HT on the expressions of coagulative and fibrinolytic factors in rat aortic endothelial cells. Endothelial cells were stimulated with various concentrations of 5-HT (0.1∼10 μM), and the expressions of tissue factor (TF), tissue factor pathway inhibitor (TFPI), plasminogen activator inhibitor-1 (PAI-1), and tissue-type plasminogen activator (TPA) messenger RNAs (mRNAs) were evaluated by Northern blot analysis. The activities of TF and PAI-1 were also measured. TF and PAI-1 mRNA were increased significantly in a concentration- and time-dependent manner. However, TFPI and TPA mRNA expression did not change. The inductions of TF and PAI-1 mRNAs were inhibited by a 5-HT1/5-HT2 receptor antagonist (methiothepin) and a selective 5-HT2A receptor antagonist (MCI-9042). These results indicate that 5-HT increases procoagulant activity and reduces fibrinolytic activities of endothelial cells through the 5-HT2A receptor. It was concluded that the modulation of procoagulant and hypofibrinolytic activities of endothelial cells by 5-HT synergistically promotes thrombus formation at the site of vessel injury with the platelet aggregation, VSMC contraction, and VSMC proliferation.
Stroke in hemoglobin (SD) sickle cell disease with moyamoya: successful hydroxyurea treatment after cerebrovascular bypass surgery
Authors: Schmugge Markus , Frischknecht Hannes , Yonekawa Yasuhiro , Baumgartner Ralf W. , Boltshauser Eugen , Humbert James
Published: July 2002

An 11-year-old boy with hemoglobin sickle disease (HbSD), bilateral stenosis of the intracranial carotid arteries, and moyamoya syndrome had recurrent ischemic strokes with aphasia and right hemiparesis. His parents (Jehovah's Witnesses) refused blood transfusions. After bilateral extracranial–intracranial (EC-IC) bypass surgery, hydroxyurea treatment increased hemoglobin F (HbF) levels to more than 30%. During a follow-up of 28 months, flow velocities in the basal cerebral arteries remained stable, neurologic sequelae regressed, and ischemic events did not recur. This is the first report of successful hydroxyurea treatment after bypass surgery for intracranial cerebral artery obstruction with moyamoya syndrome in sickle cell disease. The patient's religious background contributed to an ethically challenging therapeutic task.
Structure of a factor VIII C2 domain–immunoglobulin G4κ Fab complex: identification of an inhibitory antibody epitope on the surface of factor VIII
Authors: Spiegel Paul Clint , Jacquemin Marc , Saint-Remy Jean-Marie R. , Stoddard Barry L. , Pratt Kathleen P.
Published: July 2002

The development of an immune response to infused factor VIII is a complication affecting many patients with hemophilia A. Inhibitor antibodies bind to antigenic determinants on the factor VIII molecule and block its procoagulant activity. A patient-derived inhibitory immunoglobulin G4κ antibody (BO2C11) produced by an immortalized memory B-lymphocyte cell line interferes with the binding of factor VIII to phospholipid surfaces and to von Willebrand factor. The structure of a Fab fragment derived from this antibody complexed with the factor VIII C2 domain was determined at 2.0 Å resolution. The Fab interacts with solvent-exposed basic and hydrophobic side chains that form a membrane-association surface of factor VIII. This atomic resolution structure suggests a variety of amino acid substitutions in the C2 domain of factor VIII that might prevent the binding of anti-C2 inhibitor antibodies without significantly compromising the procoagulant functions of factor VIII.
Accelerated autoantibody clearance by intravenous immunoglobulin therapy: studies in experimental models to determine the magnitude and time course of the effect
Authors: Bleeker Wim K. , Teeling Jessica L. , Hack C. Erik
Published: July 2002

Recently, it has been postulated that the beneficial effect of intravenous immunoglobulins (IVIGs) in antibody-mediated autoimmune disorders is based on accelerated catabolism of autoantibodies. In the current study, in vivo experiments were performed with mice in which autoantibody production was mimicked by continuous infusion of monoclonal antibodies. In this model, a single dose of IVIG reduced the plasma concentrations of the infused immunoglobulin (Ig)G1 monoclonal antibody (mAb) by approximately 40% after 3 days, whereas the concentration of an IgA mAb was not affected. To extrapolate these findings to humans, a computational model for IgG clearance was established that accurately predicted the time course and magnitude of the decrease in IgG plasma levels observed in mice. Adapted for humans, this model predicted a gradually occurring decrease in autoantibody levels after IVIG administration (2 g/kg), with a maximum reduction of approximately 25% after 3 to 4 weeks and a continued decrease of several months. In conclusion, a single high dose of IVIG induces a relatively small but long-lasting reduction of autoantibody levels by accelerated IgG clearance. This mechanism has clinical relevance in the sense that it can fully explain, as the sole mechanism, the gradual decrease in autoantibody levels observed in several patient studies. However, in some clinical studies, larger or more rapid effects have been observed that cannot be explained by accelerated clearance. Hence, IVIG can also reduce autoantibody levels through mechanisms such as down-regulation of antibody production or neutralization by anti-idiotypic antibodies.
CD20 levels determine the in vitro susceptibility to rituximab and complement of B-cell chronic lymphocytic leukemia: further regulation by CD55 and CD59
Authors: Golay Josée , Lazzari Manuela , Facchinetti Valeria , Bernasconi Sergio , Borleri Gianmaria , Barbui Tiziano , Rambaldi Alessandro , Introna Martino
Published: July 2002

Complement-dependent cytotoxicity is thought to be an important mechanism of action of the anti-CD20 monoclonal antibody rituximab. This study investigates the sensitivity of freshly isolated cells obtained from 33 patients with B-cell chronic lymphocytic leukemia (B-CLL), 5 patients with prolymphocytic leukemia (PLL), and 6 patients with mantle cell lymphoma (MCL) to be lysed by rituximab and complement in vitro. The results showed that in B-CLL and PLL, the levels of CD20, measured by standard immunofluorescence or using calibrated beads, correlated linearly with the lytic response (coefficient greater than or equal to 0.9;P < .0001). Furthermore, the correlation remained highly significant when the 6 patients with MCL were included in the analysis (coefficient 0.91; P < .0001), which suggests that CD20 levels primarily determine lysis regardless of diagnostic group. The role of the complement inhibitors CD46, CD55, and CD59 was also investigated. All B-CLL and PLL cells expressed these molecules, but at different levels. CD46 was relatively weak on all samples (mean fluorescence intensity less than 100), whereas CD55 and CD59 showed variability of expression (mean fluorescence intensity 20-1200 and 20-250, respectively). Although CD55 and CD59 levels did not permit prediction of complement susceptibility, the functional block of these inhibitors demonstrated that they play an important role in regulating complement-dependent cytotoxicity. Thus, lysis of poorly responding B-CLL samples was increased 5- to 6-fold after blocking both CD55 and CD59, whereas that of high responders was essentially complete in the presence of a single blocking antibody. These data demonstrate that CD20, CD55, and CD59 are important factors determining the in vitro response to rituximab and complement and indicate potential strategies to improve the clinical response to this biologic therapy.
Rhenium 188–labeled anti-CD66 (a, b, c, e) monoclonal antibody to intensify the conditioning regimen prior to stem cell transplantation for patients with high-risk acute myeloid leukemia or myelodysplastic syndrome: results of a phase I-II study
Authors: Bunjes Donald , Buchmann Inga , Duncker Christian , Seitz Ulrike , Kotzerke Jörg , Wiesneth Markus , Dohr Dagmar , Stefanic Martin , Buck Andreas , Harsdorf Stefanie V. , Glatting Gerhard , Grimminger Wolfgang , Karakas Tunca , Munzert Gerd , Döhner Hartmut , Bergmann Lothar , Reske Sven N.
Published: July 2002

The conditioning regimen prior to stem cell transplantation in 36 patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) was intensified by treating patients with a rhenium 188–labeled anti-CD66 monoclonal antibody. Dosimetry was performed prior to therapy, and a favorable dosimetry was observed in all cases. Radioimmunotherapy with the labeled antibody provided a mean of 15.3 Gy of additional radiation to the marrow; the kidney was the normal organ receiving the highest dose of supplemental radiation (mean 7.4 Gy). Radioimmunotherapy was followed by standard full-dose conditioning with total body irradiation (12 Gy) or busulfan and high-dose cyclophosphamide with or without thiotepa. Patients subsequently received a T-cell–depleted allogeneic graft from a HLA-identical family donor (n = 15) or an alternative donor (n = 17). In 4 patients without an allogeneic donor, an unmanipulated autologous graft was used. Infusion-related toxicity due to the labeled antibody was minimal, and no increase in treatment-related mortality due to the radioimmunoconjugate was observed. Day +30 and day +100 mortalities were 3% and 6%, respectively, and after a median follow-up of 18 months treatment-related mortality was 22%. Late renal toxicity was observed in 17% of patients. The relapse rate of 15 patients undergoing transplantation in first CR (complete remission) or second CR was 20%; 21 patients not in remission at the time of transplantation had a 30% relapse rate.
Expression of functional lung resistance–related protein predicts poor outcome in adult T-cell leukemia
Authors: Ohno Nobuhito , Tani Ayako , Uozumi Kimiharu , Hanada Shuichi , Furukawa Tatsuhiko , Akiba Suminori , Sumizawa Tomoyuki , Utsunomiya Atae , Arima Terukatsu , Akiyama Shin-ichi
Published: July 2002

Chemotherapy of patients with adult T-cell leukemia (ATL) has been unsuccessful. The poor outcome is thought to be caused mainly by the drug resistance of ATL cells. Lung resistance–related protein (LRP) is a novel protein associated with drug resistance. The expression of LRP messenger RNA (mRNA) was evaluated by slot blot analysis in 55 patients with ATL. Of these patients, 36 had acute, 12 chronic, and 7 lymphoma-type ATL. The expression levels of LRP mRNA were significantly higher in chronic ATL than in lymphoma-type ATL (P = .007). The expression of LRP mRNA was higher in patients with white blood cell counts above 30 000/μL (P = .038) or with abnormal lymphocyte counts above 10 000/μL (P = .007) than in the remaining patients. The enhanced efflux of [14C]doxorubicin from nuclei isolated from ATL cells that expressed high levels of LRP was inhibited by a polyclonal antibody against LRP, and the accumulation of doxorubicin in the isolated nuclei was increased by the anti-LRP antibody. In acute and lymphoma-type ATL patients, high expression of LRP mRNA at diagnosis correlated with shorter survival, and a Cox proportional hazards model showed that LRP expression is an independent prognostic factor. These findings suggest that functionally active LRP is expressed in some ATL cells and that it is involved in drug resistance and poor prognosis in ATL.
T(11;18)(q21;q21) is associated with advanced mucosa-associated lymphoid tissue lymphoma that expresses nuclear BCL10
Authors: Liu Hongxiang , Ye Hongtao , Dogan Ahmet , Ranaldi Renzo , Hamoudi Rifat A. , Bearzi Italo , Isaacson Peter G. , Du Ming-Qing
Published: July 2002

The development of gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a multistep process and can be clinico-pathologically divided into Helicobacter pylori-associated gastritis, low-grade tumors, and high-grade tumors. The molecular events underlying this progression are largely unknown. However, identification of the genes involved in MALT lymphoma-specific t(11;18)(q21;q21) and t(1;14)(p22;q32) has provided fresh insights into the pathogenesis of this disease. T(11;18)(q21;q21) results in a chimeric transcript between the API2 and theMALT1 genes, whereas t(1;14) (p22;q32) causes aberrant nuclear BCL10 expression. Significantly, nuclear BCL10 expression also occurs frequently in MALT lymphomas without t(1;14)(p22;q32), suggesting an important role for BCL10 in lymphoma development. Thirty-three cases of H pylori gastritis, 72 MALT lymphomas, and 11 mucosal diffuse large B-cell lymphomas (DLBCL) were screened for t(11;18)(q21;q21) by reverse transcription–polymerase chain reaction followed by sequencing. BCL10 expression in lymphoma cases was examined by immunohistochemistry. The API2–MALT1 fusion transcript was not detected in H pylorigastritis and mucosal DLBCL but was found in 25 of 72 (35%) MALT lymphomas of various sites. Nuclear BCL10 expression was seen in 28 of 53 (53%) of MALT lymphomas. Of the gastric cases, the largest group studied, the frequency of both t(11;18)(q21;q21) and nuclear BCL10 expression was significantly higher in tumors that showed dissemination to local lymph nodes or distal sites (14 of 18 = 78% and 14 of 15 = 93%, respectively) than those confined to the stomach (3 of 29 = 10% and 10 of 26 = 38%). Furthermore, t(11;18)(q21;q21) closely correlated with BCL10 nuclear expression. These results indicate that both t(11;18)(q21;q21) and BCL10 nuclear expression are associated with advanced MALT lymphoma and that their oncogenic activities may be related to each other.
Immunomodulatory effects of extracorporeal photochemotherapy in patients with extensive chronic graft-versus-host disease
Authors: Alcindor Thierry , Gorgun Gullu , Miller Kenneth B. , Roberts Todd F. , Sprague Kellie , Schenkein David P. , Foss Francine M.
Published: July 2002

Extracorporeal photochemotherapy (ECP) has been associated with clinical improvement in several patients with acute and chronic graft-versus-host disease (cGVHD) after allogeneic bone marrow transplantation, but the mechanism of action is unknown. This study tested the hypothesis that in patients with cGVHD, ECP modulates alloreactivity by affecting activated lymphocyte populations or by altering the interaction between effector lymphocytes and antigen-presenting cells (APCs). Ten patients who had refractory cGVHD were treated with ECP, and the clinical response to and immunologic effects of this therapy were assessed. Seven patients had a response and 3 had no change in clinical manifestations of cGVHD. One patient died from catheter-related sepsis. Immunologic effects observed after ECP included normalization of inverted ratios of CD4 to CD8 cells, an increase in the number of CD3-CD56+ natural killer (NK) cells, and a decrease in CD80+ and CD123+ circulating dendritic cells. The results suggest that ECP modulates both NK cells and APC populations in patients with cGVHD.
Chronic myelogenous leukemia blast cell proliferation is inhibited by peptides that disrupt Grb2-SoS complexes
Authors: Kardinal Christian , Konkol Birgit , Lin Hui , Eulitz Manfred , Schmidt Enrico K. , Estrov Zeev , Talpaz Moshe , Arlinghaus Ralph B. , Feller Stephan M.
Published: July 2002

Chronic myelogenous leukemia (CML) is commonly characterized by the presence of the p210Bcr-Abl oncoprotein. Many downstream effectors of Bcr-Abl have been described, including activation of the Grb2-SoS-Ras–MAP kinase (Erk) pathway. The precise contributions of these signal-transduction proteins in CML blast cells in human patients are not yet well defined. To gain further insight into the importance of Grb2 for CML, peptides that disrupt Grb2-SoS complexes were tested. These high-affinityGrb2-binding peptides (HAGBPs) can autonomously shuttle into cells and function by binding to the N-terminal SH3 domain of Grb2. The HAGBPs were analyzed for their effects on Bcr-Abl–expressing cell lines and freshly isolated CML blast cells from patients. They induced a dramatic decrease in the proliferation of CML cell lines. This was not observed with point-mutated control peptides with abolished Grb2SH3(N) binding. As expected, Grb2-SoS complexes were greatly diminished in the HAGBP-treated cells, and MAP kinase activity was significantly reduced as determined by an activation-specific phospho-MAPK antibody. Furthermore, cell fractions that are enriched for blast cells from CML patients with active disease were also incubated with the Grb2 blocker peptides. The HAGBPs led to a significant proliferation reduction of these cells in the majority of the isolates, but not in all patients' cells. These results show that, in addition to the direct targeting of Bcr-Abl, selective inhibition of Grb2 protein complexes may be a therapeutic option for a significant number of CML patients.
Peripheral blood dendritic cells in children with acute Plasmodium falciparum malaria
Authors: Urban Britta C. , Mwangi Tabitha , Ross Amanda , Kinyanjui Samson , Mosobo Moses , Kai Oscar , Lowe Brett , Marsh Kevin , Roberts David J.
Published: July 2002

The importance of dendritic cells (DCs) for the initiation and regulation of immune responses not only to foreign organisms but also to the self has raised considerable interest in the qualitative and quantitative analysis of these cells in various human diseases.Plasmodium falciparum malaria is characterized by the poor induction of long-lasting protective immune responses. This study, therefore, investigated the percentage of peripheral blood DCs as lineage marker–negative and HLA-DR+ or CD83+cells in healthy children and in children suffering from acute malaria in Kilifi, Kenya. Comparable percentages of CD83+ DCs were found in peripheral blood of healthy children and children with malaria. However, the percentage of HLA-DR+ peripheral blood DCs was significantly reduced in children with malaria. The results suggest that a proportion of peripheral blood DCs may be functionally impaired due to the low expression of HLA-DR on their surface.
Band 3 Walton, a C-terminal deletion associated with distal renal tubular acidosis, is expressed in the red cell membrane but retained internally in kidney cells
Authors: Toye Ashley M. , Bruce Lesley J. , Unwin Robert J. , Wrong Oliver , Tanner Michael J. A.
Published: July 2002

Human band 3 Walton is an AE1 mutation that results in the deletion of the 11 COOH-terminal amino acids of the protein and is associated with dominant distal renal tubular acidosis. The properties of band 3 Walton expressed with normal band 3 in the heterozygous mutant erythrocytes and the kidney isoform expressed in Xenopusoocytes and in the Madin-Darby canine kidney cell line were examined. The mutant erythrocytes have normal hematology but have reduced band 3 Walton content. Transport studies showed that erythrocyte band 3 Walton has normal sulfate transport activity, and kidney band 3 Walton has normal chloride transport activity when expressed inXenopus oocytes. The mutant protein is clearly able to reach the cell surface of erythrocytes and oocytes. In contrast, while normal kidney band 3 was expressed at the cell surface in the kidney cell line, the Walton mutant protein was retained intracellularly within the kidney cells. The results demonstrate that band 3 Walton is targeted differently in erythrocytes and kidney cells and indicate that the COOH-terminal tail of band 3 is required to allow movement to the cell surface in kidney cells. It is proposed here that the mutant band 3 gives rise to dominant distal renal tubular acidosis by inhibiting the movement of normal band 3 to the cell surface. It is suggested that this results from the association of the normal and mutant proteins in band 3 hetero-oligomers, which causes the intracellular retention of normal band 3 with the mutant protein.
Tyrosine residues of the granulocyte colony-stimulating factor receptor transmit proliferation and differentiation signals in murine bone marrow cells
Authors: Akbarzadeh Shiva , Ward Alister C. , McPhee Dora O. M. , Alexander Warren S. , Lieschke Graham J. , Layton Judith E.
Published: July 2002

Granulocyte colony-stimulating factor (G-CSF) is the major regulator of granulopoiesis and acts through binding to its specific receptor (G-CSF-R) on neutrophilic granulocytes. Previous studies of signaling from the 4 G-CSF-R cytoplasmic tyrosine residues used model cell lines that may have idiosyncratic, nonphysiological responses. This study aimed to identify specific signals transmitted by the receptor tyrosine residues in primary myeloid cells. To bypass the presence of endogenous G-CSF-R, a chimeric receptor containing the extracellular domain of the epidermal growth factor receptor in place of the entire extracellular domain of the G-CSF-R was used. A series of chimeric receptors containing tyrosine mutations to phenylalanine, either individually or collectively, was constructed and expressed in primary bone marrow cells from G-CSF–deficient mice. Proliferation and differentiation responses of receptor-expressing bone marrow cells stimulated by epidermal growth factor were measured. An increased 50% effective concentration to stimulus of the receptor Ynullmutant indicated that specific signals from tyrosine residues were required for cell proliferation, particularly at low concentrations of stimulus. Impaired responses by mutant receptors implicated G-CSF-R Y764 in cell proliferation and Y729 in granulocyte differentiation signaling. In addition, different sensitivities to ligand stimulation between mutant receptors indicated that G-CSF-R Y744 and possibly Y729 have an inhibitory role in cell proliferation. STAT activation was not affected by tyrosine mutations, whereas ERK activation appeared to depend, at least in part, on Y764. These observations have suggested novel roles for the G-CSF-R tyrosine residues in primary cells that were not observed previously in studies in cell lines.
Expression of type 1 (interferon gamma) and type 2 (interleukin-13, interleukin-5) cytokines at distinct stages of natural killer cell differentiation from progenitor cells
Authors: Loza Matthew J. , Zamai Loris , Azzoni Livio , Rosati Emanuela , Perussia Bice
Published: July 2002

To determine whether production of type 1 and type 2 cytokines defines discrete stages of natural killer (NK) cell differentiation, cytokine expression was analyzed in human NK cells generated in vitro in the presence of interleukin-15 (IL-15) and/or IL-2 from umbilical cord blood hematopoietic progenitors. Like peripheral NK cells, the CD161+/CD56+ NK cells from these cultures contained a tumor necrosis factor alpha (TNF-α)+/granulocyte macrophage–colony-stimulating factor (GM-CSF)+ subset, an interferon gamma (IFN-γ)+ subset, mostly included within the former, and very few IFN-γ−/IL-13+ cells. Instead, most immature CD161+/CD56− NK cells, detectable only in the cultures with IL-2, produced IL-13, TNF-α, and GM-CSF, but not IFN-γ, and contained an IL-5+ subset. In short-term cultures with IL-12 and feeder cells, a proportion of the immature cells acquired the ability to produce IFN-γ. Part of these produced both IFN-γ and IL-13, irrespective of induced CD56 expression. These in vitro data indicate that ability to produce the type 2 cytokines IL-13 and IL-5 defines CD161+ NK cells at intermediate stages of differentiation, and is lost upon terminal functional differentiation, concomitant with acquired ability to produce IFN-γ.
Overexpression of SOCS-2 in advanced stages of chronic myeloid leukemia: possible inadequacy of a negative feedback mechanism
Authors: Schultheis Beate , Carapeti-Marootian Melina , Hochhaus Andreas , Weiβer Andreas , Goldman John M. , Melo Junia V.
Published: July 2002

Constitutive activation of the BCR-ABL tyrosine kinase is fundamental to the pathogenesis of chronic myeloid leukemia (CML). STI571 inhibits this activity and modulates the transcription of several genes. It was shown by differential display that the suppressor of cytokine signaling-2 (SOCS-2) gene was down-regulated by STI571 treatment in 14 of 16 BCR-ABL–positive cell lines and in 2 BCR-ABL–transfected murine lines, but not inBCR-ABL–negative counterparts. The effect was maximal at 2 hours and persisted for at least 24 hours after exposure to 1 μM STI571, whereas SOCS-1 and SOCS-3 expression were unaffected. Baseline levels of SOCS-2 were significantly higher in BCR-ABL–positive as compared withBCR-ABL–negative cell lines. It was similar in leukocytes and CD34+ cells from healthy persons (n = 44) and patients with CML in chronic phase (CP; n = 60) but significantly increased in patients with CML in blast crisis (BC; n = 20) (P < .0001). Mononuclear cells (MNCs) from 3 of 4 patients with CML in BC showed a 2-fold to 12-fold down-regulation ofSOCS-2 levels on in vitro exposure to STI571; moreover, a 2-fold to 11-fold decrease in SOCS-2 was observed in MNCs from 7 of 8 patients with CML in BC who responded to treatment with STI571. Refractoriness to STI571 or relapse after initial response was accompanied by augmentation of SOCS-2 expression. Ectopic overexpression of SOCS-2 in 32Dp210 cells slowed growth, inhibited clonogenicity, and increased their motility and sensitivity to STI571. Overall, the results suggest that SOCS-2 is a component of a negative feedback mechanism; it is induced by Bcr-Abl but cannot reverse its overall growth-promoting effects in blastic transformation.
Decisional Conflicts in Patients With Low-Risk Papillary Thyroid Microcarcinomas Considering Active Surveillance
Authors: Zhang Qianqian , Gu Xinyue , Liu Shuangyuan , Fu Rong , Wang Ying , Hegarty Josephine , Zhu Pingting , Ge Jingwu
Published: September 2024

Importance

Internationally, active surveillance has been shown to be beneficial and safe in the management of low-risk papillary thyroid microcarcinomas. However, choosing active surveillance is a difficult treatment decision for patients with low-risk papillary thyroid microcarcinomas.

Objective

To identify and analyze the antecedents and mediating processes of decisional conflicts when patients consider active surveillance as an alternative to surgery.

Design, Setting, and Participants

In this qualitative study, semistructured interviews were conducted between April 2023 and December 2023 at 3 tertiary hospitals in China. Thirty-one participants who were diagnosed with low-risk papillary thyroid microcarcinomas, who had experienced considering active surveillance as an alternative to surgery and who scored above 25 on the decision conflict scale were purposively recruited. Inductive content analysis led to emergent themes. Data analysis was performed from April 2023 to February 2024. Methods used to protect the trustworthiness of the study results included audit trails and member checks.

Main outcomes and Measures

Patients’ experience of decisional conflicts and the antecedents and mediating processes relating to these decisional conflicts.

Results

Among 31 participants (median [range] age, 39.2 [22-63] years; 22 [71%] were female and 9 [29%] were male), 3 themes were classified: (1) decisional conflicts in decision preparation, (2) decisional conflicts in decision-making, and (3) decisional conflicts in decision implementation. The patient’s experiences of decisional conflicts were diverse and occurred throughout the entire decision-making process. The antecedents of the decisional conflicts included personal influencing factors, system-level influencing factors, and the relational-situational context. Patients with low-risk papillary thyroid microcarcinomas interacted with these antecedents in the process of decision-making and eventually failed to mediate, leading to decisional conflicts.

Conclusions and relevance

This qualitative study found that patients with low-risk papillary thyroid microcarcinomas experienced clinically significant decisional conflicts and experienced considerable challenges and psychological problems in decision-making. The antecedents of decisional conflicts and accompanying mediating processes can provide guidance for individuals, health care professionals, and health care systems to provide decision support for patients with low-risk papillary thyroid microcarcinomas.
Medical Device Reprocessing—Sustainability in Otolaryngology
Authors: Lalakea M. Lauren , Dilger Amanda , Meiklejohn Duncan A.
Published: September 2024

This Viewpoint discusses the benefits and challenges to implementation of medical device reprocessing in otolaryngology.
Validation of a whole slide image management system for metabolic‐associated steatohepatitis for clinical trials
Authors: Pulaski Hanna , Mehta Shraddha S , Manigat Laryssa C , Kaufman Stephanie , Hou Hypatia , Nalbantoglu ILKe , Zhang Xuchen , Curl Emily , Taliano Ross , Kim Tae Hun , Torbenson Michael , Glickman Jonathan N , Resnick Murray B , Patel Neel , Taylor Cristin E , Bedossa Pierre , Montalto Michael C , Beck Andrew H , Wack Katy E
Published: September 2024

The gold standard for enrollment and endpoint assessment in metabolic dysfunction‐associated steatosis clinical trials is histologic assessment of a liver biopsy performed on glass slides. However, obtaining the evaluations from several expert pathologists on glass is challenging, as shipping the slides around the country or around the world is time‐consuming and comes with the hazards of slide breakage. This study demonstrated that pathologic assessment of disease activity in steatohepatitis, performed using digital images on the AISight whole slide image management system, yields results that are comparable to those obtained using glass slides. The accuracy of scoring for steatohepatitis (nonalcoholic fatty liver disease activity score ≥4 with ≥1 for each feature and absence of atypical features suggestive of other liver disease) performed on the system was evaluated against scoring conducted on glass slides. Both methods were assessed for overall percent agreement with a consensus “ground truth” score (defined as the median score of a panel of three pathologists’ glass slides). Each case was also read by three different pathologists, once on glass and once digitally with a minimum 2‐week washout period between the modalities. It was demonstrated that the average agreement across three pathologists of digital scoring with ground truth was noninferior to the average agreement of glass scoring with ground truth [noninferiority margin: −0.05; difference: −0.001; 95% CI: (−0.027, 0.026); and p < 0.0001]. For each pathologist, there was a similar average agreement of digital and glass reads with glass ground truth (pathologist A, 0.843 and 0.849; pathologist B, 0.633 and 0.605; and pathologist C, 0.755 and 0.780). Here, we demonstrate that the accuracy of digital reads for steatohepatitis using digital images is equivalent to glass reads in the context of a clinical trial for scoring using the Clinical Research Network scoring system.
Remaining Useful Life Prediction of Rolling Bearings Based on Adaptive Continuous Deep Belief Networks and Improved Kernel Extreme Learning Machine
Authors: Zhou Meng , Wang Jing , Shi Yuntao , Wang Zhenhua , Puig Vicenç
Published: September 2024

Rolling bearings are crucial components in a wide variety of machinery. Monitoring their conditions and predicting their remaining useful life (RUL) is vital to prevent unexpected breakdowns, optimize maintenance schedules, and reduce operational costs. This article proposes an approach based on adaptive continuous deep belief networks (ACDBN) and improved kernel extreme learning machine (KELM) to predict the RUL of rolling bearings. In the proposed approach, the ACDBN model is used for extracting hidden fault features and the distance between the initial health state and the real‐time degradation state is used to construct a health indicator (HI). Then, a hybrid kernel extreme learning machine prediction model optimized by the sparrow search algorithm (SSA‐KELM) is proposed to estimate the RUL using the extracted HIs. The SSA is used to find the optimal parameters of the KELM model. The proposed method has been assessed using existing bearing datasets. The obtained results indicate that the proposed method successfully improves RUL prediction accuracy compared to existing approaches in the literature.
Mechanisms, Applications, and Challenges of Utilizing Nanomaterials in Cryopreservation
Authors: Wang Ziyuan , Gao Dayong , Shu Zhiquan
Published: September 2024

Cryopreservation of biological samples, including cells, tissues, and organs, has become an essential component in various biomedical research and applications, such as cellular therapy, tissue engineering, organ transplantation, and conservation of endangered species. However, it faces critical challenges throughout the cryopreservation process, such as loading/unloading of cryoprotective agent (CPA), ice inhibition during cooling, and ultrafast and uniform heating during rewarming. Applying nanomaterials in cryopreservation has emerged as a promising solution to address these challenges in each step due to their unique properties. For instance, in order to deliver nonpermeating CPA into cells, some nanomaterials, such as polymeric nanocapsule, can carry nonpermeating CPA to penetrate into the cells, regulating the intracellular ice crystal. During cooling, some nanomaterials, such as graphene oxide, can bind to basal or prism planes of ice crystals, suppressing the ice growth. During rewarming, some nanomaterials, such as magnetic nanoparticles, can improve the heating performance, preventing devitrification and recrystallization during rewarming. However, challenges in nanomaterials‐assisted cryopreservation remain, including the need for comprehensive studies on nanomaterials toxicity and the development of scalable manufacturing processes for industrial applications. This review examines the role of nanomaterials in cryopreservation, focusing on their mechanisms, applications, and associated challenges.
Green Synthesis of Catalytic 3D Platinum Nanostructures from a Body‐Centered Cubic Pluronic Micellar Array Template
Authors: Di Spirito Nicola Antonio , Liu Wanli , Williams Stephen , Squires Adam M. , Di Lorenzo Mirella
Published: September 2024

Ordered and well‐interconnected 3D electrode nanostructures open up exciting perspectives in catalysis, sensing and energy harvesting. Here, highly ordered 3D nano‐sized Pt mesoporous structures based on the I‐Wrapped Package (I‐WP) architecture with 13.5 nm unit cell size, previously unreported for metal nanomaterials, are presented. The samples are synthetized by soft‐template electrodeposition, using the body‐centred cubic (BCC) lyotropic crystalline micellar phase of Pluronic F68 as the template. The specific surface area of the resulting Pt nanoarchitecture is 36 ± 13 m2 g−1. The oxygen reduction reaction kinetic current is 0.98 mA cm−2; the current density normalized by the electrochemical active surface area and the weight of deposited Pt are 0.92 mA cm−2 and 153.53 A g−1, respectively, showing superior properties than conventional Pt nanostructures produced by surfactant templates. These results suggest a nanostructure based on the topology of the I‐WP minimal surface, representing the first case at this length scale from a metallic material, opening up new research directions in fundamental physics based on predicted thermal and phononic properties for this topology. The water‐based template provides a chemical‐free, eco‐friendly route for ordered mesoporous conductive nanomaterials manufacturing, inspiring future trends in the field.
Gasdermin C promotes Stemness and Immune Evasion in Pancreatic Cancer via Pyroptosis‐Independent Mechanism
Authors: Wu Renfei , Li Jingwei , Aicher Alexandra , Jiang Ke , Tondi Serena , Dong Shuang , Zheng Quan , Tang Siqi , Chen Minchun , Guo Zhenyang , Šabanović Berina , Ananthanarayanan Preeta , Jiang Lingxi , Sapino Anna , Wen Chenlei , Fu Da , Shen Baiyong , Heeschen Christopher
Published: September 2024

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic and lethal disease. Gasdermins are primarily associated with necrosis via membrane permeabilization and pyroptosis, a lytic pro‐inflammatory type of cell death. In this study, GSDMC upregulation during PDAC progression is reported. GSDMC directly induces genes related to stemness, EMT, and immune evasion. Targeting Gsdmc in murine PDAC models reprograms the immunosuppressive tumor microenvironment, rescuing the recruitment of anti‐tumor immune cells through CXCL9. This not only results in diminished tumor initiation, growth and metastasis, but also enhances the response to KRASG12D inhibition and PD‐1 checkpoint blockade, respectively. Mechanistically, it is discovered that ADAM17 cleaves GSDMC, releasing nuclear fragments binding to promoter regions of stemness, metastasis, and immune evasion‐related genes. Pharmacological inhibition of GSDMC cleavage or prevention of its nuclear translocation is equally effective in suppressing GSDMC's downstream targets and inhibiting PDAC progression. The findings establish GSDMC as a potential therapeutic target for enhancing treatment response in this deadly disease.
Surface Charge Regulation of Graphene by Fluorine and Chlorine Co‐Doping for Constructing Ultra‐Stable and Large Energy Density Micro‐Supercapacitors
Authors: Liu Binbin , Hou Jiagang , Wang Kai , Xu Caixia , Zhang Qinghua , Gu Lin , Zhou Weijia , Li Qian , Wang John , Liu Hong
Published: September 2024

Settling the structure stacking of graphene (G) nanosheets to maintain the high dispersity has been an intense issue to facilitate their practical application in the microelectronics‐related devices. Herein, the co‐doping of the highest electronegative fluorine (F) and large atomic radius chlorine (Cl) into G via a one‐step electrochemical exfoliation protocol is engineered to actualize the ultralong cycling stability for flexible micro‐supercapacitors (MSCs). Density functional theoretical calculations unveiled that the F into G can form the “ionic” C─F bond to increase the repulsive force between nanosheets, and the introduction of Cl can enlarge the layer spacing of G as well as increase active sites by accumulating the charge on pore defects. The co‐doping of F and Cl generates the strong synergy to achieve high reversible capacitance and sturdy structure stability for G. The as‐constructed aqueous gel‐based MSC exhibited the superb cycling stability for 500,000 cycles with no capacitance loss and structure stacking. Furthermore, the ionic liquid gel‐based MSC demonstrated a high energy density of 113.9 mW h cm−3 under high voltage of up to 3.5 V. The current work enlightens deep insights into the design and scalable preparation of high‐performance co‐doped G electrode candidate in the field of flexible microelectronics.
Efficient Rescue of Retinal Degeneration in Pde6a Mice by Engineered Base Editing and Prime Editing
Authors: Liu Zhiquan , Chen Siyu , Davis Alexander E. , Lo Chien‐Hui , Wang Qing , Li Tingting , Ning Ke , Zhang Qi , Zhao Jingyu , Wang Sui , Sun Yang
Published: September 2024

Retinitis pigmentosa (RP) is a complex spectrum of inherited retinal diseases marked by the gradual loss of photoreceptor cells, ultimately leading to blindness. Among these, mutations in PDE6A, responsible for encoding a cGMP‐specific phosphodiesterase, stand out as pivotal in autosomal recessive RP (RP43). Unfortunately, no effective therapy currently exists for this specific form of RP. However, recent advancements in genome editing, such as base editing (BE) and prime editing (PE), offer a promising avenue for precise and efficient gene therapy. Here, it is illustrated that the engineered BE and PE systems, particularly PE, exhibit high efficiency in rescuing a target point mutation with minimal bystander effects in an RP mouse model carrying the Pde6a (c.2009A > G, p.D670G) mutation. The optimized BE and PE systems are first screened in N2a cells and subsequently assessed in electroporated mouse retinas. Notably, the optimal PE system, delivered via dual adeno‐associated virus (AAV), precisely corrects the pathogenic mutation with average 9.4% efficiency, with no detectable bystander editing. This correction restores PDE6A protein expression, preserved photoreceptors, and rescued retinal function in Pde6a mice. Therefore, this study offers a proof‐of‐concept demonstration for the treatment of Pde6a‐related retinal degeneration using BE and PE systems.
Biomimetic Liver Lobules from Multi‐Compartmental Microfluidics
Authors: Huang Danqing , Wu Zhuhao , Wang Ji , Wang Jinglin , Zhao Yuanjin
Published: September 2024

Engineered liver lobule is highly practical in hepatic disease treatment, while constructing a 3D biomimetic lobule with a heterogeneous architecture on a large scale is challenging. Here, inspired by the natural architectural construction of hepatic lobules, biomimetic hepatic lobules are proposed with coaxially through‐pores for nutrient exchange via microfluidic technology. This multi‐channel microfluidic chip is made by parallelly installing capillaries. Sodium alginate (Alg) is pumped through its central channel, while Ca2+‐loaded gelatin methacrylate (GelMA) solutions encapsulating hepatocytes, mesenchymal stem cells, and endothelia cells are pumped through surrounding channels, respectively. The rapid gelation of Alg and Ca2+ brings about an in situ formation of Alg fiber, with heterogeneous multi‐cell‐laden GelMA microcarriers forming around it. The peeled‐off microcarriers each featured with a coaxially through pore, simulating the cord‐like structure of hepatic lobule and facilitating nutrients exchange. Meanwhile, the spatially anisotropic arrangement of cells highly simulates the hepatic architecture. It is demonstrated that by transplanting these biomimetic microparticles into liver in situ, the failed liver in rat shows increased regeneration and decreased necrosis. These results indicated that the microfluidic multi‐compartmental microcarriers provide a new strategy to engineer 3D artificial livers for clinical translation.
Tandem Electroreduction of Nitrate to Ammonia Using a Cobalt–Copper Mixed Single‐Atom/Cluster Catalyst with Synergistic Effects
Authors: Suh Jungwon , Choi Hyeonuk , Kong Yujin , Oh Jihun
Published: September 2024

Electrochemical conversion of waste nitrate (NO3−) to ammonia (NH3) for environmental applications, such as carbon‐neutral energy sources and hydrogen carriers, is a promising alternative to the energy‐intensive Haber–Bosch process. However, increasing the energy efficiency is limited by the high overpotential and selectivity. Herein, a Co─Cu mixed single‐atom/cluster catalyst (Co─Cu SCC) is demonstrated—with well‐dispersed Co and Cu active sites anchored on a carbon support—that delivers high NH3 Faradaic efficiency of 91.2% at low potential (–0.3 V vs. RHE) due to synergism between the heterogenous active sites. Electrochemical analyses reveal that Cu in Co─Cu SCC preferentially catalyzes the NO3−‐to‐NO2− pathway, whereupon Co catalyzes the NO2−‐to‐NH3 pathway. This tandem electroreduction bypasses the rate‐determining steps (RDSs) for Co and Cu to lower the reaction energy barrier and surpass scaling relationship limitations. The electrocatalytic performance is amplified by the subnanoscale catalyst to increase the partial current density of NH3 by 2.3 and 5.4 times compared to those of individual Co, Cu single‐atom/cluster catalysts (Co SCC, Cu SCC), respectively. This Co─Cu SCC is operated stably for 32 h in a long‐term bipolar membrane (BPM)‐based membrane electrode assembly (MEA) system for high‐concentration NH3 synthesis to produce over 1 m NH3 for conversion into high‐purity NH4Cl at 2.1 g day−1.
Repurposing Copper(II)/THPTA as A Bioorthogonal Catalyst for Thiazolidine Bond Cleavage
Authors: Ma Chengyun , Liu Guoqing , Yin Juan , Sun Jianan , Luo Disheng , Yang Dechun , Pang Shuo , Hou Wei , Hemu Xinya , Ye Bangce , Bi Xiaobao
Published: September 2024

Metal‐mediated chemical transformations are promising approaches to manipulate and regulate proteins in fundamental biological research and therapeutic development. Nevertheless, unlike bond‐forming reactions, the exploration of selective bond cleavage reactions catalyzed by metals that are fully compatible with proteins and living systems remains relatively limited. Here, it is reported that Copper(II)/tris(3‐hydroxypropyltriazolylmethyl)amine (THPTA), commonly used in copper‐catalyzed azide‐alkyne cycloaddition (CuAAC) reaction, can be repurposed as a new bioorthogonal catalyst for thiazolidine (Thz) bond cleavage. This process liberates an α‐oxo‐aldehyde group under physiological conditions, without requiring additional additives. To showcase the utility of this method, this simple catalyst system is coupled with genetic code expansion technology to achieve on‐demand activation of genetically encoded Thz‐caged α‐oxo‐aldehydes, enabling further functionalization of proteins. For the first time, this cell‐compatible Thz uncaging reaction allows for the site‐specific installation of α‐oxo‐aldehydes at the internal positions of proteins in phage and bacterial surface display systems, expanding the chemical space of proteins. Overall, this study expands the toolkit of bioorthogonal catalysts and paves the way for metal‐promoted chemical reactions in living systems, potentially benefiting various applications in the future.
Predicting DNA Reactions with a Quantum Chemistry‐Based Deep Learning Model
Authors: Wang Likun , Li Na , Cao Mengyao , Zhu Yun , Xiong Xiewei , Li Li , Zhu Tong , Pei Hao
Published: September 2024

In this study, a deep learning model based on quantum chemistry is introduced to enhance the accuracy and efficiency of predicting DNA reaction parameters. By integrating quantum chemical calculations with self‐designed descriptor matrices, the model offers a comprehensive description of energy variations and considers a broad range of relevant factors. To overcome the challenge of limited labeled data, an active learning method is employed. The results demonstrate that this model outperforms existing methods in predicting DNA hybridization free energies and strand displacement rate constants, thus advancing the understanding of DNA molecular interactions, and aiding in the precise design and optimization of DNA‐based systems.