bluuebunny/crossref_metadata_2025 huggingface dataset:
The TEL/PDGFβR fusion in chronic myelomonocytic leukemia signals through STAT5-dependent and STAT5-independent pathways
Authors: Sternberg David W. , Tomasson Michael H. , Carroll Martin , Curley David P. , Barker George , Caprio Michael , Wilbanks Alyson , Kazlauskas Andrius , Gilliland D. Gary
Published: July 2002

The TEL/PDGFβR gene, which encodes a fusion protein containing the ETS-family member TEL fused to the protein-tyrosine kinase domain of the platelet-derived growth factor receptor-β (PDGFβR), confers interleukin 3 (IL-3)–independent growth on Ba/F3 hematopoietic cells. TEL/PDGFβR mutants have been generated that contain tyrosine-to-phenylalanine (Tyr→Phe) substitutions at phosphorylation sites present in the native PDGFβR to assess the role of these sites in cell transformation by TEL/PDGFβR. Similar to previous findings in a murine bone marrow transplantation model, full transformation of Ba/F3 cells to IL-3–independent survival and proliferation required the TEL/PDGFβR juxtamembrane and carboxy terminal phosphorylation sites. In contrast to previous reports concerning comparable mutants in the native PDGFβR, each of the TEL/PDGFβR mutants is fully active as a protein-tyrosine kinase. Expression of the TEL/PDGFβR fusion protein causes hyperphosphorylation and activation of signal transducer and activator of transcription (STAT5), and this activation of STAT5 requires the juxtamembrane Tyr579 and Tyr581 in the TEL/PDGFβR fusion. Hyperphosphosphorylation of phospholipase Cγ (PLCγ) and the p85 subunit of phosphatidylinositol 3-kinase (PI3K) requires the carboxy terminal tyrosine residues of TEL/PDGFβR. Thus, full transformation of Ba/F3 cells by TEL/PDGFβR requires engagement of PI3K and PLCγ and activation of STAT5. Taken together with the growth properties of cells transformed by the TEL/PDGFβR variants, these findings indicate that a minimal combination of these signaling intermediates contributes to hematopoietic transformation by the wild-type TEL/PDGFβR fusion.
De novo methylation of an embryonic globin gene during normal development is strand specific and spreads from the proximal transcribed region
Authors: Singal Rakesh , vanWert Jane M.
Published: July 2002

The recently discovered de novo methyltransferases DNMT3a and DNMT3b have been shown to be critical to embryonic development. However, at a single gene level, little is known about how the methylation pattern is established during development. The avian embryonic ρ-globin gene promoter is completely unmethylated in 4-day-old chicken embryonic erythroid cells, where it is expressed at a high level, and completely methylated in adult erythroid cells, where it is silent. The methylation pattern of the ρ-globin gene promoter, proximal transcribed region, and distal transcribed region on both DNA strands was examined during development in chicken erythroid cells. It was found that de novo methylation targets the CpG-dense proximal transcribed region on the coding (top) strand initially, followed by spreading into the 3′ region and into the promoter region. Methylation of the template (bottom) strand lags behind that of the coding strand, and complete methylation of both strands occurs only after the gene has been silenced. The results of the study indicate that establishment of the de novo methylation pattern involves strand-specificity and methylation spreading.
Altered apoptosis pathways in mantle cell lymphoma detected by oligonucleotide microarray
Authors: Hofmann Wolf-K. , de Vos Sven , Tsukasaki Kunihiro , Wachsman William , Pinkus Geraldine S. , Said Jonathan W. , Koeffler H. Phillip
Published: July 2002

An imbalance between cellular apoptosis and survival may be critical for the pathogenesis of lymphoma. Therefore, the gene expression pattern in lymph node preparations from patients with mantle cell lymphoma (MCL) was compared to the pattern in nonmalignant hyperplastic lymph nodes (HLs). Oligonucleotide microarray analysis was performed comparing 5 MCLs to 4 HLs using high-density microarrays. The expression data were analyzed using Genespring software. For confirmation, the expression of selected genes was analyzed by real-time polymerase chain reaction using the RNA extracted from 16 MCL and 12 HL samples. The focus was on 42 genes that were at least 3-fold down-regulated in MCL; in addition to the B-cell leukemia 2 (BCL2) system other apoptotic pathways were altered in MCL. The FAS-associated via death domain (FADD) gene that acts downstream of the FAS cascade as a key gene to induce apoptosis was more than 10-fold down-regulated in MCL. Furthermore, the death-associated protein 6(DAXX) gene, the caspase 2 (CASP2) gene, and the RIPK1 domain containing adapter with death domain(RAIDD) gene, which are key genes in other proapoptotic pathways, were also decreased in the MCL samples. The suggestion is made that in addition to the known overexpression of cyclin D1, which drives entry into the cell cycle, disturbances of pathways associated with apoptosis contribute to the development of MCL.
HTLV-1 p12I protein enhances STAT5 activation and decreases the interleukin-2 requirement for proliferation of primary human peripheral blood mononuclear cells
Authors: Nicot Christophe , Mulloy James C. , Ferrari Maria G. , Johnson Julie M. , Fu Kaisong , Fukumoto Risaku , Trovato Raffaella , Fullen Jake , Leonard Warren J. , Franchini Genoveffa
Published: July 2002

The p12I protein, encoded by the pX open reading frame I of the human T-lymphotropic virus type 1 (HTLV-1), is a hydrophobic protein that localizes to the endoplasmic reticulum and the Golgi. Although p12I contains 4 minimal proline-rich, src homology 3–binding motifs (PXXP), a characteristic commonly found in proteins involved in signaling pathways, it has not been known whether p12I has a role in modulating intracellular signaling pathways. This study demonstrated that p12I binds to the cytoplasmic domain of the interleukin-2 receptor (IL-2R) β chain that is involved in the recruitment of the Jak1 and Jak3 kinases. As a result of this interaction, p12I increases signal transducers and activators of transcription 5 (STAT5) DNA binding and transcriptional activity and this effect depends on the presence of both IL-2R β and γc chains and Jak3. Transduction of primary human peripheral blood mononuclear cells (PBMCs) with a human immunodeficiency virus type 1–based retroviral vector expressing p12I also resulted in increased STAT5 phosphorylation and DNA binding. However, p12I could increase proliferation of human PBMCs only after stimulation of T-cell receptors by treatment of cells with low concentrations of αCD3 and αCD28 antibodies. In addition, the proliferative advantage of p12I-transduced PBMCs was evident mainly at low concentrations of IL-2. Together, these data indicate that p12I may confer a proliferative advantage on HTLV-1–infected cells in the presence of suboptimal antigen stimulation and that this event may account for the clonal proliferation of infected T cells in vivo.
Phase 1 study of interleukin-12 in combination with rituximab in patients with B-cell non-Hodgkin lymphoma
Authors: Ansell Stephen M. , Witzig Thomas E. , Kurtin Paul J. , Sloan Jeff A. , Jelinek Diane F. , Howell Kyle G. , Markovic Svetomir N. , Habermann Thomas M. , Klee George G. , Atherton Pamela J. , Erlichman Charles
Published: July 2002

Rituximab is a chimeric murine/human monoclonal antibody that binds to CD20 on B lymphocytes. Although binding of the Fab domain may induce apoptosis, the Fc domain recruits immune effector functions to mediate cell lysis. Interleukin-12 (IL-12) facilitates cytolytic T-cell responses, enhances the lytic activity of natural killer (NK) cells, and induces the secretion of interferon γ (IFN-γ) by both T and NK cells. Therefore, the hypothesis was considered that combining IL-12 with rituximab would augment the immune-mediated cell lysis induced by rituximab. A phase 1 study of IL-12 in combination with rituximab was conducted in 43 adults with B-cell lymphoma to determine the optimal immunologic dose of this combination. Rituximab was administered at a dose of 375 mg/m2 by intravenous infusion weekly for 4 weeks, and IL-12 was given subcutaneously twice weekly. The starting dose of IL-12 was 30 ng/kg and this was escalated to 500 ng/kg. Constitutional symptoms and liver enzyme elevations at 500 ng/kg of IL-12 were dose limiting. A greater than 20-fold increase in the serum levels of IFN-γ and a 2.5- to 5-fold increase in inducible protein 10 (IP-10) levels was seen at IL-12 doses of 100 ng/kg or greater. Objective responses occurred in 29 of the 43 patients (69%), with 8 of 11 complete responses seen at IL-12 doses of 300 ng/kg or greater. The optimal immunologic dose of IL-12 in combination with rituximab was determined to be 300 ng/kg subcutaneously twice weekly starting on day 2. These data suggest that IL-12 and rituximab is an active combination and further studies of this combination in B-cell non-Hodgkin lymphoma are warranted.
Human hematopoiesis in murine embryos after injecting human cord blood–derived hematopoietic stem cells into murine blastocysts
Authors: Harder Friedrich , Henschler Reinhard , Junghahn Ilse , Lamers Marinus C. , Müller Albrecht M.
Published: July 2002

At different developmental stages, candidate human hematopoietic stem cells (HSCs) are present within the CD34+ CD38− population. By means of xenotransplantation, such CD34+CD38− cells were recently shown to engraft the hematopoietic system of fetal sheep and nonobese diabetic severe combined immunodeficient adult mice. Here it is demonstrated that, after their injection into murine blastocysts, human cord blood (CB)–derived CD34+and CD34+ CD38− cells repopulate the hematopoietic tissues of nonimmunocompromised murine embryos and that human donor contribution can persist to adulthood. It is further observed that human hematopoietic progenitor cells are present in murine hematopoietic tissues of midgestational chimeric embryos and that progeny of the injected human HSCs activate erythroid-specific gene expression. Thus, the early murine embryo provides a suitable environment for the survival and differentiation of human CB CD34+ CD38− cells.
Reduced tissue macrophage population in the lung by anticancer agent cyclophosphamide: restoration by local granulocyte macrophage–colony-stimulating factor gene transfer
Authors: Santosuosso Michael , Divangahi Maziar , Zganiacz Anna , Xing Zhou
Published: July 2002

Granulocytopenia is thought to be the sole mechanism underlying the increased susceptibility to bacterial infection in hosts with anticancer chemotherapy. Little is known about the functional state of tissue macrophage populations in such hosts. Using a model of chemotherapy-induced leukopenia, the number and function of alveolar macrophages (AMS) were examined during and after multiple injections of an anticancer agent, cyclophosphamide (CP). Although CP quickly reduced peripheral blood leukocytes, the number of these cells rebounded quickly 3 to 4 days after the withdrawal of CP. Accompanying blood leukopenia was a profound reduction in the number of ams. Contrary to the rapid onset of blood leukopenia, tissue macrophage deficiency was a more chronic process that worsened gradually as the CP regimen continued. Of importance, in contrast to blood leukopenia, which restored itself shortly after CP withdrawal, tissue macrophage deficiency was not immediately self-recoverable in spite of a restored number of circulating leukocytes. Although AMS had a decreased ability to proliferate during, but not after, the CP regimen, these cells retained a normal ability to release tumor necrosis factor-α and nitric oxide. To identify the potential therapeutics for recovering macrophages, a gene vector expressing granulocyte macrophage–colony-stimulating factor (GM-CSF) was delivered either systemically or locally. GM-CSF transgene was able to expand macrophage populations only when delivered to the lung after, but not during, the CP regimen. This study thus identifies tissue macrophage deficiency as a mechanism of weakened innate immunity by chemotherapy and suggests the usefulness of topical GM-CSF transgene expression for restoring innate immunity in the lung.
CEACAM1 Expression in Cutaneous Malignant Melanoma Predicts the Development of Metastatic Disease
Authors: Thies Anka , Moll Ingrid , Berger Jürgen , Wagener Christoph , Brümmer Jens , Schulze Hans-Joachim , Brunner Georg , Schumacher Udo
Published: July 2002

PURPOSE: The cell adhesion molecule CEACAM1 is involved in intercellular adhesion and subsequent signal transduction events in a number of epithelia. CEACAM1 downregulation has been demonstrated in colorectal and prostate carcinomas. This study sought to analyze whether its expression in malignant melanoma is associated with metastasis.

PATIENTS AND METHODS: CEACAM1 expression was immunohistochemically evaluated in 100 primary cutaneous malignant melanomas and correlated with metastasis in a 10-year follow-up. Furthermore, CEACAM1 expression was analyzed in metastatic lesions (11 distant metastases and six sentinel lymph node metastases). Univariate Kaplan-Meier analysis and multivariate Cox proportional hazard regression analysis adjusted for standard prognostic indicators were performed to assess the prognostic relevance of CEACAM1 expression.

RESULTS: A total of 28 of 40 patients with CEACAM1-positive primary melanomas developed metastatic disease, compared with only six of 60 patients with CEACAM1-negative melanomas. Often, the strongest CEACAM1 expression was observed at the invading front. In addition, CEACAM1 expression was preserved in the metastatic lesions. Kaplan-Meier analysis revealed a highly significant association between CEACAM1 expression and metastasis (P < .0001); multivariate Cox regression analysis, including CEACAM1 expression status adjusted for tumor thickness, presence of ulceration, and mitotic rate, confirmed that CEACAM1 is an independent factor for the risk of metastasis and demonstrated that the predictive value of CEACAM1 expression is superior to that of tumor thickness.

CONCLUSION: Expression of the cell adhesion molecule CEACAM1 in the primary tumors in melanoma patients is associated with the subsequent development of metastatic disease. This raises the possibility of a functional role for this cell adhesion molecule in the metastatic spread it indicates.
Excellent Disease Control and Survival in Patients With Advanced Nasopharyngeal Cancer Treated With Chemoradiation
Authors: Rischin Danny , Corry June , Smith Jennifer , Stewart Josephine , Hughes Peter , Peters Lester
Published: July 2002

PURPOSE: To determine the efficacy and safety of epirubicin, cisplatin, and infusional fluorouracil (5-FU) chemotherapy followed by radiation with concurrent cisplatin in patients with locally and/or regionally advanced nasopharyngeal cancer.

PATIENTS AND METHODS: Thirty-five patients were treated with three cycles of induction chemotherapy with epirubicin 50 mg/m2 and cisplatin 75 mg/m2 combined with continuous-infusion 5-FU 200 mg/m2 daily for 9 weeks, followed by concurrent chemoradiation of 60 Gy in 2-Gy fractions with cisplatin 20 mg/m2 daily for 5 days in weeks 1 and 6.

RESULTS: Median age was 43 years, 74% had World Health Organization type III histology, and 91% had stage IV disease (International Union Against Cancer, ed 4). All patients received three cycles of induction chemotherapy, and 97% completed chemoradiation. The estimated 4-year progression-free survival rate was 81% (95% CI, 59% to 93%), and the estimated 4-year overall survival rate was 90% (95% CI, 74% to 97%). Only two patients have had a locoregional relapse by the close-out date despite the use of only 60 Gy. Induction chemotherapy was well tolerated, with 11% grade 3 or 4 stomatitis, 26% grade 3 vomiting, and no episodes of febrile neutropenia. Acute toxicities of chemoradiation were as follows: 23% grade 3 or 4 vomiting, 6% febrile neutropenia, 31% grade 3 mucositis, and 23% grade 3 skin toxicity. The most prevalent grade 3 late effects were xerostomia and hearing loss.

CONCLUSION: This regimen was well tolerated, can be delivered as planned, and has resulted in excellent locoregional disease control and survival in patients with locally advanced nasopharyngeal cancer.
Supply and Geographic Distribution of Geriatric Physicians and Geriatric Nurse Practitioners
Authors: Xue Ying , Poghosyan Lusine , Lin Qinyun
Published: November 2024

Importance

The rapidly growing population of older adults and their concomitant high prevalence of chronic health conditions require an increased supply in the specialized geriatric workforce to meet increasing health care demands. Understanding trends and geographic disparities in the supply of the geriatric workforce is essential for developing effective policies.

Objectives

To examine temporal and geographic trends in the supply of geriatric physicians (GMDs) and geriatric nurse practitioners (GNPs) from 2010 to 2020 and to assess potential disparities between metropolitan and nonmetropolitan counties.

Design, Setting, and Participants

This repeated cross-sectional study used annual county-level data from 2010 to 2020, encompassing all counties in the 50 US states and Washington, DC. Statistical analysis was performed from June 2023 to March 2024.

Main Outcomes and Measures

The primary outcomes were the numbers of GMDs, GNPs, and the combined number of GMDs and GNPs per 100 000 older adults. The secondary outcome included the proportion of counties with or without any GMDs or GNPs.

Results

From 2010 to 2020, the national per capita supply of GMDs decreased by 12.7%, from 13.4 per 100 000 older adults in 2010 to 11.7 per 100 000 older adults in 2020, while GNPs increased by 125.0%, from 4.4 per 100 000 older adults in 2010 to 9.9 per 100 000 older adults in 2020. The combined GMD and GNP workforce increased by 21.3%, from 17.8 per 100 000 older adults in 2010 to 21.6 per 100 000 older adults in 2020. The distributions of older adults, GMDs, and GNPs closely resembled the distribution of metropolitan and nonmetropolitan counties, with GMDs and GNPs highly concentrated in metropolitan counties where the number of older adults was greatest. Throughout the study period, 63.9% of counties (2008 of 3142 in 2010-2019; 2009 of 3143 in 2020), predominantly small and nonmetropolitan counties, had no GMDs or GNPs, which was associated with the disparities between metropolitan and nonmetropolitan counties.

Conclusions and Relevance

This repeated cross-sectional study found that from 2010 to 2020, the overall national supply of GMDs and GNPs kept pace with the growth of the older population, largely due to the rapid growth in the number of GNPs. However, significant geographic disparities persisted, particularly in small and nonmetropolitan counties. Future efforts should focus on increasing the availability of GMDs and GNPs in underserved small and nonmetropolitan counties to ensure equitable access to geriatric care.
FoxO1 signaling in B cell malignancies and its therapeutic targeting
Authors: Hlavac Krystof , Pavelkova Petra , Ondrisova Laura , Mraz Marek
Published: November 2024

FoxO transcription factors (FoxO1, FoxO3a, FoxO4, FoxO6) are a highly evolutionary conserved subfamily of the ‘forkhead’ box proteins. They have traditionally been considered tumor suppressors, but FoxO1 also exhibits oncogenic properties. The complex nature of FoxO1 is illustrated by its various roles in B cell development and differentiation, immunoglobulin gene rearrangement and cell‐surface B cell receptor (BCR) structure, DNA damage control, cell cycle regulation, and germinal center reaction. FoxO1 is tightly regulated at a transcriptional (STAT3, HEB, EBF, FoxOs) and post‐transcriptional level (Akt, AMPK, CDK2, GSK3, IKKs, JNK, MAPK/Erk, SGK1, miRNA). In B cell malignancies, recurrent FoxO1 activating mutations (S22/T24) and aberrant nuclear export and activity have been described, underscoring the potential of its therapeutic inhibition. Here, we review FoxO1's roles across B cell and myeloid malignancies, namely acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt lymphoma (BL), Hodgkin lymphoma (HL), and multiple myeloma (MM). We also discuss preclinical evidence for FoxO1 targeting by currently available inhibitors (AS1708727, AS1842856, cpd10).
Adenoviral delivery of the CIITA transgene induces T‐cell‐mediated killing in glioblastoma organoids
Authors: Salvato Ilaria , Klein Eliane , Poli Aurélie , Rezaeipour Mahsa , Ermini Luca , Nosirov Bakhtiyor , Lipsa Anuja , Oudin Anaïs , Baus Virginie , Dore Gian Mario , Cosma Antonio , Golebiewska Anna , Marchini Antonio , Niclou Simone P.
Published: November 2024

The immunosuppressive nature of the tumor microenvironment poses a significant challenge to effective immunotherapies against glioblastoma (GB). Boosting the immune response is critical for successful therapy. Here, we adopted a cancer gene therapy approach to induce T‐cell‐mediated killing of the tumor through increased activation of the immune system. Patient‐based three‐dimensional (3D) GB models were infected with a replication‐deficient adenovirus (AdV) armed with the class II major histocompatibility complex (MHC‐II) transactivator (CIITA) gene (Ad‐CIITA). Successful induction of surface MHC‐II was achieved in infected GB cell lines and primary human GB organoids. Infection with an AdV carrying a mutant form of CIITA with a single amino acid substitution resulted in cytoplasmic accumulation of CIITA without subsequent MHC‐II expression. Co‐culture of infected tumor cells with either peripheral blood mononuclear cells (PBMCs) or isolated T‐cells led to dramatic breakdown of GB organoids. Intriguingly, both wild‐type and mutant Ad‐CIITA, but not unarmed AdV, triggered immune‐mediated tumor cell death in the co‐culture system, suggesting an at least partially MHC‐II‐independent process. We further show that the observed cancer cell killing requires the presence of either CD8+ or CD4+ T‐cells and direct contact between GB and immune cells. We did not, however, detect evidence of activation of canonical T‐cell‐mediated cell death pathways. Although the precise mechanism remains to be determined, these findings highlight the potential of AdV‐mediated CIITA delivery to enhance T‐cell‐mediated immunity against GB.
Production and Forming of Deposition‐Welded Hybrid Multimaterial Shafts
Authors: Merkel Paulina , Budde Laura , Biester Kai , Faqiri Yusuf , Prasanthan Vannila , Herrmann Paul , Kriwall Mareile , Schwarz Nick , Hermsdorf Jörg , Stonis Malte , Breidenstein Bernd , Hassel Thomas , Overmeyer Ludger , Behrens Bernd‐Arno
Published: November 2024

The combination of several materials in one component can contribute to increased performance. Herein, three types of hybrid components are manufactured using two cladding processes and one joining process. The resulting workpieces are then formed and tested to determine the potential of the different material combinations. Two types of workpieces are produced to investigate multilayer claddings made of different materials, which serve to positively adjust the residual stress. The workpieces are tested using microstructural images and hardness measurements to characterize the microstructure and properties of the intermediate layers. In addition, residual stress measurements are carried out to determine the residual stress ratios. Compressive residual stresses are present in the subsurface of the welded and subsequently formed layer, which will improve the service life in case of rolling load conditions. The third type of workpiece is a combination of aluminum alloy and steel with a cladding layer that combines the performance of the cladding material in the bearing seat with the weight reduction of the aluminum alloy. Scanning Electron Microscopy (SEM) measurements are used to determine whether the application of the cladding has an influence on the intermetallic phase seam in the joining zone of aluminum alloy and steel.
Design Rules for 3D Printing‐Assisted Pressure Sensor Manufacturing: Achieving Broad Pressure Range Linearity
Authors: Baek Jinwook , Zhang Yuxuan , Qin Fei , Fu Xingyu , Kim Min‐Seok , Song Han‐Wook , Oh Jung‐Hyun , Kim Garam , Lee Sunghwan
Published: November 2024

Recent advancements in 3D printing technology have expanded its application to manufacturing pressure sensors. By harnessing the cost‐effectiveness, streamlined processes, and design flexibility of 3D printing, sensor fabrication can be customized to meet specific performance needs. Thus far, 3D printing in pressure sensor development has been primarily limited to creating molds for transferring patterns onto flexible substrates, restricting both material selection and sensor performance. To fully unlock the potential of 3D printing in advanced pressure sensor fabrication, it is crucial to establish effective design rules focused on enhancing the figure of merit performance. This study introduces a universal design strategy aimed at maintaining high sensitivity across a wide pressure range—a challenging feat, as sensitivity significantly decreases at higher pressures. Our approach centers on engineering the deformability of 3D‐printed structures, achieving a linear increase in contact area between sensor patterns and electrodes without reaching saturation. Sensors designed with high elongation and low stiffness exhibit consistent sensitivity of 162.5 kPa⁻¹ across a broad pressure range (0.05–300 kPa). Mechanistic investigations through finite element analysis confirm that engineered deformability is key to achieving this enhanced linear response, offering robust sensing capabilities for demanding applications such as deep‐sea and space exploration.
Picosecond Operation of Optoelectronic Hybrid Phase Change Memory Based on Si‐Doped Sb Films
Authors: Liu Qianchen , Wei Tao , Zheng Yonghui , Xuan Chuantao , Sun Lihao , Hu Jing , Cheng Miao , Liu Qianqian , Wang Ruirui , Li Wanfei , Cheng Yan , Liu Bo
Published: November 2024

Phase‐change random access memory is anticipated to break the bottleneck of the “storage wall” due to its advantages in simultaneous data storage and in‐memory computing. However, operation speed constrains its application scenarios. Antimony (Sb) thin film has ultrafast phase change speeds, low power consumption, and a straightforward chemical composition. In this study, silicon (Si) doping is employed to enhance the stability of pure Sb while achieving both ultrafast operational speeds and superior thermal stability concurrently. By utilizing optoelectronic hybrid phase change memory, the SET and RESET operation speeds can reach as fast as 26 and 13 ps, respectively, when using Si‐doped Sb films. The absence of the Si─Sb bond results in simple cubic nuclei within the amorphous film, which is posited as the structural basis for the high operational speed. These novel insights into ultrafast speed and phase mechanisms are poised to have valuable evidence for future high‐speed memory designs.
Polymeric Charge‐Transporting Materials for Inverted Perovskite Solar Cells
Authors: Hu Xiaodong , Wang Lingyuan , Luo Siwei , Yan He , Chen Shangshang
Published: November 2024

Inverted perovskite solar cells (PSCs) hold exceptional promise as next‐generation photovoltaic technology, where both perovskite absorbers and charge‐transporting materials (CTMs) play critical roles in cell performance. In recent years, polymeric CTMs have played an important role in developing efficient, stable, and large‐area inverted PSCs due to their unique properties of high conductivity, tunable structures, and mechanical flexibility. This review provides a comprehensive overview of polymeric CTMs used in inverted PSCs, encompassing polymeric hole transport materials (HTMs) and electron transport materials (ETMs). the relationship between their molecular structures, modification strategies are systematically summarized and analyzed for adjusting energy levels, and improving charge extraction, enabling a deep understanding of these widely used materials. The review also explores effective strategies for designing even more efficient polymeric CTMs. Finally, an outlook is proposed on the exciting research of novel polymeric CTMs, paving the way for their commercialized applications in PSCs.
PbSe Thermoelectrics: Efficient Candidates for Power Generation and Cooling
Authors: Liu Shibo , Qin Bingchao , Zhao Li‐Dong
Published: November 2024

Thermoelectric materials enable efficient and clean conversion between heat and electricity, offering significant application prospects in waste heat recovery and solid‐state cooling. Lead selenide (PbSe) is a more abundant and cost‐effective alternative to PbTe with promising potential for mid‐temperature applications. However, things have changed very recently with the discovery of the traditional power generator PbSe being rather competitive as a thermoelectric cooler, opening new avenues for investigating this compound. This review aims to comb how the research achievements and promising performance of PbSe have shifted from medium to near‐room temperatures, by comprehensively discussing various strategies to enhance the thermoelectric efficiency at different temperature ranges. Subsequently, it is reviewed how these advances in materials have triggered deep investigations on constructing high‐efficiency power generation and cooling devices based on PbSe. Finally, a personal summary and outlook are presented on how to fully exploit the high‐ranged thermoelectric performance of PbSe materials and manufacture high‐efficiency power generators and coolers, thus promoting practical applications in the future.
Hops bitter β‐acids have antibacterial effects against sinonasal Staphylococcus aureus but also induce sinonasal cilia and mitochondrial dysfunction
Authors: Kouakou Yobouet Ines , Thompson Joel C. , Tan Li Hui , Miller Zoey A. , Ma Ray Z. , Adappa Nithin D. , Palmer James N. , Cohen Noam A. , Lee Robert J.
Published: November 2024

Background

Routine prescription of antibiotics to treat chronic rhinosinusitis (CRS) exacerbations may contribute to the propagation of antibiotic resistance. Hops bitter β‐acids lupulone and colupulone possess potent antibacterial activities and, as T2R1, T2R14, and/or T2R40 agonists, may improve the impaired mucociliary clearance described in CRS patients. We investigated these molecules as alternative treatments to antibiotics in CRS management based on their antibacterial and T2Rs agonists properties.

Methods

Human nasal primary cells (HNECs) and RPMI2650 cells cultures were used as study models. T2Rs expression in cell culture models and human nasal tissue was assessed using immunofluorescence, quantitative PCR, and Western blot. We performed calcium imaging and cilia beat frequency experiments to investigate T2Rs activation in study models in response to lupulone and colupulone stimulations. Finally, we studied hops β‐acids cytotoxicity on cells using CellEvent, crystal violet, lactate dehydrogenase assays, immunofluorescence, and transepithelial electrical resistance assays.

Results

We confirmed lupulone and colupulone potent antibacterial effect on CRS‐relevant methicillin‐resistant Staphylococcus aureus but found minimal impact on P. aeruginosa. We also report T2R1, T2R14 and T2R40 expression in HNECs and RPMI2650 cell cultures. Lupulone and colupulone induced an increase in cytosolic calcium that appeared dependent on T2Rs signaling. This response was accompanied by mitochondrial membrane depolarization, cellular energy stress, decreased cell proliferation, ciliostasis, and HNECs remodeling after a single exposure to lupulone at micromolar concentrations.

Conclusion

Our data suggest that hops β‐acids may not be beneficial as treatments in CRS patients and instead contribute to the disease by impairing cell health and further deteriorating the MCC.
ChatGPT for complex text evaluation tasks
Authors: Thelwall Mike
Published: November 2024

ChatGPT and other large language models (LLMs) have been successful at natural and computer language processing tasks with varying degrees of complexity. This brief communication summarizes the lessons learned from a series of investigations into its use for the complex text analysis task of research quality evaluation. In summary, ChatGPT is very good at understanding and carrying out complex text processing tasks in the sense of producing plausible responses with minimum input from the researcher. Nevertheless, its outputs require systematic testing to assess their value because they can be misleading. In contrast to simple tasks, the outputs from complex tasks are highly varied and better results can be obtained by repeating the prompts multiple times in different sessions and averaging the ChatGPT outputs. Varying ChatGPT's configuration parameters from their defaults does not seem to be useful, except for the length of the output requested.
Progress and Strategies of MOFs in Catalyzing Conversion Processes in Lithium‐Sulfur Batteries
Authors: Wang Yaru , Rao Xingyou , Pan Zhengdao , Zhao Yan , Zheng Yalong , Luo Yichao , Jiang Xinyu , Wu Yutong , Liu Xiang , Wang Zhoulu , Zhang Yi
Published: November 2024

Lithium‐sulfur (Li−S) batteries have attracted considerable attention due to their advantages, such as high specific capacity, high energy density, environmental friendliness, and low cost. However, the severe capacity fading caused by shuttle effect of polysulfide needs to be addressed before the practical application of Li−S batteries. Crystalline porous materials including MOFs have generated great interest in energy storage fields especially batteries, because the ordered porous frameworks can offer a fast‐ionic transportation. Nevertheless, the intrinsic low conductivity of MOFs limits their rapid development in lithium‐sulfur batteries. This review mainly discusses the latest research progress on MOF main materials in Li−S batteries. The working principle of Li−S batteries and the classical “adsorption‐catalysis‐conversion” strategy are briefly introduced. Specifically, three modification methods (non‐metal atom doping, single‐atom, and dual‐atom doping modifications) applied in MOF‐based materials are analyzed and summarized, along with their respective mechanisms and advantages and disadvantages. Ligand doping is an effective strategy that can regulate the structure and properties of MOFs, thereby enhancing their catalytic activity and adsorption capacity towards polysulfides. Through ligand doping, key parameters such as the pore size, surface charge, and active site density of MOFs can be controlled, thereby influencing the adsorption and conversion of polysulfides on MOFs surfaces. Furthermore, crucial insights for the rational design of advanced MOF‐based materials for lithium‐sulfur batteries and the exploration of the main challenges and future directions for their application were also discussed.
A comparison of isolated limb infusion/perfusion, immune checkpoint inhibitors, and intralesional therapy as first‐line treatment for patients with melanoma in‐transit metastases
Authors: DePalo Danielle K. , Dugan Michelle M. , Naqvi Syeda Mahrukh Hussnain , Ollila David W. , Hieken Tina J. , Block Matthew S. , van Houdt Winan J. , Wouters Michel W. J. M. , Reijers Sophie J. M. , Asher Nethanel , Broman Kristy K. , Duncan Zoey , Anderson Matilda , Gyorki David E. , Snow Hayden , Held Jenny , Farma Jeffrey M. , Vetto John T. , Hui Jane Y. C. , Kolbow Madison , Saw Robyn P. M. , Lo Serigne N. , Long Georgina V. , Thompson John F. , Kim Youngchul , Karapetyan Lilit , Ny Lars , van Akkooi Alexander C. J. , Olofsson Bagge Roger , Zager Jonathan S.
Published: November 2024

Background

Isolated limb infusion and perfusion (ILI/ILP) has been a mainstay treatment for unresectable melanoma in‐transit metastases (ITM), but increased use of immune checkpoint inhibitors (ICI) and intralesional therapy (talimogene laherparepvec [TVEC]) introduced several different management options. This study compares first‐line ILI/ILP, ICI, and TVEC.

Methods

Retrospective review from 12 international institutions included patients treated from 1990 to 2022 with first‐line ILI/ILP, ICI, or TVEC for unresectable melanoma ITM.

Results

A total of 551 patients were treated, with ILI/ILP (n = 356), ICI (n = 125), and TVEC (n = 70) with median follow‐up of 5.5 years. Tumor burden was highest with ILI/ILP and lowest with TVEC (p = .002). Breslow thickness was lowest with TVEC (p = .007). TVEC was mostly used in stage IIIB disease versus IIIC for ILI/ILP and ICI (p = .01). Using ICI as the reference category, TVEC had the highest odds of a complete response (CR) (odds ratio, 1.96; p = .029) and a longer local progression‐free survival (PFS) (hazard ratio [HR], 0.40; p = .003). ILI/ILP had shorter local PFS (HR, 1.72; p = .012), PFS (HR, 1.79; p < .001), distant metastasis‐free survival (DMFS) (HR, 1.75; p = .014), overall survival (HR, 1.82; p = .009), and melanoma‐specific survival (HR, 2.29; p = .004). Stage IIIB disease had longer DMFS (HR, 0.24; p < .001) compared to IIIC/D.

Conclusions

TVEC as first‐line therapy for unresectable melanoma ITM was associated with superior CR rates and local PFS. Notably, TVEC was used in patients with a lower Breslow thickness, disease stage, and tumor burden. Therefore, when compared to ILI/ILP and ICI, TVEC should be considered as first‐line therapy for unresectable stage IIIB melanoma ITM with minimal tumor burden and lower Breslow thickness.
Targeting endoplasmic reticulum stress‐induced lymphatic dysfunction for mitigating bisphosphonate‐related osteonecrosis
Authors: Qin Ziyue , Xie Hanyu , Su Pengcheng , Song Zesheng , Xu Rongyao , Guo Songsong , Fu Yu , Zhang Ping , Jiang Hongbing
Published: November 2024

Background

Bisphosphonates (BPs) are the first‐line treatment to stop bone resorption in diseases, including osteoporosis, Paget's disease, multiple myeloma and bone metastases of cancer. However, BPs‐related osteonecrosis of the jaw (BRONJ), characterized by local inflammation and jawbone necrosis, is a severe intractable complication. The cumulative inflammatory burden often accompanies impaired lymphatic drainage, but its specific impact on BRONJ and the underlying mechanisms remain unclear.

Methods

The mouse BRONJ model was established to assess the integrity and drainage function of lymphatic vessels by tissue clearing techniques, injected indocyanine green lymphatic clearance assay, flow cytometry analysis and histopathological staining. RNA sequencing, metabolome analysis, transmission electron microscopy and Western blotting were utilized to analyze the impacts of Zoledronate acid (ZA) on endoplasmic reticulum stress (ERS) and function of lymphatic endothelial cells (LECs). By constructing Lyve1creERT; SIRT6f/f and Lyve1creERT; ATG5f/f mice, we evaluated the role of ERS‐induced LECs apoptosis in the progression of BRONJ. Additionally, we developed a nanoparticle‐loaded ZA and rapamycin (ZDPR) to enhance autophagy and evaluated its potential in mitigating BRONJ.

Results

The mouse BRONJ model displayed impaired lymphatic drainage, accompanied by significant local inflammation and bone necrosis. The prolonged stimulation of ZA resulted in the extension of ERS and the inhibition of autophagy in LECs, ultimately leading to apoptosis. Mechanistically, ZA activated XBP1s through the NAD+/SIRT6 pathway, initiating ERS‐induced apoptosis in LECs. The conditional knockout mouse models demonstrated that the deletion of SIRT6 or ATG5 significantly worsened lymphatic drainage and inflammatory infiltration in BRONJ. Additionally, the innovative nanoparticle ZDPR alleviated ERS‐apoptosis in LECs and enhanced lymphatic function, facilitating inflammation resolution.

Conclusion

Our study has elucidated the role of the NAD+/SIRT6/XBP1s pathway in ERS‐induced apoptosis in ZA‐treated LECs, and further confirmed the therapeutic potential of ZDPR in restoring endothelial function and improving lymphatic drainage, thereby effectively mitigating BRONJ.

Key points

Bisphosphonate‐induced lymphatic drainage impairment exacerbates bone necrosis.

Zoledronate acid triggers endoplasmic reticulum stress and apoptosis in lymphatic endothelial cells via the NAD+/SIRT6/XBP1s pathway.

Novel nanoparticle‐loaded Zoledronate acid and rapamycin enhances autophagy, restores lymphatic function, and mitigates bisphosphonates‐related osteonecrosis of the jaw progression.
The Prospect of Artificial Intelligence‐Supported Ethics Review
Authors: Nickel Philip J.
Published: November 2024

The burden of research ethics review falls not just on researchers, but also on those who serve on research ethics committees (RECs). With the advent of automated text analysis and generative artificial intelligence (AI), it has recently become possible to teach AI models to support human judgment, for example, by highlighting relevant parts of a text and suggesting actionable precedents and explanations. It is time to consider how such tools might be used to support ethics review and oversight. This essay argues that with a suitable strategy of engagement, AI can be used in a variety of ways that genuinely support RECs to manage their workload and improve the quality of review. It would be wiser to take an active role in the development of AI tools for ethics review, rather than to adopt ad hoc tools after the fact.
Effects of Controlling Assist Robots to Follow Lumbar Load on Muscle Fatigue
Authors: Yoshida Yusuke , Kamezaki Takashi , Kushida Daisuke
Published: November 2024

We developed an assist robot that changes its assist force in real time according to the lumbar load estimated from the load information on the hand measured using a hand sensor device and the posture information. Furthermore, using the developed assist robot, the effect of the load‐following control on muscle fatigue was verified. The load was set at 6 and 1 kgf, and the amount of muscle activity in the lumbar region was measured using a muscle potential sensor during continuous flexion–extension exercises. The central frequency of the power spectrum was calculated as muscle fatigue, and its time trend was obtained. For comparison, similar experiments were also conducted without an assistive robot and with an existing assistive robot. Consequently, when load‐following control was used, muscle fatigue was reduced compared with existing assist robots in which the assist force was excessive in relation to the load. This shows the importance of load‐following control that is necessary to control the assist force according to the load when the assist robot is worn during work in which the load changes in a complex manner.
Flow Resistance Coefficient Under Rigid Vegetation Coverage: An Experimental Study
Authors: Cai Zekang , Wang Jian , Xie Jiabo , Wang Chenfeng
Published: November 2024

Rigid vegetation is prevalent in the Loess Plateau region. Most simulation studies assume that vegetation grows perpendicularly to the slope surface (BS), overlooking the influence of growth perpendicular to the horizontal plane (BH) on the slope flow resistance coefficient. Therefore, this study explores the effects of rigid vegetation on the slope flow resistance coefficient by conducting indoor simulated scouring experiments under different vegetation coverage (0–15.89%), two growth directions (BS and BH), four slopes (5°, 10°, 15° and 20°), and five flow rates (5, 10, 20, 30 and 40 L·min−1). The results showed that the resistance coefficient increased non‐linearly with vegetation coverage; however, the growth rate slowed with increasing slope at high coverage, showing a decreasing trend. The resistance coefficient under BS conditions was generally higher than that under BH conditions. As the coverage increased (0–15.89%), the resistance coefficient under BS conditions became 1.51–1.99, 1.1–1.26 and 1.52–1.59 times that under BH conditions. The resistance coefficient ratio negatively correlated with the flow rate and water depth and positively with the slope. Furthermore, the relationship between the Reynolds number (Re) and resistance coefficient under BS and BH conditions significantly differed, with a negative correlation under BS conditions and a positive one under BH conditions. The Froude number (Fr) exhibited a strong negative correlation with the resistance coefficient, and the impact became more significant as vegetation coverage increased. Through dimensional analysis and nonlinear fitting, a high‐precision resistance coefficient prediction model (adjR2 = 0.98, NSE = 0.99, RRMSE = 0.04) was developed, which provided theoretical support for engineering designs and enhancing soil and water conservation strategies on the Loess Plateau.
A contemporary simple risk score for prediction of severe acute kidney injury after heart transplantation
Authors: Zhu Shuangshuang , Qiao Weihua , Wang Yixuan , Zhou Ying , Xu Yin , Wang Shijie , Xia Tian , Wang Guohua , Chen Si , Shi Jiawei , Dong Nianguo
Published: November 2024

Background

The aim of this study was to develop a simple risk score to estimate severe acute kidney injury (AKI) risk based on a large contemporary heart transplantation (HT) cohort.

Methods

From 1 January 2015 to 31 December 2021, all consecutive HT recipients in our institute were included and analysed for the occurrence of AKI within the first seven postoperative days. Patients transplanted between 2015 and 2019 comprised the derivation cohort, and those transplanted between 2020 and 2021 formed the validation cohort. The primary endpoint was severe AKI (AKI stages 2–3). The impact of severe AKI on 90 day mortality was also evaluated.

Results

Overall, 430 HT patients were included in the derivation cohort, and 108 were included in the validation cohort. Postoperative AKI occurred in 388 (72%) patients, including 162 (30%) severe AKI. The risk of 90 day mortality significantly increased in patients with severe‐AKI. Seven independent predictors of severe AKI were found in the derivation cohort, including recipients' body mass index, history of diabetes, anaemia, preoperative inotropes, estimated glomerular filtration rate, cardiopulmonary bypass duration and intraoperative red blood cell transfusion. The occurrence of severe AKI increased gradually from the lowest to the highest of the four risk score groups in the derivation and validation cohort. The scoring prediction model showed a highly acceptable discriminating power for severe‐AKI [C statistic: 0.76, 95% confidence interval (CI): 0.71–0.80 for derivation cohort; C statistic: 0.79, 95% CI: 0.71–0.89 for validation cohort].

Conclusions

A contemporary simple risk score based on available variables from patients undergoing HT can accurately discriminate the risk of severe AKI.
Empowering Women to Lead Cybersecurity: The Effect of Female Executives on Disclosure Sentiment
Authors: Elnahass Marwa , Ahmed Yousry , Trinh Vu Quang
Published: November 2024

This study investigates the impact of gender diversity (i.e., the presence of female executives on corporate boards) on the sentiment of cybersecurity information disclosure, including its likelihood, magnitude, and tone. We develop a unique dataset providing an extensive view of the development and evolution of cybersecurity‐related disclosure practices among prominent publicly traded US companies over a 19‐year period (2002–2020). We find strong evidence that female executives are more likely to disclose, and they report significantly more cybersecurity‐related information compared to their male counterparts. Additionally, female executives adopt a more conservative, uncertain, and litigious tone in their cybersecurity disclosures than male executives. The results also support the notion of a critical mass of female executives on the board and align with various theories, emphasising the importance of gender diversity in promoting high‐quality cybersecurity disclosure practices within firms. Furthermore, we examine several channels contributing to the heterogeneity of cybersecurity disclosures between female and male executives, and consider the effects of the black swan events (i.e., the financial crisis and the COVID‐19 pandemic).