Although polycrystalline hexagonal boron nitride (PC-hBN) has been realized, defects and grain boundaries still cause charge scatterings and trap sites, impeding high-performance electronics. Here, ...we report a method of synthesizing wafer-scale single-crystalline hBN (SC-hBN) monolayer films by chemical vapor deposition. The limited solubility of boron (B) and nitrogen (N) atoms in liquid gold promotes high diffusion of adatoms on the surface of liquid at high temperature to provoke the circular hBN grains. These further evolve into closely packed unimodal grains by means of self-collimation of B and N edges inherited by electrostatic interaction between grains, eventually forming an SC-hBN film on a wafer scale. This SC-hBN film also allows for the synthesis of wafer-scale graphene/hBN heterostructure and single-crystalline tungsten disulfide.
Cyclin‐dependent kinase 12 (CDK12) has emerged as an effective therapeutic target due to its ability to regulate DNA damage repair in human cancers, but little is known about the role of CDK12 in ...driving tumorigenesis. Here, we demonstrate that CDK12 promotes tumor initiation as a novel regulator of cancer stem cells (CSCs) and induces anti‐HER2 therapy resistance in human breast cancer. High CDK12 expression caused by concurrent amplification of CDK12 and HER2 in breast cancer patients is associated with disease recurrence and poor survival. CDK12 induces self‐renewal of breast CSCs and in vivo tumor‐initiating ability, and also reduces susceptibility to trastuzumab. Furthermore, CDK12 kinase activity inhibition facilitates anticancer efficacy of trastuzumab in HER2+ tumors, and mice bearing trastuzumab‐resistant HER2+ tumor show sensitivity to an inhibitor of CDK12. Mechanistically, the catalytic activity of CDK12 is required for the expression of genes involved in the activation of ErbB‐PI3K‐AKT or WNT‐signaling cascades. These results suggest that CDK12 is a major oncogenic driver and an actionable target for HER2+ breast cancer to replace or augment current anti‐HER2 therapies.
Synopsis
CDK12, a RNA polymerase II kinase, promotes breast cancer stem cell‐like properties mediated by WNT and ErbB‐PI3K signaling. Targeting CDK12 improves trastuzumab therapy in breast cancers characterised by HER2/CDK12 co‐amplification.
CDK12 amplification induces tumor initiation and progression, and mediates trastuzumab resistance.
CDK12 is required for transcriptional upregulation of genes involved in ErbB‐PI3K and WNT pathway activation.
CDK12 inhibition alone or in combination with trastuzumab therapy has anti‐tumor activity against HER2+ breast cancers.
CDK12, a RNA polymerase II kinase, promotes breast cancer stem cell‐like properties mediated by WNT and ErbB‐PI3K signaling. Targeting CDK12 improves trastuzumab therapy in breast cancers characterised by HER2/CDK12 co‐amplification.
Supercapacitors are one of the key devices for energy‐storage applications. They have energy densities much higher than those of conventional capacitors and possess much better power delivery ...capabilities than batteries. This makes them unique devices that can outperform both batteries and conventional capacitors under special circumstances. Nanocarbons are the main electrode materials for supercapacitors. Abundant sources of nanocarbons and facile processes of modification have led to the fabrication of cheap electrodes. In this review, we focus on the capacitance performance of highly porous activated carbons and attempt to determine the role of different pores. Elaborate discussions are presented on individual contributions from micro‐ and mesopores and their mutual dependence. This article also presents a comparative performance report for both random and ordered porous nanocarbons. Novel carbon materials, such as carbon nanotubes and graphene, and their contributions in this context are discussed. We summarize key techniques for the functionalization of nanocarbons and their pseudocapacitive charge‐storage mechanisms. Nanocarbon composites with redox‐active transition‐metal oxides and conducting polymers are highlighted along with their impact as electrode materials. Ideal composite structures are highlighted and an attempt is made to determine an ideal future electrode structure for capacitors with high energy and power density.
Super power! The capacitance performance of highly porous activated carbons is described and the elucidation of the role of different pores is attempted (see picture). Elaborate discussions are also presented on the individual contributions from micro‐ and mesopores and their mutual dependence. An ideal electrode can be realized when a charge transportation pathway is obtained through the mesopores that channel ions to the micropores available on the surface.
The interaction between tumor and the immune system is still poorly understood. Significant clinical responses have been achieved in cancer patients treated with antibodies against the CTLA4 and ...PD-1/PD-L1 checkpoints; however, only a small portion of patients responded to the therapies, indicating a need to explore additional co-inhibitory molecules for cancer treatment. B7-H3, a member of the B7 superfamily, was previously shown by us to inhibit T-cell activation and autoimmunity. In this study, we have analyzed the function of BT-H3 in tumor immunity. Expression of B7-H3 was found in multiple tumor lines, tumor-infiltrating dendritic cells, and macrophages. B7-H3-deficient mice or mice treated with an antagonistic antibody to B7-H3 showed reduced growth of multiple tumors, which depended on NK and CD8^＋ T cells. With a putative receptor expressed by cytotoxic lymphocytes, B7-H3 inhibited their activation, and its deficiency resulted in increased cytotoxic lymphocyte function in tumor-bearing mice. Combining blockades of B7-H3 and PD-1 resulted in further enhanced therapeutic control of late-stage tumors. Taken together, our results indicate that the B7-H3 checkpoint may serve as a novel target for immunotherapy against cancer.
Respiratory diseases contribute to global morbidity and mortality, and temperature is a significant factor. We investigated the association between ambient temperature and emergency department (ED) ...visits for various respiratory diseases in Seoul, South Korea.
Using data from the National Emergency Department Information System (2008-2017), we analysed 1,616,644 ED visits for respiratory diseases, categorised according to the Korean Standard Classification of Diseases 7th revision codes (J00-J99). Using a time-stratified case-crossover design and a distributed lag nonlinear model, we investigated the effect of temperature exposure on ED visits for respiratory diseases, calculating the relative risk (RR) for the maximum risk temperature (MaxRT) of both cold and hot extremes compared to the minimum risk temperature (MinRT).
Cold temperatures (MaxRT: -9.0 °C) resulted in a 2.68-fold increase (RR = 2.68, 95% CI = 2.26-3.14) in ED visits for total respiratory diseases, while hot temperatures (MaxRT: 29.4 °C) led to a 1.26-fold increase (RR = 1.26, 95% CI = 1.11-1.42) compared to the MinRT (24.8 °C). Cold temperatures increased the risk of most respiratory diseases, except interstitial lung disease, whereas hot temperatures increased ED visits for acute upper respiratory infections and influenza. Cold temperatures increased ED visits for all age groups, especially those aged 18-64 (RR = 3.54, 95% CI = 2.90-4.33), while hot temperatures significantly affected those < 18 (RR = 1.45, 95% CI = 1.27-1.66). The risk levels were similar in both males and females, regardless of hot and cold temperatures.
Our findings underscore the significant impact of both cold and heat exposure on ED visits for respiratory diseases, with varying intensities and risk profiles across different population groups.
Medical education must adapt to different health care contexts, including digitalized health care systems and a digital generation of students in a hyper-connected world. The aims of this study are ...to identify and synthesize the values that medical educators need to implement in the curricula and to introduce representative educational programs.
An integrative review was conducted to combine data from various research designs. We searched for articles on PubMed, Scopus, Web of Science, and EBSCO ERIC between 2011 and 2017. Key search terms were "undergraduate medical education," "future," "twenty-first century," "millennium," "curriculum," "teaching," "learning," and "assessment." We screened and extracted them according to inclusion and exclusion criteria from titles and abstracts. All authors read the full texts and discussed them to reach a consensus about the themes and subthemes. Data appraisal was performed using a modified Hawker 's evaluation form.
Among the 7616 abstracts initially identified, 28 full-text articles were selected to reflect medical education trends and suggest suitable educational programs. The integrative themes and subthemes of future medical education are as follows: 1) a humanistic approach to patient safety that involves encouraging humanistic doctors and facilitating collaboration; 2) early experience and longitudinal integration by early exposure to patient-oriented integration and longitudinal integrated clerkships; 3) going beyond hospitals toward society by responding to changing community needs and showing respect for diversity; and 4) student-driven learning with advanced technology through active learning with individualization, social interaction, and resource accessibility.
This review integrated the trends in undergraduate medical education in readiness for the anticipated changes in medical environments. The detailed programs introduced in this study could be useful for medical educators in the development of curricula. Further research is required to integrate the educational trends into graduate and continuing medical education, and to investigate the status or effects of innovative educational programs in each medical school or environment.
Glioblastoma (GBM), the most severe and common brain tumor in adults, is characterized by multiple somatic mutations and aberrant activation of inflammatory responses. Immune cell infiltration and ...subsequent inflammation cause tumor growth and resistance to therapy. Somatic loss-of-function mutations in the gene encoding tumor suppressor protein p53 (TP53) are frequently observed in various cancers. However, numerous studies suggest that TP53 regulates malignant phenotypes by gain-of-function (GOF) mutations. Here we demonstrate that a TP53 GOF mutation promotes inflammation in GBM. Ectopic expression of a TP53 GOF mutant induced transcriptomic changes, which resulted in enrichment of gene signatures related to inflammation and chemotaxis. Bioinformatics analyses revealed that a gene signature, upregulated by the TP53 GOF mutation, is associated with progression and shorter overall survival in GBM. We also observed significant correlations between the TP53 GOF mutation signature and inflammation in the clinical database of GBM and other cancers. The TP53 GOF mutant showed upregulated C-C motif chemokine ligand 2 (CCL2) and tumor necrosis factor alpha (TNFA) expression via nuclear factor kappa B (NFκB) signaling, consequently increasing microglia and monocyte-derived immune cell infiltration. Additionally, TP53 GOF mutation and CCL2 and TNFA expression correlated positively with tumor-associated immunity in patients with GBM. Taken together, our findings suggest that the TP53 GOF mutation plays a crucial role in inflammatory responses, thereby deteriorating prognostic outcomes in patients with GBM.
Psoriasis is a chronic autoinflammatory skin disease. Although interleukin-17, derived from lymphocytes, has been shown to be critical in psoriasis, the initiation and maintenance of chronic skin ...inflammation has not been well understood. IL-25 (also called IL-17E), another IL-17 family cytokine, is well known to regulate allergic responses and type 2 immunity. Here we have shown that IL-25, also highly expressed in the lesional skin of psoriasis patients, was regulated by IL-17 in murine skin of a imiquimod (IMQ)-induced psoriasis model. IL-25 injection induced skin inflammation, whereas germline or keratinocyte-specific deletion of IL-25 caused resistance to IMQ-induced psoriasis. Via IL-17RB expression in keratinocytes, IL-25 stimulated the proliferation of keratinocytes and induced the production of inflammatory cytokines and chemokines, via activation of the STAT3 transcription factor. Thus, our data demonstrate that an IL-17-induced autoregulatory circuit in keratinocytes is mediated by IL-25 and suggest that this circuit could be targeted in the treatment of psoriasis patients.
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•IL-25 is highly expressed in psoriasis•IL-25 treatment induces psoriasis-like skin inflammation•IL-25 in keratinocytes is necessary for psoriasis-like skin inflammation•IL-25 promotes keratinocyte proliferation and pro-inflammatory response
The inflammatory mechanism of psoriasis remains incompletely understood. In this issue, Xu et al. identified IL-25 as a key pathogenic factor regulating the proliferation of keratinocytes and psoriasis development in an autocrine expression manner.
Advances in semiconductor device during last few decades enable us to improve the electronic device performance by minimizing the device dimension. However, further development of these systems ...encounters scientific and technological limits and forces us to explore better alternatives. Low‐dimensional carbon allotropes such as carbon nanotube and graphene exhibit superior electronic, optoelectronic, and mechanical properties compared to the conventional semiconductors. This Feature Article reviews the recent progresses of carbon nanotubes and graphene researches and compares their electronic properties and electric device performances. A particular focus is the comparison of the characteristics in transparent conducting films (transparency and sheet resistance) and field‐effect transistors (FETs) (device types, ambipolarity, mobility, doping strategy, FET‐performance, logic and memory operations). Finally, the performance of devices that combine graphene and carbon nanotubes is also highlighted.
Graphene and CNT exhibit excellent electronic and optoelectronic properties. This Feature Article reviews the recent progresses of carbon nanotubes and graphene research and compares their electronic and optoelectronic properties and device performances, such as transparent conducting films (transparency and sheet resistance) and field‐effect transistors (FETs) (device types, ambipolarity, mobility, doping strategy, FET‐performance, logic and memory operations), in detail.
A MoSe2 p–n diode with a van der Waals homojunction is demonstrated by stacking undoped (n‐type) and Nb‐doped (p‐type) semiconducting MoSe2 synthesized by chemical vapor transport for Nb ...substitutional doping. The p–n diode reveals an ideality factor of ≈1.0 and a high external quantum efficiency (≈52%), which increases in response to light intensity due to the negligible recombination rate at the clean homojunction interface.
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