Super-enhancer-controlled positive feedback loop BRD4/ERα-RET-ERα promotes ERα-positive breast cancer.

Estrogen and estrogen receptor alpha (ERα)-induced gene transcription is tightly associated with ERα-positive breast carcinogenesis. ERα-occupied enhancers, particularly super-enhancers, have been suggested to play a vital role in regulating such transcriptional events. However, the landscape of ERα-occupied super-enhancers (ERSEs) as well as key ERα-induced target genes associated with ERSEs remain to be fully characterized. Here, we defined the landscape of ERSEs in ERα-positive breast cancer cell lines, and demonstrated that bromodomain protein BRD4 is a master regulator of the transcriptional activation of ERSEs and cognate ERα target genes. RET, a member of the tyrosine protein kinase family of proteins, was identified to be a key ERα target gene of BRD4-regulated ERSEs, which, in turn, is vital for ERα-induced gene transcriptional activation and malignant phenotypes through activating the RAS/RAF/MEK2/ERK/p90RSK/ERα phosphorylation cascade. Combination therapy with BRD4 and RET inhibitors exhibited additive effects on suppressing ERα-positive breast cancer both in vitro and in vivo, comparable with that of standard endocrine therapy tamoxifen. Furthermore, combination therapy re-sensitized a tamoxifen-resistant ERα-positive breast cancer cell line to tamoxifen treatment. Taken together, our data uncovered the critical role of a super-enhancer-associated positive feedback loop constituting BRD4/ERα-RET-ERα in ERα-positive breast cancer, and suggested that targeting components in this loop would provide a new therapeutic avenue for treating ERα-positive breast cancer in the clinic.

BRD4 inhibition boosts the therapeutic effects of epidermal growth factor receptor-targeted chimeric antigen receptor T cells in glioblastoma.

Glioblastoma (GBM) is the deadliest brain malignancy without effective treatments. Here, we reported that epidermal growth factor receptor-targeted chimeric antigen receptor T cells (EGFR CAR-T) were effective in suppressing the growth of GBM cells in vitro and xenografts derived from GBM cell lines and patients in mice. However, mice soon acquired resistance to EGFR CAR-T cell treatment, limiting its potential use in the clinic. To find ways to improve the efficacy of EGFR CAR-T cells, we performed genomics and transcriptomics analysis for GBM cells incubated with EGFR CAR-T cells and found that a large cohort of genes, including immunosuppressive genes, as well as enhancers in vicinity are activated. BRD4, an epigenetic modulator functioning on both promoters and enhancers, was required for the activation of these immunosuppressive genes. Accordingly, inhibition of BRD4 by JQ1 blocked the activation of these immunosuppressive genes. Combination therapy with EGFR CAR-T cells and JQ1 suppressed the growth and metastasis of GBM cells and prolonged survival in mice. We demonstrated that transcriptional modulation by targeting epigenetic regulators could improve the efficacy of immunotherapy including CAR-T, providing a therapeutic avenue for treating GBM in the clinic.

Clinical characteristics and epidemiological significance of coronavirus disease 2019 in children and adolescents. / 儿童和青少年2019å† çŠ¶ç— æ¯’ç— çš„ä¸´åºŠè¡¨çŽ°åŠæµè¡Œç— å­¦æ„ä¹‰.

The epidemic of coronavirus disease 2019 (COVID-19) started in late December 2019, and spread rapidly throughout the world. In March 2020, the World Health Organization (WHO) declared global epidemic of COVID-19. According to the American Academy of Pediatrics, nearly 13 million children have been diagnosed with COVID-19 since the outbreak. In general, children and teens have milder symptoms and fewer deaths from COVID-19 than adults. Understanding the symptoms, infectivity, and transmission patterns of COVID-19 in children and adolescents is of great significance for timely identifying suspected patients and developing effective control measures. Considering that some children will not be vaccinated for quite some time in the future, it is more important to improve the understanding of the clinical and epidemiological significance of COVID-19 in children and adolescents. This article summarizes the current understanding of the clinical manifestations and epidemiological significance of COVID-19 in children and adolescents to provide a reference for clinical diagnosis and treatment and the formulation of epidemic prevention and control strategies in children's gathering institutions such as kindergartens and schools.

[Clinical features and epidemiological significance of pertussis in infants]. / å©´å„¿ç™¾æ—¥å’³çš„æµè¡Œç— å­¦æ„ä¹‰åŠå ¶ä¸´åºŠç‰¹ç‚¹.

Infantile pertussis is clear evidence for the persistent transmission of pertussis in communities. Infants are the most vulnerable population for pertussis infection and are also important nodes in pertussis transmission networks in communities, and therefore, the prevention of infantile pertussis is the core of prevention and control measures against pertussis including vaccine immunization. Although the cases of pertussis reported in China are mainly infants with pertussis, the actual number of infants with pertussis might be higher than the reported number. It is necessary in clinical practice to improve the awareness of this disease and promote related laboratory tests. On the basis of emphasizing the identification of pertussis in infants, timely diagnosis and treatment, follow-up visits, and standard management of the close contacts of infants with pertussis should be performed to reduce and block the community transmission of pertussis.

[Diagnosis and treatment of human monkeypox]. / 人感染猴痘的诊断和治疗.

The guideline for the diagnosis and treatment of monkeypox (2022 edition) issued by National Health Commission of the People's Republic of China introduces the key knowledge of the diagnosis and treatment of human monkeypox (HMPX) and does not systematically introduce the sampling methods and requirements of specimens for HMPX etiology testing and the discrepancy in diagnostic criteria between China and overseas. However, the doctors who are not engaged in dermatology lack understanding of the sampling methods and requirements of specimens for laboratory diagnosis of HMPX, and there are few relevant references available. This article collects the information on the diagnosis and treatment of HMPX, so as to provide a reference for learning, understanding, and application of this guideline.

Method for automatically identifying spectra of different wood cell wall layers in Raman imaging data set.

The technique of Raman spectroscopic imaging is finding ever-increasing applications in the field of wood science for its ability to provide spatial and spectral information about the sample. On the basis of the acquired Raman imaging data set, it is possible to determine the distribution of chemical components in various wood cell wall layers. However, the Raman imaging data set often contains thousands of spectra measured at hundreds or even thousands of individual frequencies, which results in difficulties accurately and quickly extracting all of the spectra within a specific morphological region of wood cell walls. To address this issue, the authors propose a new method to automatically identify Raman spectra of different cell wall layers on the basis of principal component analysis (PCA) and cluster analysis. A Raman imaging data set collected from a 55.5 µm × 47.5 µm cross-section of poplar tension wood was analyzed. Several thousand spectra were successfully classified into five groups in accordance with different morphological regions, namely, cell corner (CC), compound middle lamella (CML), secondary wall (SW), gelatinous layer (G-layer), and cell lumen. Their corresponding average spectra were also calculated. In addition, the relationship between different characteristic peaks in the obtained Raman spectra was estimated and it was found that the peak at 1331 cm(-1) is more related to lignin rather than cellulose. Not only can this novel method provide a convenient and accurate procedure for identifying the spectra of different cell wall layers in a Raman imaging data set, but it also can bring new insights into studying the morphology and topochemistry in wood cell walls.

A SARS-CoV-2-specific CAR-T-cell model identifies felodipine, fasudil, imatinib, and caspofungin as potential treatments for lethal COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced cytokine storm is closely associated with coronavirus disease 2019 (COVID-19) severity and lethality. However, drugs that are effective against inflammation to treat lethal COVID-19 are still urgently needed. Here, we constructed a SARS-CoV-2 spike protein-specific CAR, and human T cells infected with this CAR (SARS-CoV-2-S CAR-T) and stimulated with spike protein mimicked the T-cell responses seen in COVID-19 patients, causing cytokine storm and displaying a distinct memory, exhausted, and regulatory T-cell phenotype. THP1 remarkably augmented cytokine release in SARS-CoV-2-S CAR-T cells when they were in coculture. Based on this "two-cell" (CAR-T and THP1 cells) model, we screened an FDA-approved drug library and found that felodipine, fasudil, imatinib, and caspofungin were effective in suppressing the release of cytokines, which was likely due to their ability to suppress the NF-κB pathway in vitro. Felodipine, fasudil, imatinib, and caspofungin were further demonstrated, although to different extents, to attenuate lethal inflammation, ameliorate severe pneumonia, and prevent mortality in a SARS-CoV-2-infected Syrian hamster model, which were also linked to their suppressive role in inflammation. In summary, we established a SARS-CoV-2-specific CAR-T-cell model that can be utilized as a tool for anti-inflammatory drug screening in a fast and high-throughput manner. The drugs identified herein have great potential for early treatment to prevent COVID-19 patients from cytokine storm-induced lethality in the clinic because they are safe, inexpensive, and easily accessible for immediate use in most countries.

Targeting Triple-Negative Breast Cancer with Combination Therapy of EGFR CAR T Cells and CDK7 Inhibition.

EGFR-targeted chimeric antigen receptor (CAR) T cells are potent and specific in suppressing the growth of triple-negative breast cancer (TNBC) in vitro and in vivo. However, in this study, a subset of mice soon acquired resistance, which limits the potential use of EGFR CAR T cells. We aimed to find a way to overcome the observed resistance. Transcriptomic analysis results revealed that EGFR CAR T-cell treatment induced a set of immunosuppressive genes, presumably through IFNγ signaling, in EGFR CAR T-cell-resistant TNBC tumors. The EGFR CAR T-cell-induced immunosuppressive genes were associated with EGFR CAR T-cell-activated enhancers and were especially sensitive to THZ1, a CDK7 inhibitor we screened out of a panel of small molecules targeting epigenetic modulators. Accordingly, combination therapy with THZ1 and EGFR CAR T cells suppressed immune resistance, tumor growth, and metastasis in TNBC tumor models, including human MDA-MB-231 cell-derived and TNBC patient-derived xenografts, and mouse EMT6 cell-derived allografts. Taken together, we demonstrated that transcriptional modulation using epigenetic inhibitors could overcome CAR T-cell therapy-induced immune resistance, thus providing a therapeutic avenue for treating TNBC in the clinic.