Publications by authors named "Fansen Ji"

4 Publications

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Knockout of immunotherapy prognostic marker genes eliminates the effect of the anti-PD-1 treatment.

NPJ Precis Oncol 2021 May 7;5(1):37. Epub 2021 May 7.

Department of Basic Medical Science, School of Medicine, Tsinghua University, Beijing, China.

The efficacy of immunotherapy is largely patient-specific due to heterogeneity in tumors. Combining statistic power from a variety of immunotherapies across cancer types, we found four biological pathways significantly correlated with patient survival following immunotherapy. The expression of immunotherapy prognostic marker genes (IPMGs) in these pathways can predict the patient survival with high accuracy not only in the TCGA cohort (89.36%) but also in two other independent cohorts (80.91%), highlighting that the activity of the IPMGs can reflect the sensitivity of the tumor immune microenvironment (TIME) to immunotherapies. Using mouse models, we show that knockout of one of the IPMGs, MALT1, which is critical for the T-cell receptor signaling, can eliminate the antitumor effect of anti-PD-1 treatment completely by impairing the activation of CD8 T cells. Notably, knockout of another IPMG, CLEC4D, a C-type lectin receptor that expressed on myeloid cells, also reduced the effect of anti-PD-1 treatment potentially through maintaining the immunosuppressive effects of myeloid cells. Our results suggest that priming TIME via activating the IPMGs may increase the response rate and the effect of immune checkpoint blockers.
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http://dx.doi.org/10.1038/s41698-021-00175-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105367PMC
May 2021

Functional and genetic analysis of viral receptor ACE2 orthologs reveals a broad potential host range of SARS-CoV-2.

Proc Natl Acad Sci U S A 2021 03;118(12)

Center for Infectious Disease Research, School of Medicine, Tsinghua University, 100084 Beijing, China;

The pandemic of COVID-19, caused by SARS-CoV-2, is a major global health threat. Epidemiological studies suggest that bats () are the natural zoonotic reservoir for SARS-CoV-2. However, the host range of SARS-CoV-2 and intermediate hosts that facilitate its transmission to humans remain unknown. The interaction of coronavirus with its host receptor is a key genetic determinant of host range and cross-species transmission. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as the receptor to enter host cells in a species-dependent manner. In this study, we characterized the ability of ACE2 from diverse species to support viral entry. By analyzing the conservation of five residues in two virus-binding hotspots of ACE2 (hotspot 31Lys and hotspot 353Lys), we predicted 80 ACE2 proteins from mammals that could potentially mediate SARS-CoV-2 entry. We chose 48 ACE2 orthologs among them for functional analysis, and showed that 44 of these orthologs-including domestic animals, pets, livestock, and animals commonly found in zoos and aquaria-could bind the SARS-CoV-2 spike protein and support viral entry. In contrast, New World monkey ACE2 orthologs could not bind the SARS-CoV-2 spike protein and support viral entry. We further identified the genetic determinant of New World monkey ACE2 that restricts viral entry using genetic and functional analyses. These findings highlight a potentially broad host tropism of SARS-CoV-2 and suggest that SARS-CoV-2 might be distributed much more widely than previously recognized, underscoring the necessity to monitor susceptible hosts to prevent future outbreaks.
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http://dx.doi.org/10.1073/pnas.2025373118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000431PMC
March 2021

Hypervirulent is emerging as an increasingly prevalent pathotype responsible for nosocomial and healthcare-associated infections in Beijing, China.

Virulence 2020 12;11(1):1215-1224

Department of Pulmonary and Critical Care Medicine, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University , Beijing, China.

Objectives: Hypervirulent Klebsiella pneumoniae(hvKp) is an increasingly important pathogen. Tracking its epidemiology and evolving antimicrobial resistance will facilitate care.

Methods: A retrospective study was conducted in two hospitals. We collected the clinical data. Antimicrobial and virulence-associated phenotype and genotype, sequence type, and whole genome sequencing of selected strains were performed. HvKp was defined by the presence of some combination of rmpA, rmpA2, iucA, iroB, and peg-344, genes shown to accurately identify hvKp.

Results: Of 158 Kp clinical isolates, 79 (50%) were hvKp. Interestingly, 53/79 (67.1%) of hvKp strains were isolated from patients with nosocomial infection and 19/79 (24.1%) from patients with healthcare-associated infection, but only 7/79 (8.8%) from patients with community-acquired infections. Importantly, 27/53 (50.9%) and 4/19 (21.1%) of hvKp nosocomial and healthcare-associated isolates, respectively, were multi-drug-resistant (MDR); 25/53 (47.2%) and 5/19 (26.3%) expressed ESBLs and 14/53 (26.4%) and 2/19 (10.5%) were carbapenem-resistant. Of the hvKp isolates from community-acquired infection, 0/7 (0%) were MDR and 0/7 (0%) were carbapenem-resistant. Additionally, unique characteristics of nosocomial, healthcare-associated, and community-acquired hvKp infection were identified. In summary, 50% of K. pneumoniae infections were caused by hvKp. A concerning, novel finding from this report is a major shift in hvKp epidemiology. Ninety-one percent of hvKp infections were nosocomial or healthcare-associated, and 43.1% of these isolates were MDR.

Conclusions: These data suggest that hvKp may be replacing classical K. pneumoniae as the dominant nosocomial and healthcare-associated pathotype. Ongoing surveillance is needed to determine if this trend is occurring elsewhere.
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http://dx.doi.org/10.1080/21505594.2020.1809322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549996PMC
December 2020

p53-mediated control of aspartate-asparagine homeostasis dictates LKB1 activity and modulates cell survival.

Nat Commun 2020 04 9;11(1):1755. Epub 2020 Apr 9.

Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, 100084, Beijing, China.

Asparagine synthetase (ASNS) catalyses the ATP-dependent conversion of aspartate to asparagine. However, both the regulation and biological functions of asparagine in tumour cells remain largely unknown. Here, we report that p53 suppresses asparagine synthesis through the transcriptional downregulation of ASNS expression and disrupts asparagine-aspartate homeostasis, leading to lymphoma and colon tumour growth inhibition in vivo and in vitro. Moreover, the removal of asparagine from culture medium or the inhibition of ASNS impairs cell proliferation and induces p53/p21-dependent senescence and cell cycle arrest. Mechanistically, asparagine and aspartate regulate AMPK-mediated p53 activation by physically binding to LKB1 and oppositely modulating LKB1 activity. Thus, we found that p53 regulates asparagine metabolism and dictates cell survival by generating an auto-amplification loop via asparagine-aspartate-mediated LKB1-AMPK signalling. Our findings highlight a role for LKB1 in sensing asparagine and aspartate and connect asparagine metabolism to the cellular signalling transduction network that modulates cell survival.
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http://dx.doi.org/10.1038/s41467-020-15573-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145870PMC
April 2020