Acute promyelocytic leukemia (APL) was historically regarded as the most aggressive subtype of acute leukemia due to its high early mortality rate. The transformation in APL treatment represents a milestone in targeted cancer therapy. The discovery and clinical application of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) have dramatically improved the prognosis of APL, increasing the 5-year overall survival rate from less than 35% to over 90%. Chinese hematology/oncology community have made significant contributions to this transformation: Professor Wang Zhenyi's group pioneered ATRA-induced differentiation therapy, while Professor Zhang Tingdong's group verified the clinical efficacy of ATO. The research team of Shanghai Institute of Hematology (SIH) cloned the PML::RARA fusion gene resulting from the chromosomal translocation (15;17) and the first variant PLZF::RARA fusion gene. Based on the characterization of the leukogenesis at molecular and cellular levels and the mechanisms of action of effective drugs, the SIH team established a synergistic targeted therapy protocol for newly diagnosed APL patients, achieving a disease-free survival rate of 95.7% in a nationwide multi-center clinical trial. Subsequently, several teams explored the use of oral arsenic (Realgar-Indigo naturalis formula or oral ATO solution) combined with ATRA to treat APL, which is of high cost-effectiveness and can be promoted in resource-restricted regions. This review systematically summarizes the key therapeutic breakthroughs in APL, elucidates the underlying scientific mechanisms and clinical significance, and identifies remaining challenges for optimizing disease management.

Acute promyelocytic leukemia (APL) was historically regarded as the most aggressive subtype of acute leukemia due to its high early mortality rate. The transformation in APL treatment represents a milestone in targeted cancer therapy. The discovery and clinical application of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) have dramatically improved the prognosis of APL, increasing the 5-year overall survival rate from less than 35% to over 90%. Chinese hematology/oncology community have made significant contributions to this transformation: Professor Wang Zhenyi's group pioneered ATRA-induced differentiation therapy, while Professor Zhang Tingdong's group verified the clinical efficacy of ATO. The research team of Shanghai Institute of Hematology (SIH) cloned the PML::RARA fusion gene resulting from the chromosomal translocation (15;17) and the first variant PLZF::RARA fusion gene. Based on the characterization of the leukogenesis at molecular and cellular levels and the mechanisms of action of effective drugs, the SIH team established a synergistic targeted therapy protocol for newly diagnosed APL patients, achieving a disease-free survival rate of 95.7% in a nationwide multi-center clinical trial. Subsequently, several teams explored the use of oral arsenic (Realgar-Indigo naturalis formula or oral ATO solution) combined with ATRA to treat APL, which is of high cost-effectiveness and can be promoted in resource-restricted regions. This review systematically summarizes the key therapeutic breakthroughs in APL, elucidates the underlying scientific mechanisms and clinical significance, and identifies remaining challenges for optimizing disease management.

Chromosome karyotyping is a critical way to diagnose various hematological malignancies and genetic diseases, of which chromosome detection in raw metaphase cell images is the most critical and challenging step. In this work, focusing on the joint optimization of chromosome localization and classification, we propose ChromTR to accurately detect and classify 24 classes of chromosomes in raw metaphase cell images. ChromTR incorporates semantic feature learning and class distribution learning into a unified DETR-based detection framework. Specifically, we first propose a Semantic Feature Learning Network (SFLN) for semantic feature extraction and chromosome foreground region segmentation with object-wise supervision. Next, we construct a Semantic-Aware Transformer (SAT) with two parallel encoders and a Semantic-Aware decoder to integrate global visual and semantic features. To provide a prediction with a precise chromosome number and category distribution, a Category Distribution Reasoning Module (CDRM) is built for foreground-background objects and chromosome class distribution reasoning. We evaluate ChromTR on 1404 newly collected R-band metaphase images and the public G-band dataset AutoKary2022. Our proposed ChromTR outperforms all previous chromosome detection methods with an average precision of 92.56% in R-band chromosome detection, surpassing the baseline method by 3.02%. In a clinical test, ChromTR is also confident in tackling normal and numerically abnormal karyotypes. When extended to the chromosome enumeration task, ChromTR also demonstrates state-of-the-art performances on R-band and G-band two metaphase image datasets. Given these superior performances to other methods, our proposed method has been applied to assist clinical karyotype diagnosis.
Humans ; Metaphase ; Karyotyping/methods* ; Image Processing, Computer-Assisted/methods* ; Algorithms ; Chromosomes, Human/genetics*

The Ly-6 and uPAR (LU) domain-containing proteins represent a large family of cell-surface markers. In particular, mouse Ly-6A/Sca-1 is a widely used marker for various stem cells; however, its human ortholog is missing. In this study, based on a systematic survey and comparative genomic study of mouse and human LU domain-containing proteins, we identified a previously unannotated human gene encoding the candidate ortholog of mouse Ly-6A/Sca-1. This gene, hereby named LY6A, reversely overlaps with a lncRNA gene in the majority of exonic sequences. We found that LY6A is aberrantly expressed in pituitary tumors, but not in normal pituitary tissues, and may contribute to tumorigenesis. Similar to mouse Ly-6A/Sca-1, human LY6A is also upregulated by interferon, suggesting a conserved transcriptional regulatory mechanism between humans and mice. We cloned the full-length LY6A cDNA, whose encoded protein sequence, domain architecture, and exon-intron structures are all well conserved with mouse Ly-6A/Sca-1. Ectopic expression of the LY6A protein in cells demonstrates that it acts the same as mouse Ly-6A/Sca-1 in their processing and glycosylphosphatidylinositol anchoring to the cell membrane. Collectively, these studies unveil a novel human gene encoding a candidate biomarker and provide an interesting model gene for studying gene regulatory and evolutionary mechanisms.
Humans ; Membrane Proteins/genetics* ; Pituitary Neoplasms/genetics* ; Biomarkers

The Omicron family of SARS-CoV-2 variants are currently driving the COVID-19 pandemic. Here we analyzed the clinical laboratory test results of 9911 Omicron BA.2.2 sublineages-infected symptomatic patients without earlier infection histories during a SARS-CoV-2 outbreak in Shanghai in spring 2022. Compared to an earlier patient cohort infected by SARS-CoV-2 prototype strains in 2020, BA.2.2 infection led to distinct fluctuations of pathophysiological markers in the peripheral blood. In particular, severe/critical cases of COVID-19 post BA.2.2 infection were associated with less pro-inflammatory macrophage activation and stronger interferon alpha response in the bronchoalveolar microenvironment. Importantly, the abnormal biomarkers were significantly subdued in individuals who had been immunized by 2 or 3 doses of SARS-CoV-2 prototype-inactivated vaccines, supporting the estimation of an overall 96.02% of protection rate against severe/critical disease in the 4854 cases in our BA.2.2 patient cohort with traceable vaccination records. Furthermore, even though age was a critical risk factor of the severity of COVID-19 post BA.2.2 infection, vaccination-elicited protection against severe/critical COVID-19 reached 90.15% in patients aged ≽ 60 years old. Together, our study delineates the pathophysiological features of Omicron BA.2.2 sublineages and demonstrates significant protection conferred by prior prototype-based inactivated vaccines.
Humans ; Aged ; Middle Aged ; COVID-19/prevention & control* ; SARS-CoV-2 ; Pandemics/prevention & control* ; China/epidemiology* ; Disease Outbreaks/prevention & control* ; Vaccination

With the recent ongoing autumn/winter 2022 COVID-19 wave and the adjustment of public health control measures, there have been widespread SARS-CoV-2 infections in Chinese mainland. Here we have analyzed 369 viral genomes from recently diagnosed COVID-19 patients in Shanghai, identifying a large number of sublineages of the SARS-CoV-2 Omicron family. Phylogenetic analysis, coupled with contact history tracing, revealed simultaneous community transmission of two Omicron sublineages dominating the infections in some areas of China (BA.5.2 mainly in Guangzhou and Shanghai, and BF.7 mainly in Beijing) and two highly infectious sublineages recently imported from abroad (XBB and BQ.1). Publicly available data from August 31 to November 29, 2022 indicated an overall severe/critical case rate of 0.035% nationwide, while analysis of 5706 symptomatic patients treated at the Shanghai Public Health Center between September 1 and December 26, 2022 showed that 20 cases (0.35%) without comorbidities progressed into severe/critical conditions and 153 cases (2.68%) with COVID-19-exacerbated comorbidities progressed into severe/critical conditions. These observations shall alert healthcare providers to place more resources for the treatment of severe/critical cases. Furthermore, mathematical modeling predicts this autumn/winter wave might pass through major cities in China by the end of the year, whereas some middle and western provinces and rural areas would be hit by the upcoming infection wave in mid-to-late January 2023, and the duration and magnitude of upcoming outbreak could be dramatically enhanced by the extensive travels during the Spring Festival (January 21, 2023). Altogether, these preliminary data highlight the needs to allocate resources to early diagnosis and effective treatment of severe cases and the protection of vulnerable population, especially in the rural areas, to ensure the country's smooth exit from the ongoing pandemic and accelerate socio-economic recovery.

Humans ; COVID-19 ; China/epidemiology*

Pathogenic microbes can induce cellular dysfunction, immune response, and cause infectious disease and other diseases including cancers. However, the cellular distributions of pathogens and their impact on host cells remain rarely explored due to the limited methods. Taking advantage of single-cell RNA-sequencing (scRNA-seq) analysis, we can assess the transcriptomic features at the single-cell level. Still, the tools used to interpret pathogens (such as viruses, bacteria, and fungi) at the single-cell level remain to be explored. Here, we introduced PathogenTrack, a python-based computational pipeline that uses unmapped scRNA-seq data to identify intracellular pathogens at the single-cell level. In addition, we established an R package named Yeskit to import, integrate, analyze, and interpret pathogen abundance and transcriptomic features in host cells. Robustness of these tools has been tested on various real and simulated scRNA-seq datasets. PathogenTrack is competitive to the state-of-the-art tools such as Viral-Track, and the first tools for identifying bacteria at the single-cell level. Using the raw data of bronchoalveolar lavage fluid samples (BALF) from COVID-19 patients in the SRA database, we found the SARS-CoV-2 virus exists in multiple cell types including epithelial cells and macrophages. SARS-CoV-2-positive neutrophils showed increased expression of genes related to type I interferon pathway and antigen presenting module. Additionally, we observed the Haemophilus parahaemolyticus in some macrophage and epithelial cells, indicating a co-infection of the bacterium in some severe cases of COVID-19. The PathogenTrack pipeline and the Yeskit package are publicly available at GitHub.
COVID-19 ; Humans ; RNA ; SARS-CoV-2/genetics* ; Single-Cell Analysis/methods* ; Transcriptome

Emerging evidence indicates that the gut microbiome contributes to the host immune response to infectious diseases. Here, to explore the role of the gut microbiome in the host immune responses in COVID-19, we conducted shotgun metagenomic sequencing and immune profiling of 14 severe/critical and 24 mild/moderate COVID-19 cases as well as 31 healthy control samples. We found that the diversity of the gut microbiome was reduced in severe/critical COVID-19 cases compared to mild/moderate ones. We identified the abundance of some gut microbes altered post-SARS-CoV-2 infection and related to disease severity, such as Enterococcus faecium, Coprococcus comes, Roseburia intestinalis, Akkermansia muciniphila, Bacteroides cellulosilyticus and Blautia obeum. We further analyzed the correlation between the abundance of gut microbes and host responses, and obtained a correlation map between clinical features of COVID-19 and 16 severity-related gut microbe, including Coprococcus comes that was positively correlated with CD3⁺/CD4⁺/CD8⁺ lymphocyte counts. In addition, an integrative analysis of gut microbiome and the transcriptome of peripheral blood mononuclear cells (PBMCs) showed that genes related to viral transcription and apoptosis were up-regulated in Coprococcus comes low samples. Moreover, a number of metabolic pathways in gut microbes were also found to be differentially enriched in severe/critical or mild/moderate COVID-19 cases, including the superpathways of polyamine biosynthesis II and sulfur oxidation that were suppressed in severe/critical COVID-19. Together, our study highlighted a potential regulatory role of severity related gut microbes in the immune response of host.
COVID-19 ; Clostridiales ; Gastrointestinal Microbiome ; Humans ; Immunity ; Leukocytes, Mononuclear ; SARS-CoV-2