COVID-19 Rebound After VV116 vs Nirmatrelvir-Ritonavir Treatment: A Randomized Clinical Trial.

Importance: With the widespread use of anti-SARS-CoV-2 drugs, accumulating data have revealed potential viral load rebound after treatment. Objective: To compare COVID-19 rebound after a standard 5-day course of antiviral treatment with VV116 vs nirmatrelvir-ritonavir. Design, Setting, and Participants: This is a single-center, investigator-blinded, randomized clinical trial conducted in Shanghai, China. Adult patients with mild-to-moderate COVID-19 and within 5 days of SARS-CoV-2 infection were enrolled between December 20, 2022, and January 19, 2023, and randomly allocated to receive either VV116 or nirmatrelvir-ritonavir. Interventions: Participants in the VV116 treatment group received oral 600-mg VV116 tablets every 12 hours on day 1 and 300 mg every 12 hours on days 2 through 5. Participants in the nirmatrelvir-ritonavir treatment group received oral nirmatrelvir-ritonavir tablets with 300 mg of nirmatrelvir plus 100 mg of ritonavir every 12 hours for 5 days. Participants were followed up every other day until day 28 and every week until day 60. Main Outcomes and Measures: The primary outcome was viral load rebound (VLR), defined as a half-log increase in viral RNA copies per milliliter compared with treatment completion. Secondary outcomes included a reduction in the cycle threshold value of 1.5 or more, time until VLR, and symptom rebound, defined as an increase of more than 2 points in symptom score compared with treatment completion. The primary outcome and secondary outcomes were analyzed using the full analysis set. Sensitivity analyses were conducted using the per protocol set. Adverse events were analyzed using the safety analysis set. Results: The full analysis set included 345 participants (mean [SD] age, 53.2 [16.8] years; 175 [50.7%] were men) who received VV116 (n = 165) or nirmatrelvir-ritonavir (n = 180). Viral load rebound occurred in 33 patients (20.0%) in the VV116 group and 39 patients (21.7%) in the nirmatrelvir-ritonavir group (P = .70). Symptom rebound occurred in 41 of 160 patients (25.6%) in the VV116 group and 40 of 163 patients (24.5%) in the nirmatrelvir-ritonavir group (P = .82). Viral whole-genome sequencing of 24 rebound cases revealed the same lineage at baseline and at viral load rebound in each case. Conclusions and Relevance: In this randomized clinical trial of patients with mild-to-moderate COVID-19, viral load rebound and symptom rebound were both common after a standard 5-day course of treatment with either VV116 or nirmatrelvir-ritonavir. Prolongation of treatment duration might be investigated to reduce COVID-19 rebound. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2200066811.

Aging and comprehensive molecular profiling in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aging-related and heterogeneous hematopoietic malignancy. In this study, a total of 1,474 newly diagnosed AML patients with RNA sequencing data were enrolled, and targeted or whole exome sequencing data were obtained in 94% cases. The correlation of aging-related factors including age and clonal hematopoiesis (CH), gender, and genomic/transcriptomic profiles (gene fusions, genetic mutations, and gene expression networks or pathways) was systematically analyzed. Overall, AML patients aged 60 y and older showed an apparently dismal prognosis. Alongside age, the frequency of gene fusions defined in the World Health Organization classification decreased, while the positive rate of gene mutations, especially CH-related ones, increased. Additionally, the number of genetic mutations was higher in gene fusion-negative (GF-) patients than those with GF. Based on the status of CH- and myelodysplastic syndromes (MDS)-related mutations, three mutant subgroups were identified among the GF- AML cohort, namely, CH-AML, CH-MDS-AML, and other GF- AML. Notably, CH-MDS-AML demonstrated a predominance of elderly and male cases, cytopenia, and significantly adverse clinical outcomes. Besides, gene expression networks including HOXA/B, platelet factors, and inflammatory responses were most striking features associated with aging and poor prognosis in AML. Our work has thus unraveled the intricate regulatory circuitry of interactions among different age, gender, and molecular groups of AML.

Prospective observational study on biomarkers of response in pancreatic ductal adenocarcinoma.

Adjuvant chemotherapy benefits patients with resected pancreatic ductal adenocarcinoma (PDAC), but the compromised physical state of post-operative patients can hinder compliance. Biomarkers that identify candidates for prompt adjuvant therapy are needed. In this prospective observational study, 1,171 patients with PDAC who underwent pancreatectomy were enrolled and extensively followed-up. Proteomic profiling of 191 patient samples unveiled clinically relevant functional protein modules. A proteomics-level prognostic risk model was established for PDAC, with its utility further validated using a publicly available external cohort. More importantly, through an interaction effect regression analysis leveraging both clinical and proteomic datasets, we discovered two biomarkers (NDUFB8 and CEMIP2), indicative of the overall sensitivity of patients with PDAC to adjuvant chemotherapy. The biomarkers were validated through immunohistochemistry on an internal cohort of 386 patients. Rigorous validation extended to two external multicentic cohorts-a French multicentric cohort (230 patients) and a cohort from two grade-A tertiary hospitals in China (466 patients)-enhancing the robustness and generalizability of our findings. Moreover, experimental validation through functional assays was conducted on PDAC cell lines and patient-derived organoids. In summary, our cohort-scale integration of clinical and proteomic data demonstrates the potential of proteomics-guided prognosis and biomarker-aided adjuvant chemotherapy for PDAC.

Hereditary Hearing Loss: A Systematic Review of Potential Treatments and Interventions.

PURPOSE: The purpose of this study was to systematically review the research literature with regards to treatments and intervention methods for hereditary hearing loss. Our goal was to provide reference guidelines for the rational use of medication and gene-targeted therapy for patients with hereditary hearing loss and discuss the future development of research in this area. METHOD: We searched two core databases, PubMed and Web of Science, for relevant literature relating to potential treatments and interventional methods for hereditary hearing loss. Then, we used Microsoft Excel to perform basic statistical analysis of the data, the R language to perform bibliometric analyses, and VOSviewer and CiteSpace to visualize data. In addition, we clustered and descriptively analyzed the data and identified the relative importance of each approach with regard to precise patient outcomes. RESULTS: In this study, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standardized screening process and identified a total of 103 research articles. The average annual growth rate of publications in this area was 12.73%. The country with the highest number of publications and citations was the United States; 80 of these publications (associated with 76.92% of funding) were supported by grants from 16 countries. Potential treatments and interventions were clustered according to the stage of research and showed that 8.74% remain in the research design stage, 59.22% are in the clinical validation stage, and 32.04% are being applied in the clinic. The main research focus in this field is cochlear implants and gene therapy. CONCLUSIONS: Hereditary hearing loss is in a critical period of transition from preventive to therapeutic research. Gene-targeted interventions represent one of the most promising and effective treatments. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.24309193.

GPCR signaling contributes to immune characteristics of microenvironment and process of EBV-induced lymphomagenesis.

Epstein-Barr virus (EBV) is the oncogenic driver of multiple cancers. However, the underlying mechanism of virus-cancer immunological interaction during disease pathogenesis remains largely elusive. Here we reported the first comprehensive proteogenomic characterization of natural killer/T-cell lymphoma (NKTCL), a representative disease model to study EBV-induced lymphomagenesis, incorporating genomic, transcriptomic, and in-depth proteomic data. Our multi-omics analysis of NKTCL revealed that EBV gene pattern correlated with immune-related oncogenic signaling. Single-cell transcriptome further delineated the tumor microenvironment as immune-inflamed, -deficient, and -desert phenotypes, in association with different setpoints of cancer-immunity cycle. EBV interacted with transcriptional factors to provoke GPCR interactome (GPCRome) reprogramming. Enhanced expression of chemokine receptor-1 (CCR1) on malignant and immunosuppressive cells modulated virus-cancer interaction on microenvironment. Therapeutic targeting CCR1 showed promising efficacy with EBV eradication, T-cell activation, and lymphoma cell killing in NKTCL organoid. Collectively, our study identified a previously unknown GPCR-mediated malignant progression and translated sensors of viral molecules into EBV-specific anti-cancer therapeutics.

Global research trends in benign paroxysmal positional vertigo: a bibliometric analysis.

Background: Benign paroxysmal positional vertigo is the most common disease in which vertigo is the main clinical manifestation, and it has become a global medical problem, affecting a wide range of areas and seriously affecting the quality of human life. Objective: This article presents an analysis of the current characteristics of BPPV-related research and summarizes the current hot topics and trends, with the goal of inspiring future research into the prevention and treatment of BPPV, thereby improving the differential diagnosis and prevention of peripheral vertigo. Methods: A bibliometric approach was used to collect 1,219 eligible studies on BPPV from four databases-PubMed, Embase, Scopus, and Web of Science-published between 1974 and 2022. The characteristics and status of the accumulated scientific output were processed using R and VOSviewer so that we could visualize any trends or hotspots. Results: The results showed a significant increase in the annual number of publications, with an average annual growth rate of 21.58%. A possible reason for the especially pronounced peak in 2021 was an increase in the prevalence of BPPV as a result of COVID-19. The new coronavirus became a focus of research in 2021. A total of 3,876 authors (of whom 1,097 were first authors) published articles in 307 different journals; 15.7% of the articles were published in Acta Oto-Larygologica, Otology and Neurotology, and Frontiers in Neurology. Acta Oto-Laryngologica was well ahead of the other journals in terms of growth rate and number of articles published. American scholars generated the largest number of articles overall, and the USA was involved in the greatest number of international collaborations, followed by Italy and China. The themes of the research centered around three topics, namely the treatment of BPPV, its influencing factors, and diagnosis. Conclusions: There has been a major increase in BPPV-related research over the last 50 years, leading to an increase in related articles and rapid development of the field. Key directions for future research include the improvement of individualized treatment for residual symptoms after initial treatment of BPPV among the elderly; effective control of comorbidities such as osteoporosis; and secondary inner ear disease, such as Ménière's disease.

Single-cell atlas reveals a distinct immune profile fostered by T cell-B cell crosstalk in triple negative breast cancer.

BACKGROUND: Characterizing the unique immune microenvironment of each tumor is of great importance for better predicting prognosis and guiding cancer immunotherapy. However, the unique features of the immune microenvironment of triple negative breast cancer (TNBC) compared with other subtypes of breast cancer remain elusive. Therefore, we aimed to depict and compare the immune landscape among TNBC, human epidermal growth factor receptor 2-positive (HER2+ ) breast cancer, and luminal-like breast cancer. METHODS: Single-cell RNA sequencing (scRNA-seq) was performed on CD45+ immune cells isolated from human normal breast tissues and primary breast tumors of various subtypes. By analyzing the scRNA-seq data, immune cell clusters were identified and their proportions as well as transcriptome features were compared among TNBC, human HER2+ breast cancer, and luminal-like breast cancer. Pseudotime and cell-cell communication analyses were also conducted to characterize the immune microenvironment. RESULTS: ScRNA-seq data of 117,958 immune cells were obtained and 31 immune clusters were identified. A unique immunosuppressive microenvironment in TNBC was decoded as compared to that in HER2+ or luminal-like breast cancer, which was characterized by higher proportions of regulatory T cells (Tregs) and exhausted CD8+ T cells and accompanied by more abundant plasma cells. Tregs and exhausted CD8+ T cells in TNBC exhibited increased immunosuppression signature and dysfunctional scores. Pseudotime analyses showed that B cells tended to differentiate to plasma cells in TNBC. Cell-cell communication analyses indicated that these unique features are fostered by the diversified T cell-B cell crosstalk in TNBC. Based on the T cell-B cell crosstalk, a prognostic signature was established that could effectively predict the prognosis status for patients with TNBC. Additionally, it was found that TNBC had a higher proportion of cytotoxic natural killer (NK) cells, whereas HER2+ or luminal-like breast cancer lost this feature, suggesting that HER2+ or luminal-like breast cancer, but not TNBC, may benefit from NK-based immunotherapy. CONCLUSIONS: This study identified a distinct immune feature fostered by T cell-B cell crosstalk in TNBC, which provides better prognostic information and effective therapeutic targets for breast cancer.

Host protection against Omicron BA.2.2 sublineages by prior vaccination in spring 2022 COVID-19 outbreak in Shanghai.

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.

Primary assessment of the diversity of Omicron sublineages and the epidemiologic features of autumn/winter 2022 COVID-19 wave in Chinese mainland.

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.

Chromosome-level genome assembly defines female-biased genes associated with sex determination and differentiation in the human blood fluke Schistosoma japonicum.

Schistosomiasis is a neglected tropical disease of humans caused by blood flukes of the genus Schistosoma, the only dioecious parasitic flatworm. Although aspects of sex determination, differentiation and reproduction have been studied in some Schistosoma species, almost nothing is known for Schistosoma japonicum, the causative agent of schistosomiasis japonica. This mainly reflects the lack of high-quality genomic and transcriptomic resources for this species. As current genomes for S. japonicum are highly fragmented, we assembled and report a chromosome-level reference genome (seven autosomes, the Z-chromosome and partial W-chromosome), achieving a substantially enhanced gene annotation. Utilizing this genome, we discovered that the sex chromosomes of S. japonicum and its congener S. mansoni independently suppressed recombination during evolution, forming five and two evolutionary strata, respectively. By exploring the W-chromosome and sex-specific transcriptomes, we identified 35 W-linked genes and 257 female-preferentially transcribed genes (FTGs) from our chromosomal assembly and uncovered a signature for sex determination and differentiation in S. japonicum. These FTGs clustering within autosomes or the Z-chromosome exhibit a highly dynamic transcription profile during the pairing of female and male schistosomula, thereby representing a critical phase for the maturation of the female worms and suggesting distinct layers of regulatory control of gene transcription at this development stage. Collectively, these data provide a valuable resource for further functional genomic characterization of S. japonicum, shed light on the evolution of sex chromosomes in this highly virulent human blood fluke, and provide a pathway to identify novel targets for development of intervention tools against schistosomiasis.

Transcriptome-based molecular subtypes and differentiation hierarchies improve the classification framework of acute myeloid leukemia.

The current classification of acute myeloid leukemia (AML) relies largely on genomic alterations. Robust identification of clinically and biologically relevant molecular subtypes from nongenomic high-throughput sequencing data remains challenging. We established the largest multicenter AML cohort (n = 655) in China, with all patients subjected to RNA sequencing (RNA-Seq) and 619 (94.5%) to targeted or whole-exome sequencing (TES/WES). Based on an enhanced consensus clustering, eight stable gene expression subgroups (G1-G8) with unique clinical and biological significance were identified, including two unreported (G5 and G8) and three redefined ones (G4, G6, and G7). Apart from four well-known low-risk subgroups including PML::RARA (G1), CBFB::MYH11 (G2), RUNX1::RUNX1T1 (G3), biallelic CEBPA mutations or -like (G4), four meta-subgroups with poor outcomes were recognized. The G5 (myelodysplasia-related/-like) subgroup enriched clinical, cytogenetic and genetic features mimicking secondary AML, and hotspot mutations of IKZF1 (p.N159S) (n = 7). In contrast, most NPM1 mutations and KMT2A and NUP98 fusions clustered into G6-G8, showing high expression of HOXA/B genes and diverse differentiation stages, from hematopoietic stem/progenitor cell down to monocyte, namely HOX-primitive (G7), HOX-mixed (G8), and HOX-committed (G6). Through constructing prediction models, the eight gene expression subgroups could be reproduced in the Cancer Genome Atlas (TCGA) and Beat AML cohorts. Each subgroup was associated with distinct prognosis and drug sensitivities, supporting the clinical applicability of this transcriptome-based classification of AML. These molecular subgroups illuminate the complex molecular network of AML, which may promote systematic studies of disease pathogenesis and foster the screening of targeted agents based on omics.

Multi-omics analysis identifies osteosarcoma subtypes with distinct prognosis indicating stratified treatment.

Osteosarcoma (OS) is a primary malignant bone tumor that most commonly affects children, adolescents, and young adults. Here, we comprehensively analyze genomic, epigenomic and transcriptomic data from 121 OS patients. Somatic mutations are diverse within the cohort, and only TP53 is significantly mutated. Through unsupervised integrative clustering of the multi-omics data, we classify OS into four subtypes with distinct molecular features and clinical prognosis: (1) Immune activated (S-IA), (2) Immune suppressed (S-IS), (3) Homologous recombination deficiency dominant (S-HRD), and (4) MYC driven (S-MD). MYC amplification with HR proficiency tumors is identified with a high oxidative phosphorylation signature resulting in resistance to neoadjuvant chemotherapy. Potential therapeutic targets are identified for each subtype, including platinum-based chemotherapy, immune checkpoint inhibitors, anti-VEGFR, anti-MYC and PARPi-based synthetic lethal strategies. Our comprehensive integrated characterization provides a valuable resource that deepens our understanding of the disease, and may guide future clinical strategies for the precision treatment of OS.

A novel mutation in human EMD gene and mitochondrial dysfunction in emerin knockdown cardiomyocytes.

Emerin is an inner nuclear envelope protein encoded by the EMD gene, mutations in which cause Emery-Dreifuss muscular dystrophy type 1 (EDMD1). Cardiac involvement has become a major threat to patients with EDMD1; however, the cardiovascular phenotype spectrums of emerinopathy and the mechanisms by which emerin regulates cardiac pathophysiology remain unclear. Here, we identified a novel nonsense mutation (c.C57G, p.Y19X) in the EMD gene in a Han Chinese family through high-throughput sequencing. Two family members were found to have EDMD1 with muscle weakness and cardiac arrhythmia. Mechanistically, we first discovered that knockdown of emerin in HL-1 or H9C2 cardiomyocytes lead to impaired mitochondrial oxidative phosphorylation capacity with downregulation of electron transport chain complex I and IV and upregulation of complex III and V. Moreover, loss of emerin in HL-1 cells resulted in collapsed mitochondrial membrane potential, altered mitochondrial networks and downregulated multiple factors in RNA and protein level, such as PGC1α, DRP1, MFF, MFN2, which are involved in regulation of mitochondrial biogenesis, fission and fusion. Our findings suggest that targeting mitochondrial bioenergetics might be an effective strategy against cardiac disorders caused by EMD mutations.

Transcriptome-wide subtyping of pediatric and adult T cell acute lymphoblastic leukemia in an international study of 707 cases.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy of T cell progenitors, known to be a heterogeneous disease in pediatric and adult patients. Here we attempted to better understand the disease at the molecular level based on the transcriptomic landscape of 707 T-ALL patients (510 pediatric, 190 adult patients, and 7 with unknown age; 599 from published cohorts and 108 newly investigated). Leveraging the information of gene expression enabled us to identify 10 subtypes (G1­G10), including the previously undescribed one characterized by GATA3 mutations, with GATA3R276Q capable of affecting lymphocyte development in zebrafish. Through associating with T cell differentiation stages, we found that high expression of LYL1/LMO2/SPI1/HOXA (G1­G6) might represent the early T cell progenitor, pro/precortical/cortical stage with a relatively high age of disease onset, and lymphoblasts with TLX3/TLX1 high expression (G7­G8) could be blocked at the cortical/postcortical stage, while those with high expression of NKX2-1/TAL1/LMO1 (G9­G10) might correspond to cortical/postcortical/mature stages of T cell development. Notably, adult patients harbored more cooperative mutations among epigenetic regulators, and genes involved in JAK-STAT and RAS signaling pathways, with 44% of patients aged 40 y or above in G1 bearing DNMT3A/IDH2 mutations usually seen in acute myeloid leukemia, suggesting the nature of mixed phenotype acute leukemia.

Integrated analysis of gut microbiome and host immune responses in COVID-19.

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.

Integrating longitudinal clinical laboratory tests with targeted proteomic and transcriptomic analyses reveal the landscape of host responses in COVID-19.

The pathophysiology of coronavirus disease 19 (COVID-19) involves a multitude of host responses, yet how they unfold during the course of disease progression remains unclear. Here, through integrative analysis of clinical laboratory tests, targeted proteomes, and transcriptomes of 963 patients in Shanghai, we delineate the dynamics of multiple circulatory factors within the first 30 days post-illness onset and during convalescence. We show that hypercortisolemia represents one of the probable causes of acute lymphocytopenia at the onset of severe/critical conditions. Comparison of the transcriptomes of the bronchoalveolar microenvironment and peripheral blood indicates alveolar macrophages, alveolar epithelial cells, and monocytes in lungs as the potential main sources of elevated cytokines mediating systemic immune responses and organ damages. In addition, the transcriptomes of patient blood cells are characterized by distinct gene regulatory networks and alternative splicing events. Our study provides a panorama of the host responses in COVID-19, which may serve as the basis for developing further diagnostics and therapy.

Integration of Genomic and Transcriptomic Markers Improves the Prognosis Prediction of Acute Promyelocytic Leukemia.

PURPOSE: The current stratification system for acute promyelocytic leukemia (APL) is based on the white blood cell (WBC) and the platelet counts (i.e., Sanz score) over the past two decades. However, the borderlines among different risk groups are sometimes ambiguous, and for some patients, early death and relapse remained challenges. Besides, with the evolving of the treatment strategy from all-trans-retinoic acid (ATRA) and chemotherapy to ATRA-arsenic trioxide-based synergistic targeted therapy, the precise risk stratification with molecular markers is needed. EXPERIMENTAL DESIGN: This study performed a systematic analysis of APL genomics and transcriptomics to identify genetic abnormalities in 348 patients mainly from the APL2012 trial (NCT01987297) to illustrate the potential molecular background of Sanz score and further optimize it. The least absolute shrinkage and selection operator algorithm was used to analyze the gene expression in 323 cases to establish a scoring system (i.e., APL9 score). RESULTS: Through combining NRAS mutations, APL9 score, and WBC, 321 cases can be stratified into two groups with significantly different outcomes. The estimated 5-year overall (P = 0.00031), event-free (P < 0.0001), and disease-free (P = 0.001) survival rates in the revised standard-risk group (95.6%, 93.8%, and 98.1%, respectively) were significantly better than those in the revised high-risk group (82.9%, 77.4%, and 88.4%, respectively), which could be validated using The Cancer Genome Atlas dataset. CONCLUSIONS: We have proposed a two-category system for improving prognosis in patients with APL. Molecular markers identified in this study may also provide genomic insights into the disease mechanism for improved therapy.

Identification of functional cooperative mutations of GNAO1 in human acute lymphoblastic leukemia.

Leukemogenesis is characterized by chromosomal rearrangements with additional molecular disruptions, yet the cooperative mechanisms are still unclear. Using whole-exome sequencing of a pair of monozygotic twins who were discordant for childhood acute lymphoblastic leukemia (ALL) with ETV6-RUNX1 (E/R) gene fusion successively after birth, we identified the R209C mutation of G protein subunit α o1 (GNAO1) as a new ALL risk loci. Moreover, GNAO1 missense mutations are recurrent in ALL patients and are associated with E/R fusion. Ectopic expression of the GNAO1 R209C mutant increased its GTPase activity and promoted cell proliferation and cell neoplastic transformation. Combined with the E/R fusion, the GNAO1 R209C mutation promoted leukemogenesis through activating PI3K/Akt/mTOR signaling. Reciprocally, activated mTORC1 phosphorylated p300 acetyltransferase, which acetylated E/R and thereby enhanced the E/R transcriptional activity of GNAO1 R209C. Thus, our study provides clinical evidence of the functional cooperation of GNAO1 mutations and E/R fusion, suggesting GNAO1 as a therapeutic target in human leukemia.

Dynamic Changes in the Global Transcriptome and MicroRNAome Reveal Complex miRNA-mRNA Regulation in Early Stages of the Bi-Directional Development of Echinococcus granulosus Protoscoleces.

BACKGROUND: Cystic echinococcosis is a life-threatening disease caused by the larval stages of the dog tapeworm Echinococcus granulosus. Protoscoleces (PSCs) of this worm have the ability of bi-directional development to either larval cysts or strobilar adult worms. However, the molecular mechanisms underlying this development process are unknown. RESULTS: RNA and small RNAs sequencing was employed to characterize the gene and miRNA expression at 0-24 h and 7-14 days in the bi-directional development of PSCs. A total of 963 genes and 31 miRNAs were differentially expressed in the early development of PSCs to adult worms whereas 972 genes and 27 miRNAs were differentially expressed in the early development of PSCs to cysts. Pairwise comparison between the two developmental patterns showed that 172 genes and 15 miRNAs were differentially expressed at three time-points. Most of these genes were temporally changed at 24 h or 7 days. GO enrichment analysis revealed that the differentially expressed genes in early adult worm development are associated with nervous system development and carbohydrate metabolic process; whereas, the differentially expressed genes in early cystic development are associated with transmembrane transporter activity and nucleoside triphosphatase activity. In addition, miR-71 and miR-219 regulated genes are likely involved in oxidation reduction in adult worm development. CONCLUSION: The early stages of bi-directional development in E. granulosus PSCs are controlled by miRNAs and genes likely associated with nervous system development and carbohydrate metabolic process. ATP-dependent transporter genes are associated with cystic development. These results may be important for exploring the mechanisms underlying early development in E. granulosus providing novel information that can be used to discover new therapeutics for controlling cystic echinococcosis.