Publications by authors named "Qianghu Wang"

58 Publications

Comparative Characterization and Risk Stratification of Asymptomatic and Presymptomatic Patients With COVID-19.

Front Immunol 2021 9;12:700449. Epub 2021 Jul 9.

Central Lab of Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

The identification of asymptomatic, non-severe presymptomatic, and severe presymptomatic coronavirus disease 2019 (COVID-19) in patients may help optimize risk-stratified clinical management and improve prognosis. This single-center case series from Wuhan Huoshenshan Hospital, China, included 2,980 patients with COVID-19 who were hospitalized between February 4, 2020 and April 10, 2020. Patients were diagnosed as asymptomatic (n = 39), presymptomatic (n = 34), and symptomatic (n = 2,907) upon admission. This study provided an overview of asymptomatic, presymptomatic, and symptomatic COVID-19 patients, including detection, demographics, clinical characteristics, and outcomes. Upon admission, there was no significant difference in clinical symptoms and CT image between asymptomatic and presymptomatic patients for diagnosis reference. The mean area under the receiver operating characteristic curve (AUC) of the differential diagnosis model to discriminate presymptomatic patients from asymptomatic patients was 0.89 (95% CI, 0.81-0.98). Importantly, the severe and non-severe presymptomatic patients can be further stratified (AUC = 0.82). In conclusion, the two-step risk-stratification model based on 10 laboratory indicators can distinguish among asymptomatic, severe presymptomatic, and non-severe presymptomatic COVID-19 patients on admission. Moreover, single-cell data analyses revealed that the CD8+T cell exhaustion correlated to the progression of COVID-19.
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http://dx.doi.org/10.3389/fimmu.2021.700449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301218PMC
July 2021

Chitinase-3-like-1 protein complexes modulate macrophage-mediated immune suppression in glioblastoma.

J Clin Invest 2021 Jul 6. Epub 2021 Jul 6.

Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, United States of America.

Glioblastoma is a highly malignant and incurable brain tumor characterized by intrinsic and adaptive resistance to immunotherapies. However, how glioma cells induce tumor immunosuppression and escape immunosurveillance remains poorly understood. Here, we find upregulation of cancer-intrinsic Chitinase-3-like-1 (CHI3L1) signaling modulating an immunosuppressive microenvironment by reprogramming tumor-associated macrophages (TAMs). Mechanistically, CHI3L1 binding with Galectin-3 (Gal3) selectively promotes TAM migration and infiltration with a protumor M2-like but not an antitumor M1-like phenotype in vitro and in vivo, governed by a transcriptional program of NFκB/CEBPβ in the CHI3L1/Gal3-PI3K/AKT/mTOR axis. Conversely, Galectin-3-binding protein (Gal3BP) negatively regulates this process by competing with Gal3 to bind CHI3L1. Administration of a Gal3BP mimetic peptide in syngeneic glioblastoma mouse models reverses immune suppression and attenuates tumor progression. These results shed light on the role of CHI3L1 protein complexes in immune evasion by glioblastoma and as a potential immunotherapeutic target for this devastating disease.
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http://dx.doi.org/10.1172/JCI147552DOI Listing
July 2021

Sex-based clinical and immunological differences in COVID-19.

BMC Infect Dis 2021 Jul 5;21(1):647. Epub 2021 Jul 5.

Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.

Background: Males and females differ in their immunological responses to foreign pathogens. However, most of the current COVID-19 clinical practices and trials do not take the sex factor into consideration.

Methods: We performed a sex-based comparative analysis for the clinical outcomes, peripheral immune cells, and severe acute respiratory syndrome coronavirus (SARS-CoV-2) specific antibody levels of 1558 males and 1499 females COVID-19 patients from a single center. The lymphocyte subgroups were measured by Flow cytometry. The total antibody, Spike protein (S)-, receptor binding domain (RBD)-, and nucleoprotein (N)- specific IgM and IgG levels were measured by chemiluminescence.

Results: We found that male patients had approximately two-fold rates of ICU admission (4.7% vs. 2.7% in males and females, respectively, P = 0.005) and mortality (3% vs. 1.4%, in males and females, respectively, P = 0.004) than female patients. Survival analysis revealed that the male sex is an independent risk factor for death from COVID-19 (adjusted hazard ratio [HR] = 2.22, 95% confidence interval [CI]: 1.3-3.6, P = 0.003). The level of inflammatory cytokines in peripheral blood was higher in males during hospitalization. The renal (102/1588 [6.5%] vs. 63/1499 [4.2%], in males and females, respectively, P = 0.002) and hepatic abnormality (650/1588 [40.9%] vs. 475/1499 [31.7%], P = 0.003) were more common in male patients than in female patients. By analyzing dynamic changes of lymphocyte subsets after symptom onset, we found that the percentage of CD19+ B cells and CD4+ T cells was generally higher in female patients during the disease course of COVID-19. Notably, the protective RBD-specific IgG against SARS-CoV-2 sharply increased and reached a peak in the fourth week after symptom onset in female patients, while gradually increased and reached a peak in the seventh week after symptom onset in male patients.

Conclusions: Males had an unfavorable prognosis, higher inflammation, a lower percentage of lymphocytes, and indolent antibody responses during SARS-CoV-2 infection and recovery. Early medical intervention and close monitoring are important, especially for male COVID-19 patients.
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http://dx.doi.org/10.1186/s12879-021-06313-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256650PMC
July 2021

High Expression of and at the Resection Margin Makes Lung Cancer Survivors Susceptible to SARS-CoV-2 With Unfavorable Prognosis.

Front Oncol 2021 21;11:644575. Epub 2021 May 21.

Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

Background: Coronavirus disease 2019 (COVID-19) has rapidly spread worldwide. Systematic analysis of lung cancer survivors at molecular and clinical levels is warranted to understand the disease course and clinical characteristics.

Methods: A single-center, retrospective cohort study was conducted in 65 patients with COVID-19 from Wuhan Huoshenshan Hospital, of which 13 patients were diagnosed with lung cancer. The study was conducted from February 4 to April 11, 2020.

Results: During the course of treatment, lung cancer survivors infected with severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) had shorter median time from symptom onset to hospitalization ( = 0.016) and longer clinical symptom remission time ( = 0.020) than non-cancer individuals. No differences were observed among indicators such as time from symptom onset to hospitalization and symptom remission time between medium-term and short-term survivors. The expression of ( = 0.013) and (0.001) was elevated in lung cancer survivors as compared with that in non-cancer individuals.

Conclusions: and levels were higher at resection margins of lung cancer survivors than those in normal tissues of non-cancerous individuals and may serve as factors responsible for the high susceptibility to COVID-19 among lung cancer survivors. Lung cancer patients diagnosed with COVID-19, including medium-term survivors, have worse outcomes than the general population.
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http://dx.doi.org/10.3389/fonc.2021.644575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176089PMC
May 2021

A predictive paradigm for COVID-19 prognosis based on the longitudinal measure of biomarkers.

Brief Bioinform 2021 Jun 3. Epub 2021 Jun 3.

Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China, 211166.

Novel coronavirus disease 2019 (COVID-19) is an emerging, rapidly evolving crisis, and the ability to predict prognosis for individual COVID-19 patient is important for guiding treatment. Laboratory examinations were repeatedly measured during hospitalization for COVID-19 patients, which provide the possibility for the individualized early prediction of prognosis. However, previous studies mainly focused on risk prediction based on laboratory measurements at one time point, ignoring disease progression and changes of biomarkers over time. By using historical regression trees (HTREEs), a novel machine learning method, and joint modeling technique, we modeled the longitudinal trajectories of laboratory biomarkers and made dynamically predictions on individual prognosis for 1997 COVID-19 patients. In the discovery phase, based on 358 COVID-19 patients admitted between 10 January and 18 February 2020 from Tongji Hospital, HTREE model identified a set of important variables including 14 prognostic biomarkers. With the trajectories of those biomarkers through 5-day, 10-day and 15-day, the joint model had a good performance in discriminating the survived and deceased COVID-19 patients (mean AUCs of 88.81, 84.81 and 85.62% for the discovery set). The predictive model was successfully validated in two independent datasets (mean AUCs of 87.61, 87.55 and 87.03% for validation the first dataset including 112 patients, 94.97, 95.78 and 94.63% for the second validation dataset including 1527 patients, respectively). In conclusion, our study identified important biomarkers associated with the prognosis of COVID-19 patients, characterized the time-to-event process and obtained dynamic predictions at the individual level.
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http://dx.doi.org/10.1093/bib/bbab206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195146PMC
June 2021

Implications of cardiac markers in risk-stratification and management for COVID-19 patients.

Crit Care 2021 04 26;25(1):158. Epub 2021 Apr 26.

Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, China.

Background: COVID-19 has resulted in high mortality worldwide. Information regarding cardiac markers for precise risk-stratification is limited. We aim to discover sensitive and reliable early-warning biomarkers for optimizing management and improving the prognosis of COVID-19 patients.

Methods: A total of 2954 consecutive COVID-19 patients who were receiving treatment from the Wuhan Huoshenshan Hospital in China from February 4 to April 10 were included in this retrospective cohort. Serum levels of cardiac markers were collected after admission. Coronary artery disease diagnosis and survival status were recorded. Single-cell RNA-sequencing and bulk RNA-sequencing from different cohorts of non-COVID-19 were performed to analyze SARS-CoV-2 receptor expression.

Results: Among 2954 COVID-19 patients in the analysis, the median age was 60 years (50-68 years), 1461 (49.5%) were female, and 1515 (51.3%) were severe/critical. Compared to mild/moderate (1439, 48.7%) patients, severe/critical patients showed significantly higher levels of cardiac markers within the first week after admission. In severe/critical COVID-19 patients, those with abnormal serum levels of BNP (42 [24.6%] vs 7 [1.1%]), hs-TNI (38 [48.1%] vs 6 [1.0%]), α- HBDH (55 [10.4%] vs 2 [0.2%]), CK-MB (45 [36.3%] vs 12 [0.9%]), and LDH (56 [12.5%] vs 1 [0.1%]) had a significantly higher mortality rate compared to patients with normal levels. The same trend was observed in the ICU admission rate. Severe/critical COVID-19 patients with pre-existing coronary artery disease (165/1,155 [10.9%]) had more cases of BNP (52 [46.5%] vs 119 [16.5%]), hs-TNI (24 [26.7%] vs 9.6 [%], α- HBDH (86 [55.5%] vs 443 [34.4%]), CK-MB (27 [17.4%] vs 97 [7.5%]), and LDH (65 [41.9%] vs 382 [29.7%]), when compared with those without coronary artery disease. There was enhanced SARS-CoV-2 receptor expression in coronary artery disease compared with healthy controls. From regression analysis, patients with five elevated cardiac markers were at a higher risk of death (hazards ratio 3.4 [95% CI 2.4-4.8]).

Conclusions: COVID-19 patients with pre-existing coronary artery disease represented a higher abnormal percentage of cardiac markers, accompanied by high mortality and ICU admission rate. BNP together with hs-TNI, α- HBDH, CK-MB and LDH act as a prognostic biomarker in COVID-19 patients with or without pre-existing coronary artery disease.
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http://dx.doi.org/10.1186/s13054-021-03555-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074282PMC
April 2021

Implications of liver injury in risk-stratification and management of patients with COVID-19.

Hepatol Int 2021 Feb 6;15(1):202-212. Epub 2021 Feb 6.

Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China.

Background: Infection with SARS-CoV-2 has been associated with liver dysfunction, aggravation of liver burden, and liver injury. This study aimed to assess the effects of liver injuries on the clinical outcomes of patients with COVID-19.

Methods: A total of 1520 patients with severe or critical COVID-19 from Huoshenshan Hospital, Wuhan, were enrolled. Chronic liver disease (CLD) was confirmed by consensus diagnostic criteria. Laboratory test results were compared between different groups. scRNA-seq data and bulk gene expression profiles were used to identify cell types associated with liver injury.

Results: A total of 10.98% of patients with severe or critical COVID-19 developed liver injury after admission that was associated with significantly higher rates of mortality (21.74%, p < 0.001) and intensive care unit admission (26.71%, p < 0.001). Pre-existing CLDs were not associated with a higher risk. However, fatty liver disease and cirrhosis were associated with higher risks, supported by evidences from single cell and bulk transcriptome analysis that showed more TMPRSS2 cells in these tissues. By generating a model, we were able to predict the risk and severity of liver injury during hospitalization.

Conclusion: We demonstrate that liver injury occurring during therapy as well as pre-existing CLDs like fatty liver disease and cirrhosis in patients with COVID-19 is significantly associated with the severity of disease and mortality, but the presence of other CLD is not associated. We provide a risk-score model that can predict whether patients with COVID-19 will develop liver injury or proceed to higher-risk stages during subsequent hospitalizations.
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http://dx.doi.org/10.1007/s12072-020-10123-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865118PMC
February 2021

Therapy-Induced Transdifferentiation Promotes Glioma Growth Independent of EGFR Signaling.

Cancer Res 2021 03 28;81(6):1528-1539. Epub 2021 Jan 28.

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York.

EGFR is frequently amplified, mutated, and overexpressed in malignant gliomas. Yet the EGFR-targeted therapies have thus far produced only marginal clinical responses, and the underlying mechanism remains poorly understood. Using an inducible oncogenic EGFR-driven glioma mouse model system, our current study reveals that a small population of glioma cells can evade therapy-initiated apoptosis and potentiate relapse development by adopting a mesenchymal-like phenotypic state that no longer depends on oncogenic EGFR signaling. Transcriptome analyses of proximal and distal treatment responses identified TGFβ/YAP/Slug signaling cascade activation as a major regulatory mechanism that promotes therapy-induced glioma mesenchymal lineage transdifferentiation. Following anti-EGFR treatment, TGFβ secreted from stressed glioma cells acted to promote YAP nuclear translocation that stimulated upregulation of the pro-mesenchymal transcriptional factor SLUG and subsequent glioma lineage transdifferentiation toward a stable therapy-refractory state. Blockade of this adaptive response through suppression of TGFβ-mediated YAP activation significantly delayed anti-EGFR relapse and prolonged animal survival. Together, our findings shed new insight into EGFR-targeted therapy resistance and suggest that combinatorial therapies of targeting both EGFR and mechanisms underlying glioma lineage transdifferentiation could ultimately lead to deeper and more durable responses. SIGNIFICANCE: This study demonstrates that molecular reprogramming and lineage transdifferentiation underlie anti-EGFR therapy resistance and are clinically relevant to the development of new combinatorial targeting strategies against malignant gliomas with aberrant EGFR signaling.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1810DOI Listing
March 2021

A comparative genomics analysis of lung adenocarcinoma for Chinese population by using panel of recurrent mutations.

J Biomed Res 2020 Aug;35(1):11-20

Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.

Previous studies have demonstrated that Chinese lung adenocarcinoma (LUAD) patients have unique genetic characteristics, however, the specific genomic features relating to the development and treatment of LUAD in the Chinese population are not fully understood. Here, we applied the ultra-deep targeted sequencing to 66 Chinese LUAD samples, accompanied by comparative analysis with 162 Caucasian LUAD in The Cancer Genome Atlas. We focused on the 68 recurrently mutated genes and results revealed that the panel-based tumor mutational burden (pTMB) is significantly higher in the Chinese LUAD ( =0.0017). Additionally, the percentage of smoking-associated C>A transversion is significantly lower in Chinese LUAD (15.5% 39.7%, =5.69×10 ), while C>T transition is more frequent in Chinese LUAD (35.8% 25.7%, =2.67×10 ), which indicated the ethnic difference in mutation types. Notably, novel driver genes ( and ) that are peculiar to Chinese LUAD were identified, and a more convergent distribution of mutations was observed in the Chinese cohort ( =0.012) compared with scattered mutations in Caucasian LUAD. Our results present a distinct genomic profile of Chinese LUAD compared to Caucasians LUAD and elucidate the ethnic difference in mutation distribution besides the type and rate.
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http://dx.doi.org/10.7555/JBR.34.20200068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874268PMC
August 2020

Dynamic changes in anti-SARS-CoV-2 antibodies during SARS-CoV-2 infection and recovery from COVID-19.

Nat Commun 2020 11 27;11(1):6044. Epub 2020 Nov 27.

Department of Laboratory Medicine & Blood Transfusion, Wuhan Huoshenshan Hospital, 430100, Wuhan, Hubei, China.

Deciphering the dynamic changes in antibodies against SARS-CoV-2 is essential for understanding the immune response in COVID-19 patients. Here we analyze the laboratory findings of 1,850 patients to describe the dynamic changes of the total antibody, spike protein (S)-, receptor-binding domain (RBD)-, and nucleoprotein (N)-specific immunoglobulin M (IgM) and G (IgG) levels during SARS-CoV-2 infection and recovery. The generation of S-, RBD-, and N-specific IgG occurs one week later in patients with severe/critical COVID-19 compared to patients with mild/moderate disease, while S- and RBD-specific IgG levels are 1.5-fold higher in severe/critical patients during hospitalization. The RBD-specific IgG levels are 4-fold higher in older patients than in younger patients during hospitalization. In addition, the S- and RBD-specific IgG levels are 2-fold higher in the recovered patients who are SARS-CoV-2 RNA negative than those who are RNA positive. Lower S-, RBD-, and N-specific IgG levels are associated with a lower lymphocyte percentage, higher neutrophil percentage, and a longer duration of viral shedding. Patients with low antibody levels on discharge might thereby have a high chance of being tested positive for SARS-CoV-2 RNA after recovery. Our study provides important information for COVID-19 diagnosis, treatment, and vaccine development.
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http://dx.doi.org/10.1038/s41467-020-19943-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699636PMC
November 2020

Transcriptional regulatory networks of tumor-associated macrophages that drive malignancy in mesenchymal glioblastoma.

Genome Biol 2020 08 26;21(1):216. Epub 2020 Aug 26.

Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Glioblastoma (GBM) is a complex disease with extensive molecular and transcriptional heterogeneity. GBM can be subcategorized into four distinct subtypes; tumors that shift towards the mesenchymal phenotype upon recurrence are generally associated with treatment resistance, unfavorable prognosis, and the infiltration of pro-tumorigenic macrophages.

Results: We explore the transcriptional regulatory networks of mesenchymal-associated tumor-associated macrophages (MA-TAMs), which drive the malignant phenotypic state of GBM, and identify macrophage receptor with collagenous structure (MARCO) as the most highly differentially expressed gene. MARCO TAMs induce a phenotypic shift towards mesenchymal cellular state of glioma stem cells, promoting both invasive and proliferative activities, as well as therapeutic resistance to irradiation. MARCO TAMs also significantly accelerate tumor engraftment and growth in vivo. Moreover, both MA-TAM master regulators and their target genes are significantly correlated with poor clinical outcomes and are often associated with genomic aberrations in neurofibromin 1 (NF1) and phosphoinositide 3-kinases/mammalian target of rapamycin/Akt pathway (PI3K-mTOR-AKT)-related genes. We further demonstrate the origination of MA-TAMs from peripheral blood, as well as their potential association with tumor-induced polarization states and immunosuppressive environments.

Conclusions: Collectively, our study characterizes the global transcriptional profile of TAMs driving mesenchymal GBM pathogenesis, providing potential therapeutic targets for improving the effectiveness of GBM immunotherapy.
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http://dx.doi.org/10.1186/s13059-020-02140-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448990PMC
August 2020

Implications of SARS-CoV-2 infection for patients with rheumatic disease.

Ann Rheum Dis 2020 Aug 13. Epub 2020 Aug 13.

Bioinformatics, Nanjing Medical University, Nanjing, China

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http://dx.doi.org/10.1136/annrheumdis-2020-218050DOI Listing
August 2020

Mature myelin maintenance requires Qki to coactivate PPARβ-RXRα-mediated lipid metabolism.

J Clin Invest 2020 05;130(5):2220-2236

Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Lipid-rich myelin forms electrically insulating, axon-wrapping multilayers that are essential for neural function, and mature myelin is traditionally considered metabolically inert. Surprisingly, we discovered that mature myelin lipids undergo rapid turnover, and quaking (Qki) is a major regulator of myelin lipid homeostasis. Oligodendrocyte-specific Qki depletion, without affecting oligodendrocyte survival, resulted in rapid demyelination, within 1 week, and gradually neurological deficits in adult mice. Myelin lipids, especially the monounsaturated fatty acids and very-long-chain fatty acids, were dramatically reduced by Qki depletion, whereas the major myelin proteins remained intact, and the demyelinating phenotypes of Qki-depleted mice were alleviated by a high-fat diet. Mechanistically, Qki serves as a coactivator of the PPARβ-RXRα complex, which controls the transcription of lipid-metabolism genes, particularly those involved in fatty acid desaturation and elongation. Treatment of Qki-depleted mice with PPARβ/RXR agonists significantly alleviated neurological disability and extended survival durations. Furthermore, a subset of lesions from patients with primary progressive multiple sclerosis were characterized by preferential reductions in myelin lipid contents, activities of various lipid metabolism pathways, and expression level of QKI-5 in human oligodendrocytes. Together, our results demonstrate that continuous lipid synthesis is indispensable for mature myelin maintenance and highlight an underappreciated role of lipid metabolism in demyelinating diseases.
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http://dx.doi.org/10.1172/JCI131800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191000PMC
May 2020

Genomic and Phenotypic Characterization of a Broad Panel of Patient-Derived Xenografts Reflects the Diversity of Glioblastoma.

Clin Cancer Res 2020 03 18;26(5):1094-1104. Epub 2019 Dec 18.

Mayo Clinic Arizona, Scottsdale, Arizona.

Purpose: Glioblastoma is the most frequent and lethal primary brain tumor. Development of novel therapies relies on the availability of relevant preclinical models. We have established a panel of 96 glioblastoma patient-derived xenografts (PDX) and undertaken its genomic and phenotypic characterization.

Experimental Design: PDXs were established from glioblastoma, IDH-wildtype ( = 93), glioblastoma, IDH-mutant ( = 2), diffuse midline glioma, H3 K27M-mutant ( = 1), and both primary ( = 60) and recurrent ( = 34) tumors. Tumor growth rates, histopathology, and treatment response were characterized. Integrated molecular profiling was performed by whole-exome sequencing (WES, = 83), RNA-sequencing ( = 68), and genome-wide methylation profiling ( = 76). WES data from 24 patient tumors was compared with derivative models.

Results: PDXs recapitulate many key phenotypic and molecular features of patient tumors. Orthotopic PDXs show characteristic tumor morphology and invasion patterns, but largely lack microvascular proliferation and necrosis. PDXs capture common and rare molecular drivers, including alterations of , and , most at frequencies comparable with human glioblastoma. However, amplification was absent. RNA-sequencing and genome-wide methylation profiling demonstrated broad representation of glioblastoma molecular subtypes. promoter methylation correlated with increased survival in response to temozolomide. WES of 24 matched patient tumors showed preservation of most genetic driver alterations, including amplification. However, in four patient-PDX pairs, driver alterations were gained or lost on engraftment, consistent with clonal selection.

Conclusions: Our PDX panel captures the molecular heterogeneity of glioblastoma and recapitulates many salient genetic and phenotypic features. All models and genomic data are openly available to investigators.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056576PMC
March 2020

The androgen receptor expression and association with patient's survival in different cancers.

Genomics 2020 03 20;112(2):1926-1940. Epub 2019 Nov 20.

State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing 211166, China; Department of Pathology, School of Basic Medical Sciences & The Affiliated Sir Run Run Hospital, Nanjing Medical University, Nanjing 21116, China. Electronic address:

To understand the androgen receptor (AR) in different human malignancies, we conducted a pan-cancer analysis of AR in different tumor tissues and association with patient survival and obtained AR expression data from The Cancer Genome Atlas. Pan-Cancer Analysis of AR indicated that 12 tumor types had decreased AR expression in the tumor, while glioblastoma multiforme has overexpressed AR. The survival analysis showed that high AR mRNA is associated with poor survival of stomach adenocarcinoma and low-grade glioma, but better survival of adrenocortical carcinoma, kidney renal clear cell carcinoma, acute myeloid leukemia, liver hepatocellular carcinoma, ovarian serous cystadenocarcinoma, and skin cutaneous melanoma based on AR mRNA, protein or AR-score. AR was associated with different clinical characteristics and AR correlated genes enriched in cancer-related pathways. These data indicate that AR signaling may be strongly associated with some cancer development and patients' survival, which is promising for potential treatment using antiandrogen therapies.
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http://dx.doi.org/10.1016/j.ygeno.2019.11.005DOI Listing
March 2020

A PET Radiomics Model to Predict Refractory Mediastinal Hodgkin Lymphoma.

Sci Rep 2019 02 4;9(1):1322. Epub 2019 Feb 4.

Department of Radiation Oncology, Division of Radiation Oncology, MD Anderson Cancer Center, Houston, TX, USA.

First-order radiomic features, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG), are associated with disease progression in early-stage classical Hodgkin lymphoma (HL). We hypothesized that a model incorporating first- and second-order radiomic features would more accurately predict outcome than MTV or TLG alone. We assessed whether radiomic features extracted from baseline PET scans predicted relapsed or refractory disease status in a cohort of 251 patients with stage I-II HL who were managed at a tertiary cancer center. Models were developed and tested using a machine-learning algorithm. Features extracted from mediastinal sites were highly predictive of primary refractory disease. A model incorporating 5 of the most predictive features had an area under the curve (AUC) of 95.2% and total error rate of 1.8%. By comparison, the AUC was 78% for both MTV and TLG and was 65% for maximum standardize uptake value (SUV). Furthermore, among the patients with refractory mediastinal disease, our model distinguished those who were successfully salvaged from those who ultimately died of HL. We conclude that our PET radiomic model may improve upfront stratification of early-stage HL patients with mediastinal disease and thus contribute to risk-adapted, individualized management.
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http://dx.doi.org/10.1038/s41598-018-37197-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361903PMC
February 2019

The Role of Fibrinogen-Like Protein 2 on Immunosuppression and Malignant Progression in Glioma.

J Natl Cancer Inst 2019 03;111(3):292-300

Departments of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX.

Background: Virtually all low-grade gliomas (LGGs) will progress to high-grade gliomas (HGGs), including glioblastoma, the most common malignant primary brain tumor in adults. A key regulator of immunosuppression, fibrinogen-like protein 2 (FGL2), may play an important role in the malignant transformation of LGG to HGG. We sought to determine the mechanism of FGL2 on tumor progression and to show that inhibiting FGL2 expression had a therapeutic effect.

Methods: We analyzed human gliomas that had progressed from low- to high-grade for FGL2 expression. We modeled FGL2 overexpression in an immunocompetent genetically engineered mouse model to determine its effect on tumor progression. Tumors and their associated microenvironments were analyzed for their immune cell infiltration. Mice were treated with an FGL2 antibody to determine a therapeutic effect. Statistical tests were two-sided.

Results: We identified increased expression of FGL2 in surgically resected tumors that progressed from low to high grade (n = 10). The Cancer Genome Atlas data showed that LGG cases with overexpression of FGL2 (n = 195) had statistically significantly shorter survival (median = 62.9 months) compared with cases with low expression (n = 325, median = 94.4 months, P < .001). In a murine glioma model, HGGs induced with FGL2 exhibited a mesenchymal phenotype and increased CD4+ forkhead box P3 (FoxP3)+ Treg cells, implicating immunosuppression as a mechanism for tumor progression. Macrophages in these tumors were skewed toward the immunosuppressive M2 phenotype. Depletion of Treg cells with anti-FGL2 statistically significantly prolonged survival in mice compared with controls (n = 11 per group, median survival = 90 days vs 62 days, P = .004), shifted the phenotype from mesenchymal HGG to proneural LGG, and decreased M2 macrophage skewing.

Conclusions: FGL2 facilitates glioma progression from low to high grade. Suppressing FGL2 expression holds therapeutic promise for halting malignant transformation in glioma.
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http://dx.doi.org/10.1093/jnci/djy107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410946PMC
March 2019

Whole-genome sequencing reveals genomic signatures associated with the inflammatory microenvironments in Chinese NSCLC patients.

Nat Commun 2018 05 24;9(1):2054. Epub 2018 May 24.

Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, 211116, Nanjing, China.

Chinese lung cancer patients have distinct epidemiologic and genomic features, highlighting the presence of specific etiologic mechanisms other than smoking. Here, we present a comprehensive genomic landscape of 149 non-small cell lung cancer (NSCLC) cases and identify 15 potential driver genes. We reveal that Chinese patients are specially characterized by not only highly clustered EGFR mutations but a mutational signature (MS3, 33.7%), that is associated with inflammatory tumor-infiltrating B lymphocytes (P = 0.001). The EGFR mutation rate is significantly increased with the proportion of the MS3 signature (P = 9.37 × 10). TCGA data confirm that the infiltrating B lymphocyte abundance is significantly higher in the EGFR-mutated patients (P = 0.007). Additionally, MS3-high patients carry a higher contribution of distant chromosomal rearrangements >1 Mb (P = 1.35 × 10), some of which result in fusions involving genes with important functions (i.e., ALK and RET). Thus, inflammatory infiltration may contribute to the accumulation of EGFR mutations, especially in never-smokers.
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http://dx.doi.org/10.1038/s41467-018-04492-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5967326PMC
May 2018

Gene array analysis of PD-1H overexpressing monocytes reveals a pro-inflammatory profile.

Heliyon 2018 Feb 1;4(2):e00545. Epub 2018 Mar 1.

Center of Emphasis in Infectious Diseases, Department of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, United States.

We have previously reported that overexpression of Programmed Death -1 Homolog (PD-1H) in human monocytes leads to activation and spontaneous secretion of multiple pro inflammatory cytokines. Here we evaluate changes in monocytes gene expression after enforced PD-1H expression by gene array. The results show that there are significant alterations in 51 potential candidate genes that relate to immune response, cell adhesion and metabolism. Genes corresponding to pro-inflammatory cytokines showed the highest upregulation, 7, 3.2, 3.0, 5.8, 4.4 and 3.1 fold upregulation of TNF-α, IL-1 β, IFN-α, γ, λ and IL-27 relative to vector control. The data are in agreement with cytometric bead array analysis showing induction of proinflammatory cytokines, IL-6, IL-1β and TNF-α by PD-1H. Other genes related to inflammation, include transglutaminase 2 (TG2), NF-κB (p65 and p50) and toll like receptors (TLR) 3 and 4 were upregulated 5, 4.5 and 2.5 fold, respectively. Gene set enrichment analysis (GSEA) also revealed that signaling pathways related to inflammatory response, such as NFκB, AT1R, PYK2, MAPK, RELA, TNFR1, MTOR and proteasomal degradation, were significantly upregulated in response to PD-1H overexpression. We validated the results utilizing a standard inflammatory sepsis model in humanized BLT mice, finding that PD-1H expression was highly correlated with proinflammatory cytokine production. We therefore conclude that PD-1H functions to enhance monocyte activation and the induction of a pro-inflammatory gene expression profile.
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http://dx.doi.org/10.1016/j.heliyon.2018.e00545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842328PMC
February 2018

Large Scale Identification of Variant Proteins in Glioma Stem Cells.

ACS Chem Neurosci 2018 01 21;9(1):73-79. Epub 2017 Dec 21.

Center of Excellence in Biological and Medical Mass Spectrometry, Lund University , Klinikgatan 32, SE-221 84 Lund, Sweden.

Glioblastoma (GBM), the most malignant of primary brain tumors, is a devastating and deadly disease, with a median survival of 14 months from diagnosis, despite standard regimens of radical brain tumor surgery, maximal safe radiation, and concomitant chemotherapy. GBM tumors nearly always re-emerge after initial treatment and frequently display resistance to current treatments. One theory that may explain GBM re-emergence is the existence of glioma stemlike cells (GSCs). We sought to identify variant protein features expressed in low passage GSCs derived from patient tumors. To this end, we developed a proteomic database that reflected variant and nonvariant sequences in the human proteome, and applied a novel retrograde proteomic workflow, to identify and validate the expression of 126 protein variants in 33 glioma stem cell strains. These newly identified proteins may harbor a subset of novel protein targets for future development of GBM therapy.
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http://dx.doi.org/10.1021/acschemneuro.7b00362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008157PMC
January 2018

A relative increase in circulating platelets following chemoradiation predicts for poor survival of patients with glioblastoma.

Oncotarget 2017 Oct 12;8(52):90488-90495. Epub 2017 Oct 12.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: Thrombocytosis is triggered by and promotes tumor growth. The relationship between the change in circulating platelets after chemoradiation therapy (CRT) or adjuvant temozolomide (TMZ) and survival in glioblastoma remains unclear. We hypothesized that an increase in platelets after these treatments would be predictive of a shorter survival.

Methods: We retrospectively reviewed data on 122 patients with newly diagnosed, pathologically proven glioblastoma who had been treated with surgery, followed by CRT and adjuvant TMZ, from 2007 to 2016. The association between the changes in blood count levels and survival was analyzed by the log-rank test. To adjust for confounding, we performed a multivariate analysis using known prognostic co-variates.

Results: Patients were dichotomized on the basis of the relative change in platelets after CRT from the baseline: ≤30% increase, low ( = 101) >30% increase, high ( = 12). The median survival for high . low platelets were 11 28 months ( = 0.0062). No significant survival differences were observed on the basis of platelet changes during adjuvant TMZ. Similarly, changes in lymphocyte counts were not significantly prognostic. On multivariate analysis, MGMT, performance status, and an increase in platelets after CRT were significantly associated with survival (HR for platelets, 4.5; 95% confidence interval, 1.6-12.6).

Conclusions: Increased platelet counts after CRT are predictive of poor survival in glioblastoma. The effect is platelet specific and does not reflect bone marrow changes, as lymphocyte changes were not significantly prognostic. These results suggest an interaction between platelets and tumor aggressiveness. Thus, platelets serve as a novel, minimally invasive liquid biopsy for predicting outcome.
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http://dx.doi.org/10.18632/oncotarget.21799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685768PMC
October 2017

TumorFusions: an integrative resource for cancer-associated transcript fusions.

Nucleic Acids Res 2018 01;46(D1):D1144-D1149

The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.

Gene fusion represents a class of molecular aberrations in cancer and has been exploited for therapeutic purposes. In this paper we describe TumorFusions, a data portal that catalogues 20 731 gene fusions detected in 9966 well characterized cancer samples and 648 normal specimens from The Cancer Genome Atlas (TCGA). The portal spans 33 cancer types in TCGA. Fusion transcripts were identified via a uniform pipeline, including filtering against a list of 3838 transcript fusions detected in a panel of 648 non-neoplastic samples. Fusions were mapped to somatic DNA rearrangements identified using whole genome sequencing data from 561 cancer samples as a means of validation. We observed that 65% of transcript fusions were associated with a chromosomal alteration, which is annotated in the portal. Other features of the portal include links to SNP array-based copy number levels and mutational patterns, exon and transcript level expressions of the partner genes, and a network-based centrality score for prioritizing functional fusions. Our portal aims to be a broadly applicable and user friendly resource for cancer gene annotation and is publicly available at http://www.tumorfusions.org.
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http://dx.doi.org/10.1093/nar/gkx1018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753333PMC
January 2018

PAF promotes stemness and radioresistance of glioma stem cells.

Proc Natl Acad Sci U S A 2017 10 9;114(43):E9086-E9095. Epub 2017 Oct 9.

Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;

An integrated genomic and functional analysis to elucidate DNA damage signaling factors promoting self-renewal of glioma stem cells (GSCs) identified proliferating cell nuclear antigen (PCNA)-associated factor () up-regulation in glioblastoma. PAF is preferentially overexpressed in GSCs. Its depletion impairs maintenance of self-renewal without promoting differentiation and reduces tumor-initiating cell frequency. Combined transcriptomic and metabolomic analyses revealed that PAF supports GSC maintenance, in part, by influencing DNA replication and pyrimidine metabolism pathways. PAF interacts with PCNA and regulates PCNA-associated DNA translesion synthesis (TLS); consequently, PAF depletion in combination with radiation generated fewer tumorspheres compared with radiation alone. Correspondingly, pharmacological impairment of DNA replication and TLS phenocopied the effect of PAF depletion in compromising GSC self-renewal and radioresistance, providing preclinical proof of principle that combined TLS inhibition and radiation therapy may be a viable therapeutic option in the treatment of glioblastoma multiforme (GBM).
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http://dx.doi.org/10.1073/pnas.1708122114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664518PMC
October 2017

EGFR heterogeneity and implications for therapeutic intervention in glioblastoma.

Neuro Oncol 2018 05;20(6):743-752

Department of Biomedicine, University of Bergen, Norway.

Patients with glioblastoma (GBM) have a universally poor prognosis and are in urgent need of effective treatment strategies. Recent advances in sequencing techniques unraveled the complete genomic landscape of GBMs and revealed profound heterogeneity of individual tumors even at the single cell level. Genomic profiling has detected epidermal growth factor receptor (EGFR) gene alterations in more than half of GBMs. Major genetic events include amplification and mutation of EGFR. Yet, treatment strategies targeting EGFR have thus far failed in clinical trials. In this review, we discuss the clonal and functional heterogeneity of EGFRs in GBM development and critically reassess the potential of EGFRs as therapeutic targets.
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http://dx.doi.org/10.1093/neuonc/nox191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5961011PMC
May 2018

Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment.

Cancer Cell 2017 07;32(1):42-56.e6

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

We leveraged IDH wild-type glioblastomas, derivative neurospheres, and single-cell gene expression profiles to define three tumor-intrinsic transcriptional subtypes designated as proneural, mesenchymal, and classical. Transcriptomic subtype multiplicity correlated with increased intratumoral heterogeneity and presence of tumor microenvironment. In silico cell sorting identified macrophages/microglia, CD4 T lymphocytes, and neutrophils in the glioma microenvironment. NF1 deficiency resulted in increased tumor-associated macrophages/microglia infiltration. Longitudinal transcriptome analysis showed that expression subtype is retained in 55% of cases. Gene signature-based tumor microenvironment inference revealed a decrease in invading monocytes and a subtype-dependent increase in macrophages/microglia cells upon disease recurrence. Hypermutation at diagnosis or at recurrence associated with CD8 T cell enrichment. Frequency of M2 macrophages detection associated with short-term relapse after radiation therapy.
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http://dx.doi.org/10.1016/j.ccell.2017.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5599156PMC
July 2017

Systematic analysis of telomere length and somatic alterations in 31 cancer types.

Nat Genet 2017 Mar 30;49(3):349-357. Epub 2017 Jan 30.

The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.

Cancer cells survive cellular crisis through telomere maintenance mechanisms. We report telomere lengths in 18,430 samples, including tumors and non-neoplastic samples, across 31 cancer types. Telomeres were shorter in tumors than in normal tissues and longer in sarcomas and gliomas than in other cancers. Among 6,835 cancers, 73% expressed telomerase reverse transcriptase (TERT), which was associated with TERT point mutations, rearrangements, DNA amplifications and transcript fusions and predictive of telomerase activity. TERT promoter methylation provided an additional deregulatory TERT expression mechanism. Five percent of cases, characterized by undetectable TERT expression and alterations in ATRX or DAXX, demonstrated elongated telomeres and increased telomeric repeat-containing RNA (TERRA). The remaining 22% of tumors neither expressed TERT nor harbored alterations in ATRX or DAXX. In this group, telomere length positively correlated with TP53 and RB1 mutations. Our analysis integrates TERT abnormalities, telomerase activity and genomic alterations with telomere length in cancer.
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http://dx.doi.org/10.1038/ng.3781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571729PMC
March 2017

GlioVis data portal for visualization and analysis of brain tumor expression datasets.

Neuro Oncol 2017 01 9;19(1):139-141. Epub 2016 Nov 9.

Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA (R.L.B.); Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA (Q.W., R.G.V.); Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA (Q.W.); Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA (Q.W., R.G.V.); Bioinformatics unit, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid, Spain (A.C.); Department of Computational Biology, The Jackson Laboratory, Farmington, Connecticut, USA (R.G.V.); Seve Ballesteros Foundation Brain Tumor Group, Cancer Cell Biology Programme, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid, Spain (M.S.)

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http://dx.doi.org/10.1093/neuonc/now247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5193031PMC
January 2017

Epigenetic Activation of WNT5A Drives Glioblastoma Stem Cell Differentiation and Invasive Growth.

Cell 2016 11;167(5):1281-1295.e18

Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Glioblastoma stem cells (GSCs) are implicated in tumor neovascularization, invasiveness, and therapeutic resistance. To illuminate mechanisms governing these hallmark features, we developed a de novo glioblastoma multiforme (GBM) model derived from immortalized human neural stem/progenitor cells (hNSCs) to enable precise system-level comparisons of pre-malignant and oncogene-induced malignant states of NSCs. Integrated transcriptomic and epigenomic analyses uncovered a PAX6/DLX5 transcriptional program driving WNT5A-mediated GSC differentiation into endothelial-like cells (GdECs). GdECs recruit existing endothelial cells to promote peritumoral satellite lesions, which serve as a niche supporting the growth of invasive glioma cells away from the primary tumor. Clinical data reveal higher WNT5A and GdECs expression in peritumoral and recurrent GBMs relative to matched intratumoral and primary GBMs, respectively, supporting WNT5A-mediated GSC differentiation and invasive growth in disease recurrence. Thus, the PAX6/DLX5-WNT5A axis governs the diffuse spread of glioma cells throughout the brain parenchyma, contributing to the lethality of GBM.
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http://dx.doi.org/10.1016/j.cell.2016.10.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5320931PMC
November 2016
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