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Supplementary Figure from Large-Scale In Vitro and In Vivo CRISPR-Cas9 Knockout Screens Identify a 16-Gene Fitness Score for Improved Risk Assessment in Acute Myeloid Leukemia

Supplementary Table from Large-Scale In Vitro and In Vivo CRISPR-Cas9 Knockout Screens Identify a 16-Gene Fitness Score for Improved Risk Assessment in Acute Myeloid Leukemia

Purpose:The molecular complexity of acute myeloid leukemia (AML) presents a considerable challenge to implementation of clinical genetic testing for accurate risk stratification. Identification of better biomarkers therefore remains a high priority to enable improving established stratification and guiding risk-adapted therapy decisions.Experimental Design:We systematically integrated and analyzed the genome-wide CRISPR-Cas9 data from more than 1,000 in vitro and in vivo knockout screens to identify the AML-specific fitness genes. A prognostic fitness score was developed using the sparse regression analysis in a training cohort of 618 cases and validated in five publicly available independent cohorts (n = 1,570) and our RJAML cohort (n = 157) with matched RNA sequencing and targeted gene sequencing performed.Results:A total of 280 genes were identified as AML fitness genes and a 16-gene AML fitness (AFG16) score was further generated and displayed highly prognostic power in more than 2,300 patients with AML. The AFG16 score was able to distill downstream consequences of several genetic abnormalities and can substantially improve the European LeukemiaNet classification. The multi-omics data from the RJAML cohort further demonstrated its clinical applicability. Patients with high AFG16 scores had significantly poor response to induction chemotherapy. Ex vivo drug screening indicated that patients with high AFG16 scores were more sensitive to the cell-cycle inhibitors flavopiridol and SNS-032, and exhibited strongly activated cell-cycle signaling.Conclusions:Our findings demonstrated the utility of the AFG16 score as a powerful tool for better risk stratification and selecting patients most likely to benefit from chemotherapy and alternative experimental therapies.

Supplementary Data from Large-Scale In Vitro and In Vivo CRISPR-Cas9 Knockout Screens Identify a 16-Gene Fitness Score for Improved Risk Assessment in Acute Myeloid Leukemia

Background The epidemiology of Gram-negative bacteria in patients with febrile neutropenia (FN) and their susceptibility to initial empirical antibiotic therapy is key to successful treatment during the treatment of hematologic malignancies. Methods A retrospective study was conducted. Patients with FN and confirmed laboratory results of Gram-negative bacteria infections were included. If no direct sensitivity of the identified pathogen to the initially prescribed antibiotic regimen was confirmed, it was defined as inappropriate initial antibiotic treatment (IIAT). Results A total of 247 patients with FN were proven to be infected with Gram-negative bacteria, and 200 were diagnosed with acute leukemia. The most commonly detected bacteria were Escherichia coli (40%), Klebsiella pneumoniae (20%), and Pseudomonas aeruginosa (11%). In sum, 176 patients were classified as IIAT. The mortality rate in the IIAT group was significantly higher (37.7% vs 23.9%, P=0.038). With monotherapy as empirical treatment, high possibility of IIAT with fluoroquinolones (52%) and cephalosporins (35%) was detected, while more sensitivity to carbapenems (16%) and glycopeptides antibiotics (19%) was noticed. With combined treatment, cephalosporins/carbapenems had with the lowest percentage of IIAT (18%). Conclusion In conclusion, inappropriate initial empirical antibiotic treatments were associated with higher mortality in patients with hematologic malignancies. The current empirical antibiotic regimen needs to be further optimized.

Purpose: The molecular complexity of acute myeloid leukemia (AML) presents a considerable challenge to implementation of clinical genetic testing for accurate risk stratification. Identification of better biomarkers therefore remains a high priority to enable improving established stratification and guiding risk-adapted therapy decisions. Experimental Design: We systematically integrated and analyzed the genome-wide CRISPR-Cas9 data from more than 1,000 in vitro and in vivo knockout screens to identify the AML-specific fitness genes. A prognostic fitness score was developed using the sparse regression analysis in a training cohort of 618 cases and validated in five publicly available independent cohorts (n = 1,570) and our RJAML cohort (n = 157) with matched RNA sequencing and targeted gene sequencing performed. Results: A total of 280 genes were identified as AML fitness genes and a 16-gene AML fitness (AFG16) score was further generated and displayed highly prognostic power in more than 2,300 patients with AML. The AFG16 score was able to distill downstream consequences of several genetic abnormalities and can substantially improve the European LeukemiaNet classification. The multi-omics data from the RJAML cohort further demonstrated its clinical applicability. Patients with high AFG16 scores had significantly poor response to induction chemotherapy. Ex vivo drug screening indicated that patients with high AFG16 scores were more sensitive to the cell-cycle inhibitors flavopiridol and SNS-032, and exhibited strongly activated cell-cycle signaling. Conclusions: Our findings demonstrated the utility of the AFG16 score as a powerful tool for better risk stratification and selecting patients most likely to benefit from chemotherapy and alternative experimental therapies.

Previous studies have demonstrated an association between high body mass index (BMI) and acute myeloid leukemias (AML), particularly acute promyelocytic leukemia (APL). However, the effect of obesity and overweight on the incidence of AML is not supported by all studies, and the relationship between obesity and prognosis of AML and APL has not been established. Thus, we conducted a meta-analysis to determine the role of BMI on the risk and clinical outcome of AML, including APL. Twenty-six eligible studies enrolling 12,971 AML (including 866 APL) patients were retrieved and analyzed. Overweight and obesity was associated with an increased incidence of AML (relative risk [RR], 1.23; 95% confidence interval [CI], 1.12–1.35; P

Objective:To determine the predictive value of clinical assessment and dopamine transporter (DAT) uptake for the early development of neurodegenerative synucleinopathy diseases from idiopathic REM sleep behavior disorder (iRBD) over 5 years in a Chinese population.Methods:Forty-three patients with iRBD were administered clinical assessment tests, and 35 were examined by DAT-SPECT imaging during 2011. Cox proportional hazard and Kaplan-Meier analyses were used to evaluate the predictive value of the markers in a follow-up study over 5 years.Results:Eighteen patients (41.9%) developed neurodegenerative synucleinopathy diseases after a median of 4.1 years of prospective follow-up (median interval of 10.5 years from the estimated onset of iRBD symptoms). Patients with higher scores on the Nonmotor Symptom Questionnaire (hazard ratio [HR] 3.11, 95% confidence interval [CI] 1.15–8.40, p = 0.026) and Scale for Outcomes in Parkinson Disease–Autonomic questionnaire (HR 4.46, 95% CI 1.64–12.10, p = 0.003) were more likely to develop neurodegenerative synucleinopathy diseases. Furthermore, the population with decreased 99mTc-TRODAT-1 binding in the left striatum (HR 2.7, 95% CI 1.02–7.14, p = 0.046) and putamen (HR 3.23, 95% CI 1.16–8.33, p = 0.024) had a relatively higher risk of developing neurodegenerative synucleinopathy diseases.Conclusions:Our findings elucidate the predictive value of autonomic dysfunction and DAT uptake in identifying patients with iRBD at a high risk of progressing into neurodegenerative synucleinopathy diseases and could form a basis for future disease-prevention trials.

The present study was to evaluate the diagnostic value of salivary total and oligomeric α-synuclein levels in PD. Furthermore, we sought to explore the relationship between salivary total α-synuclein and α-synuclein SNP variants levels. 201 PD patients and 67 controls were recruited, of which there also had the genetic information of two positive α-synuclein (SNCA) loci. Salivary total α-synuclein was assayed using a highly sensitive Luminex assay and oligomeric α-synuclein was quantified by the combination of Gel filtration chromatography and Western blot, respectively. From our analysis,No difference in salivary total α-synuclein levels was found between PD patients and healthy controls, it decreased with age in PD patients and was closely associated with genotypic distribution of rs11931074 and rs894278 in PD, respectively. After controlled for age and genders, G allele of rs11931074 was correlated with lower salivary total α-synuclein levels, while G allele of rs894278 was also correlated with the higher levels. Simultaneously, the further study was shown that salivary oligomeric α-synuclein in PD patients significantly increased comparing to healthy controls. In conclusions,our study firstly demonstrated that salivary total α-synuclein levels could be manipulated by different α-synuclein SNPs and salivary oligomeric α-synuclein could be a potential diagnostic indicator of PD.

Catechol-O-methyltransferase (COMT) is one of the cardinal enzymes that metabolize dopamine and other catecholamine neurotransmitters in the central and peripheral nervous system. Recent studies have shown that the impact of COMT haplotypes on the development of wearing-off phenomenon is in dispute, while the relationship between COMT haplotypes and wearing-off phenomenon in ethnic Chinese population is lacking. The purpose of this study was to characterize the correlation between the Val158Met polymorphism in the COMT gene and the motor complication "wearing-off" in Chinese PD patients. We have sequenced the COMT gene in 259 PD patients and 257 healthy controls. Our results demonstrated that Met/Met homozygosity of the COMT Val158Met polymorphism was related to a decreased risk of developing wearing-off. This finding suggests that COMT Val158Met may affect susceptibility to wearing-off in PD.