Monoclonal B-cell lymphocytosis (MBL), the presence in the blood of monoclonal B cells in numbers below 5000 per cubic millimeter with no other features of a B-cell lymphoproliferative disorder, ...occurs in 3 to 5% of the population over the age of 50 years. In some instances, MBL can evolve into chronic lymphocytic leukemia (CLL), but whether CLL is always preceded by MBL is unknown. This study of a unique population found monoclonal B-cell clones in the blood for up to 6.4 years before the diagnosis of CLL in 44 of 45 patients.
Monoclonal B-cell lymphocytosis occurs in 3 to 5% of the population over the age of 50 years. This study of a unique population found monoclonal B-cell clones in the blood for up to 6.4 years before the diagnosis of chronic lymphocytic leukemia in 44 of 45 patients.
Chronic lymphocytic leukemia (CLL), the most common leukemia among adults in Western countries,
1
is characterized by an accumulation of mature B cells.
2
Although male sex, advanced age, white race, and a family history of CLL or other lymphoproliferative cancers are recognized risk factors,
3
,
4
the cause and pathogenesis of CLL are largely unknown. Genetic factors are important in the development of CLL on the basis of evidence from multiply affected families, case series, and registry studies of twins and case–control and population-based subjects.
1
–
11
Also, findings of an association between polymorphisms and an increased susceptibility to CLL support a role . . .
Background and aims
Patients with cirrhosis commonly experience minimal hepatic encephalopathy (MHE), and alterations in neurotransmitters have been thought to be related to cognitive function. ...However, the relationship between alterations in peripheral and central butyrylcholinesterase (BuChE) with MHE disease progression remains unknown. As such, this study was designed to investigate potential changes in peripheral and central BuChE activity and their effects on cognitive function in the context of MHE.
Materials and methods
We enrolled 43 patients with cirrhosis secondary to hepatitis B, 20 without MHE and 23 with MHE, and 25 with healthy controls (HC). All the selected subjects underwent resting-state functional MRI, and the original images were processed to obtain the regional homogeneity (ReHo) brain maps. Thereafter, the correlation of BuChE activity with ReHo, number connection test of type A (NCT-A), and digital symbol test (DST) scores with MHE patients were analyzed using
Person
correlation analysis. Meanwhile, we purchased 12 Sprague-Dawley (SD) rats and divided them into an experimental group (
n
= 6) and a control group (
n
= 6). The rats in the experimental group were intraperitoneally injected with thioacetamide (TAA) to prepare MHE model rats. After modeling, we used the Morris water maze (MWM) and elevated plus maze (EPM) to assess the cognition function and exploratory behavior of all rats. The activity of serum, hippocampus, and frontal lobe tissue BuChE was detected by ELISA.
Results
BuChE activity gradually decreased among the HC, patients with cirrhosis, and MHE groups (all
P
< 0.01). We observed a linear correlation between serum BuChE and NCT-A and DST scores in MHE patients (all
P
< 0.01). We noted that BuChE activity can negatively correlate with ReHo values in the left middle temporal gyrus and left inferior temporal gyrus, and positively correlate with ReHo values in the right inferior frontal gyrus, and also found that the peripheral BuChE activity of MHE rats was significantly lower than their control counterparts, and the BuChE activity in frontal lobe extracts was significantly higher than the control rats (all
P
< 0.05).
Conclusion
The altered activity of BuChE may contribute to cognitive impairment in MHE patients, which may be a potential biomarker of disease evolution in the context of MHE.
HER2 and hormone receptors are biomarkers for selecting breast cancer therapy and predicting outcomes. In the era of antibody‐drug conjugates (ADC), a relatively low HER2 expression level is adequate ...for targeting tumor cells. We explored the potential of RNA profiling, determined by next generation sequencing (NGS), to provide more flexible clinical biomarkers as compared with immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH). Data from 57 breast cancers was used to study biomarker levels as detected by routine clinical transcriptomic tests. HER2 (ERBB2), estrogen receptor alpha (ESR1), and androgen receptor (AR) mRNA levels were compared with IHC and FISH results. There was a significant overlap in the levels of ERBB2 mRNA between cases scored by IHC as zero, 1+, and 2+. This variation correlated with progression‐free survival (PFS). Similarly, the ESR1 RNA accurately reflected estrogen receptor (ER) status. Patients with high AR mRNA had better PFS (p = 0.05). Patients expressing high ER and AR levels had better PFS than those expressing low ESR1 and AR (p = 0.03). These findings suggest that RNA analysis can be an alternative to IHC and FISH and provides continuous data that can better determine cut‐off points for predicting response to ADC.
Introduction
Cytogenetic analysis is important for stratifying patients with various neoplasms. We explored the use of targeted next generation sequencing (NGS) in detecting chromosomal structural ...abnormalities or copy number variations (CNVs) in patients with myeloid neoplasms.
Methods
Plasma cell-free DNA (cfDNA) from 2821 myeloid or lymphoid neoplasm patients were collected. cfDNA was sequenced using a 275 gene panel. CNVkit software was used for analyzing and visualizing CNVs. Cytogenetic data from corresponding bone marrow (BM) samples was available on 89 myeloid samples.
Results
Of the 2821 samples, 1539 (54.5%) showed evidence of mutations consistent with the presence of neoplastic clones in circulation. Of these 1539 samples, 906 (59%) showed abnormalities associated with myeloid neoplasms and 633 (41%) with lymphoid neoplasms. Chromosomal structural abnormalities in cfDNA were detected in 146 (16%) myeloid samples and 76 (12%) lymphoid samples. Upon comparison of the myeloid samples with 89 BM patients, NGS testing was able to reliably detect chromosomal gain or loss, except for fusion abnormalities. When cytogenetic abnormalities were classified according to prognostic classes, there was a complete (100%) concordance between cfDNA NGS data and cytogenetic data.
Conclusions
This data shows that liquid biopsy using targeted NGS is reliable in detecting chromosomal structural abnormalities in myeloid neoplasms. In specific circumstances, targeted NGS may be reliable and efficient to provide adequate information without the need for BM biopsy considering broad mutation profiling can be obtained through adequate sequencing within the same test. Overall, this study supports the use of liquid biopsy for early diagnosis and monitoring of patients with myeloid neoplasms.
Current use of liquid biopsy is based on cell-free DNA (cfDNA) and the evaluation of mutations or methylation pattern. However, expressed RNA can capture mutations, changes in expression levels due ...to methylation, and provide information on cell of origin, growth, and proliferation status. We developed an approach to isolate cell-free total nucleic acid (cfDNA) and used targeted next generation sequencing to sequence cell-free RNA (cfRNA) and cfDNA as new approach in liquid biopsy. We demonstrate that cfRNA is overall more sensitive than cfDNA in detecting mutations. We show that cfRNA is reliable in detecting fusion genes and cfDNA is reliable in detecting chromosomal gains and losses. cfRNA levels of various solid tumor biomarkers were significantly higher (P < 0.0001) in samples from solid tumors as compared with normal control. Similarly, cfRNA lymphoid markers and cfRNA myeloid markers were all higher in lymphoid and myeloid neoplasms, respectively as compared with control (P < 0.0001). Using machine learning we demonstrate cfRNA was highly predictive of diagnosis (AUC >0.98) of solid tumors, B-cell lymphoid neoplasms, T-cell lymphoid neoplasms, and myeloid neoplasms. In evaluating the host immune system, cfRNA CD4:CD8B and CD3D:CD19 ratios in normal controls were as expected (median: 5.92 and 6.87, respectively) and were significantly lower in solid tumors (P < 0.0002). This data suggests that liquid biopsy combining analysis of cfRNA with cfDNA is practical and may provide helpful information in predicting genomic abnormalities, diagnosis of neoplasms and evaluating both the tumor biology and the host response.
Here, we describe the JAK2 mutation profile in a series of approximately 20,000 blood samples from patients with clinically suspected myeloproliferative neoplasias. Using a sensitive reverse ...transcription-PCR and direct sequencing approach on RNA rather than DNA, we detected JAK2 mutations in exons 12–15 in approximately 20% of these patients. We identified new mutations in addition to the known V617F and exon 12 mutations, which were the most common. Most of the novel mutations are located in the pseudokinase domain and therefore are expected to relieve the autoinhibitory function of this domain on JAK2 kinase activity. Our data suggest that molecular testing of JAK2 mutations should not be restricted to the V617F and exon 12 mutations, but perhaps should extend to most of the pseudokinase domain coding region as well. Furthermore, mutation screening using RNA is highly sensitive and could replace DNA-based testing because of the relative abundance of target transcripts and the ease in detecting deletion of the entire exon.
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