Electrical Sympathetic Neuromodulation Protects Bone Marrow Niche and Drives Hematopoietic Regeneration during Chemotherapy.

The sympathetic nervous system (SNS) of the bone marrow regulates the regeneration and mobilization of hematopoietic stem cells. Chemotherapy can damage bone marrow SNS, which impairs hematopoietic regeneration and aggravates hematologic toxicities. This leads to long-term bone marrow niche damage and increases mortality in patients undergoing chemotherapy. Electrical neuromodulation has been used to improve functional recovery after peripheral nerve injury. This study demonstrates that electrical sympathetic neuromodulation (ESN) of bone marrow can protect the bone marrow niche from chemotherapy-induced injury. Using carboplatin-treated rats, the SNS via the sciatic nerve innervating the femoral marrow with the effective protocol for bone marrow sympathetic activation is electrically stimulated. ESN can mediate several hematopoietic stem cells maintenance factors and promote hematopoietic regeneration after chemotherapy. It also activates adrenergic signals and reduces the release of pro-inflammatory cytokines, particularly interleukin-1 ß, which contribute to chemotherapy-related nerve injury. Consequently, the severity of chemotherapy-related leukopenia, thrombocytopenia, and mortality can be reduced by ESN. As a result, in contrast to current drug-based treatment, such as granulocyte colony-stimulating factor, ESN can be a disruptive adjuvant treatment by protecting and modulating bone marrow function to reduce hematologic toxicity during chemotherapy.

Genome-wide association study of age at menarche in the Taiwan Biobank suggests NOL4 as a novel associated gene.

Sexual maturation is a complex physiological process that involves multiple variables, such as genetic and environmental factors. Among females, age at menarche (AM) is a critical milestone for sexual maturation. This study aimed to identify genetic markers of AM using nationwide population cohort data in Taiwan. Females with self-reported AM between 10 and 16 years (N = 39,827) were eligible for the final analysis. To identify genetic signals related to AM, we conducted a genome-wide association study using a linear regression model and split-half meta-analysis method to verify our findings. The Functional Mapping and Annotation web-based platform was used for positional mapping and gene-based and gene-set analyses. The meta-analysis identified four significant loci, i.e., LIN28B (pooled P = 1.39 × 10-21), NOL4 (pooled P = 8.94 × 10-9), GPR45 (pooled P = 4.19 × 10-11), and LOC105373831 (pooled P = 4.37 × 10-8), that were associated with AM. MAGMA gene-based analysis revealed that LIN28B (P = 1.13 × 10-8), NOL4 (P = 2.27 × 10-7), RXRG (P = 4.34 × 10-7), ETV5 (P = 1.75 × 10-6), and HACE1 (P = 1.82 × 10-6) were significantly associated with AM, while the gene-set analysis identified a significantly enriched pathway involving mTOR signaling complex (FDR corrected P = 1.28 × 10-2). The results replicated evidence for several genetic markers associated with AM in the Taiwanese female population. Our analysis identified a novel locus (rs7239368) in NOL4 associated with AM (ß = 0.051 ± 0.009 years, pooled P = 8.94 × 10-9), whereas additional research is needed to validate its molecular role in sexual maturation.

Comprehensive evaluation of noise reduction methods for single-cell RNA sequencing data.

Normalization and batch correction are critical steps in processing single-cell RNA sequencing (scRNA-seq) data, which remove technical effects and systematic biases to unmask biological signals of interest. Although a number of computational methods have been developed, there is no guidance for choosing appropriate procedures in different scenarios. In this study, we assessed the performance of 28 scRNA-seq noise reduction procedures in 55 scenarios using simulated and real datasets. The scenarios accounted for multiple biological and technical factors that greatly affect the denoising performance, including relative magnitude of batch effects, the extent of cell population imbalance, the complexity of cell group structures, the proportion and the similarity of nonoverlapping cell populations, dropout rates and variable library sizes. We used multiple quantitative metrics and visualization of low-dimensional cell embeddings to evaluate the performance on batch mixing while preserving the original cell group and gene structures. Based on our results, we specified technical or biological factors affecting the performance of each method and recommended proper methods in different scenarios. In addition, we highlighted one challenging scenario where most methods failed and resulted in overcorrection. Our studies not only provided a comprehensive guideline for selecting suitable noise reduction procedures but also pointed out unsolved issues in the field, especially the urgent need of developing metrics for assessing batch correction on imperceptible cell-type mixing.

Genetic ancestry plays a central role in population pharmacogenomics.

Recent studies have pointed out the essential role of genetic ancestry in population pharmacogenetics. In this study, we analyzed the whole-genome sequencing data from The 1000 Genomes Project (Phase 3) and the pharmacogenetic information from Drug Bank, PharmGKB, PharmaADME, and Biotransformation. Here we show that ancestry-informative markers are enriched in pharmacogenetic loci, suggesting that trans-ancestry differentiation must be carefully considered in population pharmacogenetics studies. Ancestry-informative pharmacogenetic loci are located in both protein-coding and non-protein-coding regions, illustrating that a whole-genome analysis is necessary for an unbiased examination over pharmacogenetic loci. Finally, those ancestry-informative pharmacogenetic loci that target multiple drugs are often a functional variant, which reflects their importance in biological functions and pathways. In summary, we develop an efficient algorithm for an ultrahigh-dimensional principal component analysis. We create genetic catalogs of ancestry-informative markers and genes. We explore pharmacogenetic patterns and establish a high-accuracy prediction panel of genetic ancestry. Moreover, we construct a genetic ancestry pharmacogenomic database Genetic Ancestry PhD ( http://hcyang.stat.sinica.edu.tw/databases/genetic_ancestry_phd/ ).

Immune-Related Adverse Events and Immune Checkpoint Inhibitor Efficacy in Patients with Gastrointestinal Cancer with Food and Drug Administration-Approved Indications for Immunotherapy.

INTRODUCTION: Immune-related adverse event (IRAE) onset may represent a clinical biomarker for anti-programmed cell death protein 1 (PD-1) antibody response based on emerging evidence from patients with various advanced malignancies. This phenomenon has not been previously reported in a multidisease cohort of patients with gastrointestinal (GI) cancer with Food and Drug Administration (FDA)-approved indications to receive immune checkpoint inhibitor therapy. MATERIALS AND METHODS: The study was a multicenter retrospective cohort analysis of 76 patients with GI cancer who had received anti-PD-1 antibodies for FDA-approved indications. The primary and secondary outcomes of the study were progression-free survival (PFS) and overall survival (OS) in patients based upon IRAE presence, respectively. PFS and OS were estimated by the Kaplan-Meier method; a Cox proportional-hazards model adjusted for IRAE onset, patient age, and enrolling institution was used to analyze outcomes. RESULTS: Median PFS and OS were prolonged in patients who experienced IRAEs compared with those who did not experience them (PFS: not reached [NR] vs. 3.9 months [hazard ratio (HR) 0.13, 95% confidence interval (CI) 0.05-0.3, p < .001]; OS: NR vs. 7.4 months [HR 0.11, 95% CI 0.03-0.36, p < .001]). Among patients who experienced IRAEs, there were no significant differences in PFS and OS by either initial IRAE severity, management, or time to onset. CONCLUSION: Patients with gastrointestinal cancer who experienced IRAEs while on anti-PD-1 antibodies demonstrated significant improvements in PFS and OS compared with their counterparts who did not develop IRAEs. Although these findings add to results from studies in other tumor types, larger prospective studies are needed prior to clinical adoption of IRAE onset as a biomarker for immune checkpoint inhibitor response. IMPLICATIONS FOR PRACTICE: Predictive clinical biomarkers for immune checkpoint inhibitor response have been understudied in the field of immuno-oncology. Immune-related adverse event onset appears to be one such biomarker. Across tumor types, immune-related adverse event onset has been associated with response to anti-programmed cell death protein 1 (PD-1) antibodies. The results of this study demonstrate this for the first time in patients with gastrointestinal cancer receiving anti-PD-1 antibodies. Before immune-related adverse event onset can be adopted clinically as a predictive biomarker for immune checkpoint inhibitor response, however, larger prospective studies are needed to better understand the nuances between immune-related adverse event characteristics (severity, site, management, timing of onset) and immune checkpoint inhibitor effectiveness.

Interethnic DNA methylation difference and its implications in pharmacoepigenetics.

AIM: This is the first systematic study to examine the population differentiation effect of DNA methylation on the treatment response and drug absorption, distribution, metabolism and excretion in multiple tissue types and cancer types. MATERIALS & METHODS: We analyzed the whole methylome and transcriptome data of primary tumor tissues of four cancer types (breast, colon, head & neck and uterine corpus) and lymphoblastoid cell lines for African and European ancestry populations. RESULTS: Ethnicity-associated CpG sites exhibited similar methylation patterns in the two studied populations, but the patterns differed between tumor tissues and lymphoblastoid cell lines. Ethnicity-associated CpG sites may have triggered gene expression, influenced drug absorption, distribution, metabolism and excretion, and showed tumor-specific patterns of methylation and gene regulation. CONCLUSION: Ethnicity should be carefully accounted for in future pharmacoepigenetics research.

Pharmacogenomics study on cadherin 2 network with regard to HIV infection and methadone treatment outcome.

Heroin dependent patients have a high incidence of HIV infection. In contrast to the gene expression method, we developed a systemic correlation analysis method built upon the results of pharmacogenomics study in a methadone maintenance treatment (MMT) cohort consisting of 344 Taiwanese heroin dependent patients. We identified genetic variants and their encoding proteins that may be involved with HIV infection and MMT treatment outcome. Cadherin 2 (CDH2) genetic determinants were identified through the genome-wide pharmacogenomic study. We found significant correlations among HIV infection status, plasma levels of CDH2, cytokine IL-7, ADAM10, and the treatment responses to methadone. Two single nucleotide polymorphisms located within CDH2 gene showed associations with blood pressure and plasma CDH2 concentration. Plasma concentration of CDH2 showed correlations with the level of cytokine IL-7, status of HIV infection, and urine morphine test result. Plasma level of IL-7 was correlated with corrected QT interval (QTc) and gooseflesh skin withdrawal symptom score, while level of ADAM10 was correlated with plasma concentrations of vitamin D metabolite, nicotine metabolite, and R-methadone. The results suggest a novel network involving HIV infection and methadone treatment outcome.

Genome-Wide Pharmacogenomic Study on Methadone Maintenance Treatment Identifies SNP rs17180299 and Multiple Haplotypes on CYP2B6, SPON1, and GSG1L Associated with Plasma Concentrations of Methadone R- and S-enantiomers in Heroin-Dependent Patients.

Methadone maintenance treatment (MMT) is commonly used for controlling opioid dependence, preventing withdrawal symptoms, and improving the quality of life of heroin-dependent patients. A steady-state plasma concentration of methadone enantiomers, a measure of methadone metabolism, is an index of treatment response and efficacy of MMT. Although the methadone metabolism pathway has been partially revealed, no genome-wide pharmacogenomic study has been performed to identify genetic determinants and characterize genetic mechanisms for the plasma concentrations of methadone R- and S-enantiomers. This study was the first genome-wide pharmacogenomic study to identify genes associated with the plasma concentrations of methadone R- and S-enantiomers and their respective metabolites in a methadone maintenance cohort. After data quality control was ensured, a dataset of 344 heroin-dependent patients in the Han Chinese population of Taiwan who underwent MMT was analyzed. Genome-wide single-locus and haplotype-based association tests were performed to analyze four quantitative traits: the plasma concentrations of methadone R- and S-enantiomers and their respective metabolites. A significant single nucleotide polymorphism (SNP), rs17180299 (raw p = 2.24 × 10(-8)), was identified, accounting for 9.541% of the variation in the plasma concentration of the methadone R-enantiomer. In addition, 17 haplotypes were identified on SPON1, GSG1L, and CYP450 genes associated with the plasma concentration of methadone S-enantiomer. These haplotypes accounted for approximately one-fourth of the variation of the overall S-methadone plasma concentration. The association between the S-methadone plasma concentration and CYP2B6, SPON1, and GSG1L were replicated in another independent study. A gene expression experiment revealed that CYP2B6, SPON1, and GSG1L can be activated concomitantly through a constitutive androstane receptor (CAR) activation pathway. In conclusion, this study revealed new genes associated with the plasma concentration of methadone, providing insight into the genetic foundation of methadone metabolism. The results can be applied to predict treatment responses and methadone-related deaths for individualized MMTs.