Turicibacter and Acidaminococcus predict immune-related adverse events and efficacy of immune checkpoint inhibitor

IntroductionImmune checkpoint inhibitors have had a major impact on cancer treatment. Gut microbiota plays a major role in the cancer microenvironment, affecting treatment response. The gut microbiota is highly individual, and varies with factors, such as age and race. Gut microbiota composition in Japanese cancer patients and the efficacy of immunotherapy remain unknown. MethodsWe investigated the gut microbiota of 26 patients with solid tumors prior to immune checkpoint inhibitor monotherapy to identify bacteria involved in the efficacy of these drugs and immune-related adverse events (irAEs).ResultsThe genera Prevotella and Parabacteroides were relatively common in the group showing efficacy towards the anti-PD-1 antibody treatment (effective group). The proportions of Catenibacterium (P = 0.022) and Turicibacter (P = 0.049) were significantly higher in the effective group than in the ineffective group. In addition, the proportion of Desulfovibrion (P = 0.033) was significantly higher in the ineffective group. Next, they were divided into irAE and non-irAE groups. The proportions of Turicibacter (P = 0.001) and Acidaminococcus (P = 0.001) were significantly higher in the group with irAEs than in those without, while the proportions of Blautia (P = 0.013) and the unclassified Clostridiales (P = 0.027) were significantly higher in the group without irAEs than those with. Furthermore, within the Effective group, Acidaminococcus and Turicibacter (both P = 0.001) were more abundant in the subgroup with irAEs than in those without them. In contrast, Blautia (P = 0.021) and Bilophila (P= 0.033) were statistically significantly more common in those without irAEs.DiscussionOur Study suggests that the analysis of the gut microbiota may provide future predictive markers for the efficacy of cancer immunotherapy or the selection of candidates for fecal transplantation for cancer immunotherapy

Isolated nigral degeneration without pathological protein aggregation in autopsied brains with LRRK2 p.R1441H homozygous and heterozygous mutations

Abstract Leucine-rich repeat kinase 2 (LRRK2) is the most common causative gene for autosomal dominant Parkinson’s disease (PD) and is also known to be a susceptibility gene for sporadic PD. Although clinical symptoms with LRRK2 mutations are similar to those in sporadic PD, their pathologies are heterogeneous and include nigral degeneration with abnormal inclusions containing alpha-synuclein, tau, TAR DNA-binding protein 43, and ubiquitin, or pure nigral degeneration with no protein aggregation pathologies. We discovered two families harboring heterozygous and homozygous c.4332 G > A; p.R1441H in LRRK2 with consanguinity, sharing a common founder. They lived in the city of Makurazaki, located in a rural area of the southern region, the Kagoshima prefecture, in Kyushu, Japan. All patients presented late-onset parkinsonism without apparent cognitive decline and demonstrated a good response to levodopa. We obtained three autopsied cases that all presented with isolated nigral degeneration with no alpha-synuclein or other protein inclusions. This is the first report of neuropathological findings in patients with LRRK2 p.R1441H mutations that includes both homozygous and heterozygous mutations. Our findings in this study suggest that isolated nigral degeneration is the primary pathology in patients with LRRK2 p.R1441H mutations, and that protein aggregation of alpha-synuclein or tau might be secondary changes

Activation of Weak Monochromic Photocurrents by White Light Irradiation for Accurate IPCE Measurements of Carbon-Based Multi-Porous-Layered-Electrode Perovskite Solar Cells

Variations in the time courses of the activation of fully-printable carbon-based multi-porous-layered-electrode perovskite solar cells (MPLE-PSCs) can lead to differences between the photocurrent density (Jsc) values obtained from one-sun photocurrent density-voltage (J–V) measurements and from incident-photon-to-current efficiency (IPCE) integration when using monochromic light. In the present work, the Jsc calculated from IPCE data was initially equal to half that obtained from one-sun J–V measurements. However, equivalent values were obtained when the J–V measurements were performed after 10 min of irradiation by a white light LED from the side of the device. This finding will be very important with regard to permitting accurate photovoltaic evaluation of MPLE-PSCs in the future

Distinct microRNAs expression profile in primary biliary cirrhosis and evaluation of miR 505-3p and miR197-3p as novel biomarkers.

BACKGROUND AND AIMS: MicroRNAs are small endogenous RNA molecules with specific expression patterns that can serve as biomarkers for numerous diseases. However, little is known about the expression profile of serum miRNAs in PBC. METHODS: First, we employed Illumina deep sequencing for the initial screening to indicate the read numbers of miRNA expression in 10 PBC, 5 CH-C, 5 CH-B patients and 5 healthy controls. Comparing the differentially expressed miRNAs in the 4 groups, analysis of variance was performed on the number of sequence reads to evaluate the statistical significance. Hierarchical clustering was performed using an R platform and we have found candidates for specific miRNAs in the PBC patients. Second, a quantitative reverse transcription PCR validation study was conducted in 10 samples in each group. The expression levels of the selected miRNAs were presented as fold-changes (2(-ΔΔCt)). Finally, computer analysis was conducted to predict target genes and biological functions with MiRror 2.0 and DAVID v6.7. RESULTS: We obtained about 12 million 32-mer short RNA reads on average per sample and the mapping rates to miRBase were 16.60% and 81.66% to hg19. In the statistical significance testing, the expression levels of 81 miRNAs were found to be differentially expressed in the 4 groups. The heat map and hierarchical clustering demonstrated that the miRNA profiles from PBC clustered with those of CH-B, CH-C and healthy controls. Additionally, the circulating levels of hsa-miR-505-3p, 197-3p, and 500a-3p were significantly decreased in PBC compared with healthy controls and the expression levels of hsa-miR-505-3p, 139-5p and 197-3p were significantly reduced compared with the viral hepatitis group. CONCLUSIONS: Our results indicate that sera from patients with PBC have a unique miRNA expression profile and that the down-regulated expression of hsa-miR-505-3p and miR-197-3p can serve as clinical biomarkers of PBC

Heat map and hierarchical clustering.

<p>Individual miRNA expression were calculated by R platform and heat map was computed and described using a function of heatmap.2 in gplots. It uses hierarchical clustering with Euclidean distance; Pearson Linear Correlation and Ward's method to generate the hierarchical tree <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0066086#pone.0066086-Ward1" target="_blank">[56]</a>. ANOVA was applied to extract differentially expressed miRNAs and adjustment of the p-value by multiple comparisons was performed by calculating FDR. Those miRNAs with FDR<0.1 were presented. The red indicates high level of miRNA expression and the blue shows low.</p

Differentially expressed miRNAs in serum from PBC patients compared with the second group (CH-C, CH-B, Healthy).

<p>Differentially expressed miRNAs in serum from PBC patients compared with the second group (CH-C, CH-B, Healthy).</p

Predicted target genes of 9 differentially expressed miRNA by Illumina sequencing in PBC.

*<p>miRIS :miRror Internal Score ranges from 0 top 1 by average 2 components (number of databases and input hits).</p

Clinical data for patients enrolled in Illumina sequencing analysis.

a<p>We used the Scheuer score in PBC and fibrosis score of histological activity index (HAI) in CH-B and CH-C <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0066086#pone.0066086-Knodell1" target="_blank">[53]</a><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0066086#pone.0066086-Ludwig1" target="_blank">[54]</a><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0066086#pone.0066086-Scheuer1" target="_blank">[55]</a>.</p>b<p>URSO is the abbreviation for ursodeoxycholic acid, IFN for interferon and NA for nucleos(t)ide analogue.</p

Clinical information of patients enrolled in the validation study.

a<p>The numbers of patients are indicated in the parentheses.</p>b<p>The range of laboratory data is indicated in the parentheses.</p

The number of small RNAs in serum detected by Illumina sequencing.

<p>The number of small RNAs in serum detected by Illumina sequencing.</p