Microbial and metabolic features in renal transplant recipients with post-transplantation diabetes mellitus.

OBJECTIVE: Post-transplantation diabetes mellitus (PTDM) is a common complication in renal transplant recipients (RTRs). Gut microbiome plays important roles in a variety of chronic metabolic diseases, but its association with the occurrence and development of PTDM is still unknown. The present study integrates the analysis of gut microbiome and metabolites to further identify the characteristics of PTDM. METHODS: A total of 100 RTRs fecal samples were collected in our study. Among them, 55 samples were submitted to Hiseq sequencing, and 100 samples were used for non-targeted metabolomics analysis. The gut microbiome and metabolomics of RTRs were comprehensively characterized. RESULTS: The species Dialister invisus was significantly associated with fasting plasma glucose (FPG). The functions of tryptophan and phenylalanine biosynthesis were enhanced in RTRs with PTDM, while the functions of fructose and butyric acid metabolism were reduced. Fecal metabolome analysis indicated that RTRs with PTDM had unique metabolite distribution characteristics, and two differentially expressed specific metabolites were significantly correlated with FPG. The correlation analysis of gut microbiome and metabolites showed that gut microbiome had an obvious effect on the metabolic characteristics of RTRs with PTDM. Moreover, the relative abundance of microbial function is associated with the expression of several specific gut microbiome and metabolites. CONCLUSIONS: Our study identified the characteristics of gut microbiome and fecal metabolites in RTRs with PTDM, and we also found two important metabolites and a bacterium were significantly associated with PTDM, which might be used as novel targets in the research field of PTDM.

Longitudinal genomic alternations and clonal dynamics analysis of primary malignant melanoma of the esophagus.

Primary malignant melanoma of the esophagus (PMME) is a rare gastrointestinal melanoma with a high rate of recurrence and metastasis. The standard of care for PMME has not been established yet due to a lack of understanding of its clinical and molecular pathogenesis. Thus, we performed genomic profiling on a recurrent PMME case to seek novel opportunities for the management of this rare disease. Between 2013 and 2016, 6 tissue samples including 3 from the primary tumors, 2 from the relapsed tumors, and 1 from a normal control were collected from a patient diagnosed with PMME and were subjected to whole-exome sequencing to track the dynamic genetic changes. Additionally, we also analyzed a cohort of 398 samples obtained from the TCGA skin cutanesous melanoma (TCGA-SKCM) dataset to assess the frequency and determine the clinical implications of genomic events found in the presented study. ARHGAP35 (p.L1022M) was the only mutation shared across temporal PMME lesions. The PMME samples showed higher levels of genetic instability and intra-tumor heterogeneity. They also shared several concordant copy number variations (CNV). All lesions were concordant with the evolution trajectory, and shrinkage of the founding clone caused the subclonal population to become dominant in PT1c, which was likely the reason behind metastatic seeding. ARHGAP35 mutations were found in 6% of the TCGA-SKCM cohort samples. The presence of the mutations was associated with poor progression-free survival (PFS) by both univariate and multivariate Cox regression analyses. Our study showed that the primary tumor clone disseminates earlier in PMME. This highlights the need to understand the mechanism involved in the early PMME recurrence to optimize treatment.

Next-generation Sequencing Reveals Age-dependent Genetic Underpinnings in Lung adenocarcinoma.

Background: More than 40% of lung cancer patients are diagnosed at ages over 70. However, the genomic and clinical characteristics among them remain elusive. Here, we performed targeted capture sequence to characterize the mutational spectrum of Chinese lung adenocarcinoma (LUAD) patients across ages. Patients and Methods: 2025 LUAD patients were divided into three groups: young (≤50 years old) (n=416, 20.54%), intermediate (51~69 years old) (n=1271, 62.77%), and aged (≥70 years old) (n=338, 16.69%). 1,021-gene panel and 59-gene panel were used for sequencing with tissue samples. Genetic alterations and tumor mutation burden (TMB) in LUAD patients were investigated. Results: The frequency of mutations affecting 20 genes were significantly higher in aged group than in young group, and fourteen of them were not reported before, including involved in cell cycle/apoptosis signaling (FAT1, FAT2), DNA damage repair (FANCA and FANCM), chromatin histone modification (KDM6A), RTK/RAS/PI3K signaling (FLT4 and MTOR), NOTCH signaling (NOTCH1, NOTCH2 and NOTCH4) and other signaling pathway or cellular regulatory factor (KEAP1, ASXL1, EPHB1 and ABCB1). Six previously reported mutated genes (RBM10, KRAS, LRP1B, CDKN2A and KMT2C/D) were also significantly more frequent in aged group. Among clinical actionable mutation sites, KRAS mutation was presented more common in aged group; both MET exon 14 skipping and MET amplification were significantly positively correlated with old age; the fusions of ALK, ROS1, RET and ERBB2 exon 20 insertion were less frequent in aged group. Furthermore, a higher level of TMB was found in aged group compared with young group. Conclusion: In this study, we revealed the differences of somatic genetic mutations and TMB between young and aged LUAD patients, which may provide directions of targeted therapy and advantages of immunotherapy for the elderly in the future.

Serum Procalcitonin Correlates With Renal Function and Immune Components in Early-Stage Renal Transplant Recipients.

BACKGROUND: In renal transplantation, monitoring procalcitonin (PCT) in the early post-transplant period can be a promising method for early tracking of infectious complications. However, the correlation between PCT and infection-related factors and immune components and renal function remains unclear. PATIENTS AND METHODS: Between November 2017 and December 2018, 62 early-stage renal transplant recipients were selected, and 4 mL peripheral blood samples were collected to detect the changes of specific immune cells and cytokines. Our study was in compliance with the Helsinki Congress and the Declaration of Istanbul; no prisoners were used, and participants were neither paid nor coerced in our study. RESULTS: According to serum PCT levels, recipients were divided into a high group (PCT ≥ 0.5 ng/mL) and a low group (PCT < 0.5 ng/mL). Compared with the low group, creatinine, cystatin C, urea, T helper type (Th) 22 cells, IL-22 + Th17 cells, interleukin (IL)-22, tumor necrosis factor alpha, and IL-17A increased while estimated glomerular filtration rate (eGFR) was decreased in the high group. In addition, PCT was significantly correlated with eGFR in the high group. CONCLUSIONS: Serum PCT is related with renal function and seems to be associated with immune components in early-stage renal transplant recipients.

Genomic Landscape and Tumor Mutational Burden Determination of Circulating Tumor DNA in Over 5,000 Chinese Patients with Lung Cancer.

PURPOSE: Having emerged as a noninvasive and clinically applicable approach for molecular determination of lung cancer, a genomic overview of circulating tumor DNA (ctDNA) of large-scale cohort may be helpful in novel biomarker development and therapeutic innovation. EXPERIMENTAL DESIGN: Primary cohort encompasses 5,671 blood samples from 4,892 patients with lung cancer. Pair-wise tissue samples from 579 patients and additional 358 sample pairs were collected to evaluate the correlation between blood and tissue tumor mutational burden (TMB). Parallel sequencing with plasma/tissue and white blood cells was performed using a 1,021-gene panel. RESULTS: Histologic subtyping was the most relevant to ctDNA detectability independent of other demographic characteristics, with small cell lung cancer showing the highest detectability, ctDNA abundance, and blood TMB (bTMB). Mutational landscape demonstrated significant differences, and integrated clonality analysis highlighted distinct driver-pattern and functional pathway interaction among various subtypes. The clonality and concurrent genes of EGFR mutations could predict the therapeutic efficacy of tyrosine kinase inhibitors (TKI), and RB1 mutations in non-small cell lung cancer characterized a subset with high bTMB, elevated ctDNA level, and potential small cell transformation. Most importantly, we developed an adjusted algorithm for bTMB in samples with extremely low ctDNA level and validated its correlation with tissue TMB in an independent cohort. CONCLUSIONS: ctDNA could serve as a promising alternative in genomic profiling for lung cancer. The novel identification of ctDNA clonality and adjusted bTMB might improve therapeutic and prognostic evaluation. This dataset was also a valuable resource for the development of new therapeutic targets and new genomically guided clinical trials.