Clinical and molecular significance of homologous recombination deficiency positive non-small cell lung cancer in Chinese population: An integrated genomic and transcriptional analysis.

Objective: The clinical significance of homologous recombination deficiency (HRD) in breast cancer, ovarian cancer, and prostate cancer has been established, but the value of HRD in non-small cell lung cancer (NSCLC) has not been fully investigated. This study aimed to systematically analyze the HRD status of untreated NSCLC and its relationship with patient prognosis to further guide clinical care. Methods: A total of 355 treatment-naïve NSCLC patients were retrospectively enrolled. HRD status was assessed using the AmoyDx Genomic Scar Score (GSS), with a score of ≥50 considered HRD-positive. Genomic, transcriptomic, tumor microenvironmental characteristics and prognosis between HRD-positive and HRD-negative patients were analyzed. Results: Of the patients, 25.1% (89/355) were HRD-positive. Compared to HRD-negative patients, HRD-positive patients had more somatic pathogenic homologous recombination repair (HRR) mutations, higher tumor mutation burden (TMB) (P<0.001), and fewer driver gene mutations (P<0.001). Furthermore, HRD-positive NSCLC had more amplifications in PI3K pathway and cell cycle genes, MET and MYC in epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) mutant NSCLC, and more PIK3CA and AURKA in EGFR/ALK wild-type NSCLC. HRD-positive NSCLC displayed higher tumor proliferation and immunosuppression activity. HRD-negative NSCLC showed activated signatures of major histocompatibility complex (MHC)-II, interferon (IFN)-γ and effector memory CD8+ T cells. HRD-positive patients had a worse prognosis and shorter progression-free survival (PFS) to targeted therapy (first- and third-generation EGFR-TKIs) (P=0.042). Additionally, HRD-positive, EGFR/ALK wild-type patients showed a numerically lower response to platinum-free immunotherapy regimens. Conclusions: Unique genomic and transcriptional characteristics were found in HRD-positive NSCLC. Poor prognosis and poor response to EGFR-TKIs and immunotherapy were observed in HRD-positive NSCLC. This study highlights potential actionable alterations in HRD-positive NSCLC, suggesting possible combinational therapeutic strategies for these patients.

Predicting therapeutic response to neoadjuvant immunotherapy based on an integration model in resectable stage IIIA (N2) non-small cell lung cancer.

OBJECTIVE: Accurately predicting response during neoadjuvant chemoimmunotherapy for resectable non-small cell lung cancer remains clinically challenging. In this study, we investigated the effectiveness of blood-based tumor mutational burden (bTMB) and a deep learning (DL) model in predicting major pathologic response (MPR) and survival from a phase 2 trial. METHODS: Blood samples were prospectively collected from 45 patients with stage IIIA (N2) non-small cell lung cancer undergoing neoadjuvant chemoimmunotherapy. An integrated model, combining the computed tomography-based DL score, bTMB, and clinical factors, was developed to predict tumor response to neoadjuvant chemoimmunotherapy. RESULTS: At baseline, bTMB were detected in 77.8% (35 of 45) of patients. Baseline bTMB ≥11 mutations/megabase was associated with significantly greater MPR rates (77.8% vs 38.5%, P = .042), and longer disease-free survival (P = .043), but not overall survival (P = .131), compared with bTMB <11 mutations/megabase in 35 patients with bTMB available. The developed DL model achieved an area under the curve of 0.703 in all patients. Importantly, the predictive performance of the integrated model improved to an area under the curve of 0.820 when combining the DL score with bTMB and clinical factors. Baseline circulating tumor DNA (ctDNA) status was not associated with pathologic response and survival. Compared with ctDNA residual, ctDNA clearance before surgery was associated with significantly greater MPR rates (88.2% vs 11.1%, P < .001) and improved disease-free survival (P = .010). CONCLUSIONS: The integrated model shows promise as a predictor of tumor response to neoadjuvant chemoimmunotherapy. Serial ctDNA dynamics provide a reliable tool for monitoring tumor response.

The Meloidogyne javanica effector Mj2G02 interferes with jasmonic acid signalling to suppress cell death and promote parasitism in Arabidopsis.

Plant-parasitic nematodes can cause devastating damage to crops. These nematodes secrete effectors that suppress the host immune responses to enhance their survival. In this study, Mj2G02, an effector from Meloidogyne javanica, is described. In situ hybridization and transcriptional analysis showed that Mj2G02 was highly expressed in the early infection stages and exclusively expressed in the nematode subventral oesophageal gland cells. In planta RNA interference targeting Mj2G02 impaired M. javanica parasitism, and Mj2G02-transgenic Arabidopsis lines displayed more susceptibility to M. javanica. Using an Agrobacterium-mediated transient expression system and plant immune response assays, we demonstrated that Mj2G02 localized in the plant cell nuclei and could suppress Gpa2/RBP-1-induced cell death. Moreover, by RNA-Seq and quantitative reverse transcription PCR analyses, we showed that Mj2G02 was capable of interfering with the host jasmonic acid (JA) signalling pathway. Multiple jasmonate ZIM-domain (JAZ) genes were significantly upregulated, whereas the JAR1 gene and four JA-responsive genes, MYC3, UPI, THI2.1, and WRKY75, were significantly downregulated. In addition, HPLC analysis showed that the endogenous jasmonoyl-isoleucine (JA-Ile) level in Mj2G02-transgenic Arabidopsis lines was significantly decreased compared to that in wildtype plants. Our results indicate that the M. javanica effector Mj2G02 suppresses the plant immune response, therefore facilitating nematode parasitism. This process is probably mediated by a JA-Ile reduction and JAZ enhancement to repress JA-responsive genes.

The chromosome-level reference genome of Coptis chinensis provides insights into genomic evolution and berberine biosynthesis.

Coptis chinensis Franch, a perennial herb, is mainly distributed in southeastern China. The rhizome of C. chinensis has been used as a traditional medicine for more than 2000 years in China and many other Asian countries. The pharmacological activities of C. chinensis have been validated by research. Here, we present a de novo high-quality genome of C. chinensis with a chromosome-level genome of ~958.20 Mb, a contig N50 of 1.58 Mb, and a scaffold N50 of 4.53 Mb. We found that the relatively large genome size of C. chinensis was caused by the amplification of long terminal repeat (LTR) retrotransposons. In addition, a whole-genome duplication event in ancestral Ranunculales was discovered. Comparative genomic analysis revealed that the tyrosine decarboxylase (TYDC) and (S)-norcoclaurine synthase (NCS) genes were expanded and that the aspartate aminotransferase gene (ASP5) was positively selected in the berberine metabolic pathway. Expression level and HPLC analyses showed that the berberine content was highest in the roots of C. chinensis in the third and fourth years. The chromosome-level reference genome of C. chinensis provides important genomic data for molecular-assisted breeding and active ingredient biosynthesis.

The Acer truncatum genome provides insights into nervonic acid biosynthesis.

Acer truncatum (purpleblow maple) is a woody tree species that produces seeds with high levels of valuable fatty acids (especially nervonic acid). However, the lack of a complete genome sequence has limited both basic and applied research on A. truncatum. We describe a high-quality draft genome assembly comprising 633.28 Mb (contig N50 = 773.17 kb; scaffold N50 = 46.36 Mb) with at least 28 438 predicted genes. The genome underwent an ancient triplication, similar to the core eudicots, but there have been no recent whole-genome duplication events. Acer yangbiense and A. truncatum are estimated to have diverged about 9.4 million years ago. A combined genomic, transcriptomic, metabonomic, and cell ultrastructural analysis provided new insights into the biosynthesis of very long-chain monounsaturated fatty acids. In addition, three KCS genes were found that may contribute to regulating nervonic acid biosynthesis. The KCS paralogous gene family expanded to 28 members, with 10 genes clustered together and distributed in the 0.27-Mb region of pseudochromosome 4. Our chromosome-scale genomic characterization may facilitate the discovery of agronomically important genes and stimulate functional genetic research on A. truncatum. Furthermore, the data presented also offer important foundations from which to study the molecular mechanisms influencing the production of nervonic acids.

Comparative genome-wide survey of single nucleotide variation uncovers the genetic diversity and potential biomedical applications among six Macaca species.

Macaca is of great importance in evolutionary and biomedical research. Aiming at elucidating genetic diversity patterns and potential biomedical applications of macaques, we characterized single nucleotide variations (SNVs) of six Macaca species based on the reference genome of Macaca mulatta. Using eight whole-genome sequences, representing the most comprehensive genomic SNV study in Macaca to date, we focused on discovery and comparison of nonsynonymous SNVs (nsSNVs) with bioinformatic tools. We observed that SNV distribution patterns were generally congruent among the eight individuals. Outlier tests of nsSNV distribution patterns detected 319 bins with significantly distinct genetic divergence among macaques, including differences in genes associated with taste transduction, homologous recombination, and fat and protein digestion. Genes with specific nsSNVs in various macaques were differentially enriched for metabolism pathways, such as glycolysis, protein digestion and absorption. On average, 24.95% and 11.67% specific nsSNVs were putatively deleterious according to PolyPhen2 and SIFT4G, respectively, among which the shared deleterious SNVs were located in 564⁻1981 genes. These genes displayed enrichment signals in the 'obesity-related traits' disease category for all surveyed macaques, confirming that they were suitable models for obesity related studies. Additional enriched disease categories were observed in some macaques, exhibiting promising potential for biomedical application. Positively selected genes identified by PAML in most tested Macaca species played roles in immune and nervous system, growth and development, and fat metabolism. We propose that metabolism and body size play important roles in the evolutionary adaptation of macaques.

Genome-wide mining and comparative analysis of microsatellites in three macaque species.

Microsatellites are found in taxonomically different organisms, and such repeats are related with genomic structure, function and certain diseases. To characterize microsatellites for macaques, we searched and compared SSRs with 1-6 bp nucleotide motifs in rhesus, cynomolgus and pigtailed macaque. A total of 1395671, 1284929 and 1266348 perfect SSRs were mined, respectively. The most frequent perfect SSRs were mononucleotide SSRs. The most GC-content was in dinucleotide SSRs and the least was in the mononucleotide SSRs. Chromosome size was positively correlated with SSR number and negatively correlated with the relative frequency and density of SSRs. The GC content of chromosome SSRs were negatively correlated with relative frequency of SSRs and GC content of chromosome sequences. The features of microsatellite distribution in assembled genomes of the three species were greatly similar, which revealed that the distributional pattern of microsatellites is probably conservative in genus Macaca. The degenerated number of repeat motifs was found to be different in pentanucleotide and hexanucleotide repeats. Species-specific motifs for each macaque were significantly underrepresented. Overall, SSR frequencies of each chromosome in rhesus macaque were higher than in cynomolgus macaque. The maximum repeat times of mono- to pentanucleotide repeats in cynomolgus macaque was more than other two macaques. These results emphasize the genetic diversity and phylogenetic relationship of genus Macaca species. Our data will be beneficial for comparative genome mapping, understanding the distribution of SSRs and genome structure between these animal models, and provide a foundation for further development and identification of more macaque-specific SSRs.

FNA biopsy of secondary nonlymphomatous malignancies in salivary glands: A multi-institutional study of 184 cases.

BACKGROUND: Secondary malignancies of salivary glands (SMSGs) are among the most common malignant neoplasms to involve the salivary glands. Fine-needle aspiration biopsy (FNAB) of SMSG can present diagnostic challenges. The current report presents the largest such FNAB series to date. METHODS: A search of the pathology database from 6 academic institutions identified 184 FNAB cases of nonlymphomatous SMSG. RESULTS: Of the 184 cases, 171 were of the parotid glands, and 13 were of the submandibular glands; 130 patients were men, and 54 were women, and the mean patient age at diagnosis was 68 years. Metastatic squamous cell carcinoma (SCC) from all sites (n = 87) and melanoma (n = 67) constituted the majority of SMSGs. Less frequent SMSGs were comprised of metastatic carcinomas from distant organs (n = 16), including sites in the breast, lung, kidney, thyroid, pancreatobiliary, prostate, and bladder. Other uncommon SMSGs, including nasopharyngeal carcinoma (n = 3), sarcoma (n = 4), other metastatic skin-derived carcinomas (n = 6), and metastatic chordoma (n = 1), also were observed. Ancillary tests were performed on 37 FNAB specimens (20.1%) to aid the evaluation. One hundred forty-seven specimens (79.9%) had a definitive diagnosis with accurate tumor subtyping, 21 (11.4%) had a definitive malignant diagnosis but without specifying subtype, 9 (4.9%) had an indeterminate diagnosis, and 7 (3.8%) had a false-negative diagnosis. CONCLUSIONS: SMSGs originate predominately from the head and neck and are more common in older men. Overall, the FNAB diagnosis of SMSG is accurate, but diagnostic challenges can be encountered, especially in SCC types of SMSG. Ancillary studies are needed for the definitive diagnosis of challenging cases. Cancer Cytopathol 2017;125:91-103. © 2016 American Cancer Society.

Identification of CR1 retroposons in Arborophila rufipectus and their application to Phasianidae phylogeny.

Chicken repeat 1 (CR1), a member of non-LTR retroposon, is an important phylogenetic marker in avian systematics. In this study, we reported several characteristics of CR1 elements in a draft genome of Arborophila rufipectus (Sichuan partridge). According to the analyses of RepeatMasker, approximately 254 966 CR1 elements were identified in A. rufipectus, covering 6.7% of the genome. Subsequently, we selected eighteen novel CR1 elements by comparing the chicken genome, turkey genome and assembled A. rufipectus scaffolds. Here, a combined data set comprising of 22 CR1 loci, mitochondrial genomes and eight unlinked introns was analysed to infer the evolutionary relationships of twelve Phasianidae species. The applicability of CR1 sequences for inferring avian phylogeny relative to mtDNA and intron sequences was investigated as well. Our results elucidated the position of A. rufipectus in Phasianidae with robust supports that it presented a sister clade to Arborophila ardens/Arborophila brunneopectus, and implied that genus Arborophila was in a basal phylogenetic position within Phasianidae and a phylogenetic affinity between Meleagris gallopavo and Pucrasia macrolopha. Therefore, this work not only resolved some of the confounding relationships among Phasianidae, but also suggested CR1 sequences could provide powerful complementary data for phylogeny reconstruction.

Structural conservation of the B subunit in the ammonia monooxygenase/particulate methane monooxygenase superfamily.

The ammonia monooxygenase (AMO)/particulate methane monooxygenase (pMMO) superfamily is a diverse group of membrane-bound enzymes of which only pMMO has been characterized on the molecular level. The pMMO active site is believed to reside in the soluble N-terminal region of the pmoB subunit. To understand the degree of structural conservation within this superfamily, the crystal structure of the corresponding domain of an archaeal amoB subunit from Nitrosocaldus yellowstonii has been determined to 1.8 Å resolution. The structure reveals a remarkable conservation of overall fold and copper binding site location as well as several notable differences that may have implications for function and stability.

[Study on reflectance spectra morphological character of the hyperspectral mixed pixels at different component proportion].

Under the experimental condition, the hyperspectral reflectance spectra of the mixed pixel of lotus and water body were acquired using the multi-angles dichotic reflex platform and ASD spectrum instrument. The reflectance spectral morphological character index variation of the hyperspectral mixed pixel at different component proportion was analyzed. The conclusions are as follows: the correlation between these morphological indexes was obvious, and the best morphological index was chosen by removing the index whose R2 was greater than 0.5 (R is correlation coefficient); the variation of different morphological index was obvious; the cluster analysis shows that there was a critical value in the progress of the transformation from the pure pixel (water) to mixed pixel. If the proportion was less than the critical value, the reflectance spectra reflected the reflection characteristics of pure pixel; otherwise, it was the reflection of characteristics of mixed pixel.

[Study on the nonlinear characteristics of the mixed pixel's reflectance in hyperspectral space].

Under the experimental condition of the 50 degree incidence zenith angle and 45 degree detection azimuth, 24 groups of reflectance spectral of the mixed pixel of lotus and water body acquired using the reflex platform and FieldSpec 3 Hi-Res portable spectrum instrument. The hyperspectral space was built based on the reflectance character. The relationship between similarity and the index of lotus area ratio was analyzed using the linear, logarithm and quadratic curve fitting, and the goodness of fitting is 63.6%, 76.2% and 82.9% respectively. According to the real relationship of the mixed pixel spectral vector and the reference spectral, the best fitting model has nonlinear characteristics. The idea that the mixed pixel may have the critical value was proposed on the base of the analysis. The research result will help understand the mixed pixel further, and provide a new direction for unmixing the mixed pixel.

[Analysis of the polarization properties of snow in a different melting state].

Nowdays, under the circumstance of global warming, the traditional study of solid-state snow can not meet the current needs. The present paper involves qualitative analysis of the polarization reflectance spectrum of snow in a different melting state. Special attention is paid to the investigation of the relationship among polarization angles, azimuth angles, the light incidence zenith angles, the detection zenith angles and the different types of snowmelt. It turns out that all these factors have certain influences on the polarization reflectance spectrum of different types of snowmelt. At the waveband of the visible light, the polarization reflectance of snowmelt is the largest at 90 degrees, and the smallest at 0 degrees. The wider the detection angles and the incidence angles, the larger the polarization reflectance. Anomalies (unusual phenomena), different from other spectra, occur when the polarization reflectance spectrum of snowmelt is observed at different azimuth angles. The characteristics of polarization spectra at some certain wavebands play an important role in determining the water content of snowmelt, and meanwhile with the increase of which, the polarization reflectance will go down obviously. These rules have laid a solid foundation for the quantitative analysis of snowmelt properties by using polarization spectrum in the future and are also of great importance in fresh water management as well as monitoring natural disasters such as the spring flood.

[Studies of the thermal radiation multi-angle polarization properties of snow].

This paper, catering to the need of the study of remote sensing for thermal radiation polarization properties of ground features, detects the thermal radiation multi-angle polarization properties of snow, and makes analysis of effects of four factors, i. e. detecting zenith angle, detecting azimuth angle, bands and polarizing angle, on the thermal radiation properties of snow. The results show that the radiance and brightness temperature of snow increases with the detecting zenith angle. When the detecting zenith angle is greater than 30 degrees, the growth accelerated, and the effect of detecting zenith angle on the brightness temperature of snow is more significant than that of the radiance; the changes in detecting azimuth angle have some effect on the radiance and brightness temperature of snow, and have much influence on the brightness temperature than that of the radiance; the radiance and brightness temperature of snow is significantly affected by the changes in bands, and the effect on the radiance is more significant; the changes in polarizing angle have some effect on the radiance and brightness temperature of the snow, and have much influence on its brightness temperature. The results of the study provide new ideas and methods for the application of remote sensing technology to carrying out the thermal infrared quantitative study of snow, and have important theoretical significance and potential applications.

[Studies of the thermal radiation characteristics of urban typical surface features].

The use of thermal infrared technology to monitor the land surface temperature has received mature development, and the acceleration of urbanization makes the urban heat effect emerge, thus, studies of the thermal radiation characteristics of urban typical surface features make great significance for the analysis of the causes and distribution of the thermal phenomenon. Based on the study of ground measured data of Baoding city, we have found that, the feature types, the observation time and wall orientations are principal factors that exert an influence on the thermal radiation brightness temperature of urban typical surface features. The results show that different types of surface features will significantly affect the brightness temperature, but "different things with the same spectrum" still exists; the observation time has direct impact on the intensity of thermal radiation and to a large extent on the brightness temperature difference of each channel; the brightness temperature of different wall orientations are also different, and the difference changes with the change in observation time. Studies of thermal radiation characteristics of urban typical surface features have theoretical and practical significance, providing basis for thermal infrared remote sensing to monitor the urban heat effect.

[Study on the reflected and hyperspectral mixed-pixel character of aquatic plants and water].

A study on the reflected and hyperspectral mixed-pixel of aquatic plants and water was given by using a orthogonal experimental design with three factors and two levels. The results of F test suggest that for the single factors, the band and the area ratio of mixed-pixel on the reflected and hyperspectral mixed-pixel of the reflection effects are particularly significant, however, the detector angle had no significant effect under these experimental conditions; For the interaction, the band and the area ratio of mixed-pixel, the detector and the area ratio of mixed-pixel, the effects of these two interactions on the reflected and hyperspectral mixed-pixel are also particularly significant, This study did quantitative analysis of the factors affecting the reflected and hyperspectral mixed-pixel character and their interaction, and provided a new method for the indepth study of mixed-pixel.