Image-guided interstitial brachytherapy for recurrent cervical cancer after radiotherapy: A single institution experience

PurposeThe aim of this study is to evaluate the efficacy and toxicity of image-guided high-dose rate (HDR) interstitial brachytherapy (ISBT) for the reirradiation of cervical cancer within a previously irradiated area.Methods and materialsTwenty-three consecutive patients with cervical cancer were reirradiated with curative intent using brachytherapy (BT) with or without external beam irradiation. The median biologically equivalent dose in 2-Gy fractions (EQD2) for reirradiation was 64.0 Gy (range: 31.3–95.1 Gy), and the median cumulative EQD2 (for primary treatment and reirradiation) was 152.4 Gy (range: 97.8–200.9 Gy). The average clinical target volume was 82.9 cm3 (range: 26.9–208.3 cm3), and the median treatment-free interval (TFI) was 13 months (range: 3–93 months).ResultsThe median follow-up time was 19 months (range: 2–59 months). The complete response rate after reirradiation was 56.5%. The 1-, 2- 3-, and 4-year post-relapse survival (PRS) rates were 65.2%, 43.5%, 33.8%, and 27.1%, respectively. The median reirradiation EQD2 D2cc of rectum and bladder was 39.5 Gy (range = 14.6–96.2 Gy) and 52.1 Gy (range = 29.1–114.2 Gy). The median cumulative EQD2 D2cc of rectum and bladder was 115.0 Gy (range = 84.4–189.3 Gy) and 130.5 Gy (range = 95.5–173.5 Gy). During follow-up, nine (39.1%) patients had experienced grade 3 or 4 late toxicities. Grade ≥3 rectal toxicity occurred in three patients (13.0%). Grade ≥3 urinary toxicity occurred in five patients (21.7%). One patient (4.3%) had both grade ≥3 urinary and rectal toxicity. Tumor volume, TFI, tumor invasion organ number, and local control were significant prognostic factors adversely affecting OS.ConclusionsFor recurrent cervical cancer after radiotherapy, reirradiation of HDR-ISBT is feasible, even if the local tumor invasion is large, with a good chance of survival and acceptable side effects

Effects of forage type on the rumen microbiota, growth performance, carcass traits, and meat quality in fattening goats

Forages fed to goats influence ruminal microbiota, and further contribute to affect growth performance, meat quality and its nutritional composition. Our objective for current study was to investigate the effects of different forages on growth performance, carcass traits, meat nutritional composition, rumen microflora, and the relationships between key bacteria and amino acids and fatty acids in the longissimus dorsi and semimembranosus muscles of goats. Boer crossbred goats were separately fed commercial concentrate diet supplemented with Hemarthria altissima (HA), Pennisetum sinese (PS), or forage maize (FG), and then slaughtered 90 days after the beginning of the experiment. Growth performances did not vary but carcass traits of dressing percentage, semi-eviscerated slaughter percentage, and eviscerated slaughter percentage displayed significant difference with the treatment studied. Meats from goats fed forage maize, especially semimembranosus muscles are rich in essential amino acids, as well as an increase in the amount of beneficial fatty acids. Our 16S rRNA gene sequencing results showed that the Firmicutes, Bacteroidetes, and Proteobacteria were the most dominant phyla in all groups but different in relative abundance. Further, the taxonomic analysis and linear discriminant analysis effect size (LEfSe) identified the specific taxa that were differentially represented among three forage treatments. The spearman’s correlation analysis showed that rumen microbiota was significantly associated with the goat meat nutritional composition, and more significant positive correlations were identified in semimembranosus muscles when compared with longissimus dorsi muscles. More specifically, the lipid metabolism-related bacteria Rikenellaceae_RC9_gut_group showed positively correlated with meat amino acid profile, while genera Oscillospiraceae_UCG-005 were positively correlated with fatty acid composition. These bacteria genera might have the potential to improve nutritional value and meat quality. Collectively, our results showed that different forages alter the carcass traits, meat nutritional composition, and rumen microflora in fattening goats, and forage maize induced an improvement in its nutritional value

Tumour suppressor ING1b maintains genomic stability upon replication stress

The lesion bypass pathway, which is regulated by monoubiquitination of proliferating cell nuclear antigen (PCNA), is essential for resolving replication stalling due to DNA lesions. This process is important for preventing genomic instability and cancer development. Previously, it was shown that cells deficient in tumour suppressor p33ING1 (ING1b) are hypersensitive to DNA damaging agents via unknown mechanism. In this study, we demonstrated a novel tumour suppressive function of ING1b in preserving genomic stability upon replication stress through regulating PCNA monoubiquitination. We found that ING1b knockdown cells are more sensitive to UV due to defects in recovering from UV-induced replication blockage, leading to enhanced genomic instability. We revealed that ING1b is required for the E3 ligase Rad18-mediated PCNA monoubiquitination in lesion bypass. Interestingly, ING1b-mediated PCNA monoubiquitination is associated with the regulation of histone H4 acetylation. Results indicate that chromatin remodelling contributes to the stabilization of stalled replication fork and to the regulation of PCNA monoubiquitination during lesion bypass

Identification and characterization of novel therapeutic targets and biomarkers in chronic myeloid leukemia

Chronic myeloid leukemia (CML) has long served as a paradigm for new insights into the cellular origin, pathogenesis and treatment of human cancers. ABL tyrosine kinase inhibitor (TKI) therapies have had remarkable effects on treatment of early phase CML. However, TKI monotherapies are not curative, and initial and acquired TKI resistance remain clinically challenging. Particularly, CML stem/progenitor cells are insensitive to TKIs. Therefore, novel treatments and predictive biomarkers are clearly needed. In this work, I studied the biological effects of dual BCR-ABL and JAK2 suppressions on TKI-nonresponder stem/progenitor cells, and identified and characterized novel microRNA (miRNA) biomarkers in these cells. I examined the biological effects of a new JAK2 inhibitor, BMS-911543, in combination with TKIs on CD34⁺ CML cells from IM-nonresponders. I demonstrated that combination therapy significantly reduces JAK2/STAT5 and CRKL activities, induces apoptosis, inhibits colony growth, and eliminates leukemic stem cells in vitro, while sparing healthy counterparts. I further showed that oral BMS-911543 combined with dasatinib is more effective in eliminating leukemic cells in an aggressive mouse model of BCR-ABL⁺ human leukemia. Next, I identified differentially expressed miRNAs in CD34⁺ CML cells using RNA-seq analysis, and validated the results in additional samples using high-throughput qPCR. Potential miRNA target genes were also identified by integrating miRNA expression profiles with gene expression profiles using strand-specific RNA-seq. These studies revealed that expression of miR-185 is significantly reduced in CD34⁺ CML cells from TKI-nonresponders compared to TKI-responders. Restoration of miR-185 expression by lentiviral transduction in CD34⁺ TKI-nonresponder cells significantly impairs survival of these cells and sensitizes them to TKI treatment in vitro and in vivo. Additionally, I validated the target genes of miR-185 to rationalize its roles in CML. Lastly, I demonstrated that the expression levels of several miRNAs, including miR185, were restored in patients treated with nilotinib, suggesting their potential as biomarkers to predict clinical response to TKI therapies. These studies have uncovered the biological significance of JAK2 and miR-185 in regulation of the properties of drug-insensitive CML stem/progenitor cells, and their potential as therapeutic targets for improved treatments with TKIs especially in patients at risk of developing TKI resistance.Medicine, Faculty ofExperimental Medicine, Division ofMedicine, Department ofGraduat

Role of SWI/SNF chromatin remodeling complex in melanoma development

Human cutaneous malignant melanoma is an aggressive form of skin cancer, for its ability to metastasize rapidly and its resistance to conventional radiotherapy and chemotherapy. The mammalian SWI/SNF complex mediates ATP-dependent chromatin remodeling processes that are critical for transcriptional regulation, control of cellular processes, and involvement in DNA repair. Therefore, aberrant expression of SWI/SNF chromatin remodeling complex is involved in cancer development. To investigate the role of SWI/SNF complex in the development of melanoma, we used tissue microarray technology and immunohistochemistry to evaluate the expression of SNF5, the common core subunit, and BRG1, the ATPase subunit, in melanocytic lesions at different stages, and we analyzed the correlation between SNF5 and BRG1 expression and clinicopathologic variables and patient survival. In addition, we also investigated the role of SNF5 in nucleotide excision repair (NER), a type of DNA repair mechanism that removes ultraviolet-induced DNA lesions. We found that reduced SNF5 expression is significantly associated with melanoma progression and a worse patient survival, and that SNF5 is an independent prognostic factor for human melanoma. Furthermore, we showed that downregulation of SNF5 protein level in melanoma cell lines enhanced chemoresistance of melanoma cells. This suggests that SNF5 plays an important role in melanomagenesis and may serve as a promising prognostic marker for melanoma. BRG1 expression, on the other hand, was found to be increased in primary and metastatic melanoma compared to dysplastic nevi. Knockdown of BRG1 in human melanoma cell lines reduced cell proliferation due to G1 phase arrest. This suggests that BRG1 might play a role in the initiation stage of melanomagenesis. As for the role of SWI/SNF complex in NER, our current observation demonstrated that in human keratinocytes, SNF5 is required for efficient removal of CPD and is required for UV-induced histone acetylation. In human melanoma cells, SNF5 does not seem to play a major role in NER, for it is not required for removal of CPD and UV-induced global chromatin relaxation. Taken together, these data implicate that SWI/SNF complex plays an essential role in melanoma development and may serve as a promising therapeutic target for melanoma.Medicine, Faculty ofMedicine, Department ofExperimental Medicine, Division ofGraduat

The Architecture of the Nuclear Pore Complex

Nucleocytoplasmic transport, the regulated trafficking of macromolecules in and out of the nucleus, occurs primarily through nuclear pore complexes (NPCs). NPCs are massive macromolecular machines embedded in the nuclear envelope which generate ~40 nanometer transport channels to facilitate transport. Because of its size and complexity (~1000 subunits, ~120 MDa), the structure of the NPC has remained poorly understood. This thesis presents a bottom-up approach to understanding the structure and function of the NPC through reconstitution of the proteins and structural and biochemical studies. The first three chapters present work towards determining the composite structure of the symmetric core of the NPC. X-ray crystal structures are described for many of the components of the symmetric core. This includes a heterohexameric coat nucleoporin complex containing Nup120, Nup85, Nup145C, Sec13, Seh1, and Nup84, revealing how these proteins assemble into one of the main subcomplexes in the NPC. Reconstitution of the symmetric core components and analysis of the protein-protein interaction between the components provides a detailed biochemical map for the protein interaction network in the NPC. X-ray crystal structures of overlapping fragments facilitate the generation of accurate atomic model for full-length proteins. An iterative, sequential docking approach is developed to dock these models into a cryoelectron tomographic reconstruction of the human NPC, yielding a composite model for the structure of the symmetric core of the NPC. In the next two chapters, this analysis is extended to the cytoplasmic-specific decorations of the NPC. The structure of the C-terminal domain of Nup358 is reported and its catalytic activity is described. Lastly, reconstitution of human DDX19 activation by the NPC reveals mechanistic insight into how the NPC directly regulates the last step of mRNA export

Multiple Introductions and Distinct Genetic Groups of Canada Goldenrod (<i>Solidago canadensis</i>) in China Revealed by Genomic Single-Nucleotide Polymorphisms

Despite numerous studies reported in the context of ecology, the introduction history of the infamous invasive plant Canada goldenrod (Solidago canadensis L.) remains elusive. In the present study, we explored the sources and the number of introduction events of this species from its native areas into China. Using the genotyping-by-sequencing approach, we identified 34,035 selectively neutral single-nucleotide polymorphism (SNP) markers to infer the evolutionary trajectories of 77 S. canadensis individuals. Both the principal component analysis and the ADMIXTURE analysis revealed two genetic groups that are sympatric to each other in China and suggested the absence of genetic admixtures. The phylogenetic analysis indicated three feasible introduction routes and multiple introduction events of Canada goldenrod into China. Specifically, the one from the USA directly into China, the other from the USA into China through Japan, and the third from the USA into China through Europe. Based on the site frequency spectrum of these identified SNPs, we inferred strong bottleneck events for both genetic groups, and that the multiple introductions did not rescue the decline of genetic diversity. To conclude, multiple introduction events, genetic bottlenecks, and potential human-mediated spread characterize the introduction history of Canada goldenrod in China. The present study harnesses the power of SNP data in deciphering the evolutionary trajectory of invasive plants and paves the way for future studies concerning the invasion mechanism of Canada goldenrod

Research on Service-Driven Benign Market with Platform Subsidy Strategy

The benign consumption of two-sided markets and the quality improvement of the supply side is the core of the sustainable development of platform ecology. This paper discusses how the platform uses personalized service values to influence the decision making of manufacturers and consumers, thus improving the health development of the platform ecosystem. By constructing the vertical differentiation model, we find that, different from the unified pricing strategy in the benchmark market, manufacturers in the platform market can implement personalized pricing, according to the different types of consumers’ quality preferences. When the platform service value is less than the product cost difference between manufacturers, low-quality manufacturers may benefit from the platform. Meanwhile, when the platform service value is greater than the product cost difference between manufacturers, the lemon market may appear and platforms should set the differentiated subsidy strategy according to the type of market consumers; this is a dominant strategy. In addition, when the number of consumers with low-quality demand in the market is large, the platform’s subsidies for high-quality products to consumers will guide consumers to buy high-quality products; this will not only promote the development of the benign market, but also improve the platform’s revenue. Finally, the sensitivity analysis shows that the platform service value has a U-shaped impact on the platform revenue and an inverted U-shaped impact on the manufacturers’ revenues

An Analysis Framework to Reveal Automobile Users’ Preferences from Online User-Generated Content

This work attempts to develop a novel framework to reveal the preferences of Chinese car users from online user-generated content (UGC) and guides automotive companies to allocate resources reasonably for sustainable design and improve existing product or service attributes. Specifically, a novel unsupervised word-boundary-identified algorithm for the Chinese language is used to extract domain professional feature words, and a set of sentiment scoring rules is constructed. By matching feature-sentiment word pairs, we calculate car users’ satisfaction with different attributes based on the rules and weigh the importance of attributes using the TF-IDF method, thus constructing an importance-satisfaction gap analysis (ISGA) model. Finally, a case study is used to realize the framework evaluation and analysis of the twenty top-mentioned attributes of a small-sized sedan, and the dynamic ISGA-time model is constructed to analyze the changing trend of the importance of user demand and satisfaction. The results show the priority of resource allocation/adjustment. Fuel consumption and driving experience urgently need resource input and management