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Promoter-sequence determinants and structural basis of primer-dependent transcription initiation in Escherichia coli
Get PDFA multiple genome alignment workflow shows the impact of repeat masking and parameter tuning on alignment of functional regions in plants
Get PDFAlignments of multiple genomes are a cornerstone of comparative genomics, but generating these alignments remains technically challenging and often impractical. We developed the msa_pipeline workflow (https://bitbucket.org/bucklerlab/msa_pipeline) based on the LAST aligner to allow practical and sensitive multiple alignment of diverged plant genomes with minimal user inputs. Our workflow only requires a set of genomes in FASTA format as input. The workflow outputs multiple alignments in MAF format, and includes utilities to help calculate genome-wide conservation scores. As high repeat content and genomic divergence are substantial challenges in plant genome alignment, we also explored the impact of different masking approaches and alignment parameters using genome assemblies of 33 grass species. Compared to conventional masking with RepeatMasker, a k-mer masking approach increased the alignment rate of CDS and non-coding functional regions by 25% and 14% respectively. We further found that default alignment parameters generally perform well, but parameter tuning can increase the alignment rate for non-coding functional regions by over 52% compared to default LAST settings. Finally, by increasing alignment sensitivity from the default baseline, parameter tuning can increase the number of non-coding sites that can be scored for conservation by over 76%
The CLV3 Homolog in Setaria viridis Selectively Controls Inflorescence Meristem Size.
Get PDFThe CLAVATA pathway controls meristem size during inflorescence development in both eudicots and grasses, and is initiated by peptide ligands encoded by CLV3/ESR-related (CLE) genes. While CLV3 controls all shoot meristems in Arabidopsis, evidence from cereal grasses indicates that different meristem types are regulated by different CLE peptides. The rice peptide FON2 primarily controls the size of the floral meristem, whereas the orthologous peptides CLE7 and CLE14 in maize have their most dramatic effects on inflorescence and branch meristems, hinting at diversification among CLE responses in the grasses. Setaria viridis is more closely related to maize than to rice, so can be used to test whether the maize CLE network can be generalized to all members of subfamily Panicoideae. We used CRISPR-Cas9 in S. viridis to knock out the SvFON2 gene, the closest homolog to CLV3 and FON2. Svfon2 mutants developed larger inflorescence meristems, as in maize, but had normal floral meristems, unlike Osfon2, suggesting a panicoid-specific CLE network. Vegetative traits such as plant height, tiller number and leaf number were not significantly different between mutant and wild type plants, but time to heading was shorter in the mutants. In situ hybridization showed strong expression of Svfon2 in the inflorescence and branch meristems, consistent with the mutant phenotype. Using bioinformatic analysis, we predicted the co-expression network of SvFON2 and its signaling components, which included genes known to control inflorescence architecture in maize as well as genes of unknown function. The similarity between SvFON2 function in Setaria and maize suggests that its developmental specialization in inflorescence meristem control may be shared among panicoid grasses
Fighting the Sixth Decade of the Cancer War with Better Cancer Models.
No full textCancer models have helped solve many mysteries of cancer research, and are poised to bring our understanding to the next level as we dissect the relevance of cancer-associated alleles and heterocellular interactions. However, the ability of cancer models to correctly identify new therapeutic methods has been less fruitful, and a reconsideration of model designs and model applications should help develop more effective approaches for patients
Diversity and Biology of Cancer-Associated Fibroblasts.
No full textEfforts to develop anti-cancer therapies have largely focused on targeting the epithelial compartment, despite the presence of non-neoplastic stromal components that substantially contribute to the progression of the tumor. Indeed, cancer cell survival, growth, migration, and even dormancy are influenced by the surrounding tumor microenvironment (TME). Within the TME, cancer-associated fibroblasts (CAFs) have been shown to play several roles in the development of a tumor. They secrete growth factors, inflammatory ligands, and extracellular matrix proteins that promote cancer cell proliferation, therapy resistance, and immune exclusion. However, recent work indicates that CAFs may also restrain tumor progression in some circumstances. In this review, we summarize the body of work on CAFs, with a particular focus on the most recent discoveries about fibroblast heterogeneity, plasticity, and functions. We also highlight the commonalities of fibroblasts present across different cancer types, and in normal and inflammatory states. Finally, we present the latest advances regarding therapeutic strategies targeting CAFs that are undergoing preclinical and clinical evaluation
Next generation cereal crop yield enhancement: From knowledge of inflorescence development to practical engineering by genome editing
Get PDFArtificial domestication and improvement of the majority of crops began approximately 10,000 years ago, in different parts of the world, to achieve high productivity, good quality, and widespread adaptability. It was initiated from a phenotype-based selection by local farmers and developed to current biotechnology-based breeding to feed over 7 billion people. For most cereal crops, yield relates to grain production, which could be enhanced by increasing grain number and weight. Grain number is typically determined during inflorescence development. Many mutants and genes for inflorescence development have already been characterized in cereal crops. Therefore, optimization of such genes could fine-tune yield-related traits, such as grain number. With the rapidly advancing genome-editing technologies and understanding of yield-related traits, knowledge-driven breeding by design is becoming a reality. This review introduces knowledge about inflorescence yield-related traits in cereal crops, focusing on rice, maize, and wheat. Next, emerging genome-editing technologies and recent studies that apply this technology to engineer crop yield improvement by targeting inflorescence development are reviewed. These approaches promise to usher in a new era of breeding practice
TERT promoter hotspot mutations and gene amplification in metaplastic breast cancer.
Get PDFMetaplastic breast cancers (MBCs) are characterized by complex genomes, which seem to vary according to their histologic subtype. TERT promoter hotspot mutations and gene amplification are rare in common forms of breast cancer, but present in a subset of phyllodes tumors. Here, we sought to determine the frequency of genetic alterations affecting TERT in a cohort of 60 MBCs with distinct predominant metaplastic components (squamous, 23%; spindle, 27%; osseous, 8%; chondroid, 42%), and to compare the repertoire of genetic alterations of MBCs according to the presence of TERT promoter hotspot mutations or gene amplification. Forty-four MBCs were subjected to: whole-exome sequencing (WES; n = 27) or targeted sequencing of 341-468 cancer-related genes (n = 17); 16 MBCs were subjected to Sanger sequencing of the TERT promoter, TP53 and selected exons of PIK3CA, HRAS, and BRAF. TERT promoter hotspot mutations (n = 9) and TERT gene amplification (n = 1) were found in 10 of the 60 MBCs analyzed, respectively. These TERT alterations were less frequently found in MBCs with predominant chondroid differentiation than in other MBC subtypes (p = 0.01, Fisher's exact test) and were mutually exclusive with TP53 mutations (p < 0.001, CoMEt). In addition, a comparative analysis of the MBCs subjected to WES or targeted cancer gene sequencing (n = 44) revealed that MBCs harboring TERT promoter hotspot mutations or gene amplification (n = 6) more frequently harbored PIK3CA than TERT wild-type MBCs (n = 38; p = 0.001; Fisher's exact test). In conclusion, TERT somatic genetic alterations are found in a subset of TP53 wild-type MBCs with squamous/spindle differentiation, highlighting the genetic diversity of these cancers
Accuracy of Magnetic Resonance Imaging-Guided Biopsy to Verify Breast Cancer Pathologic Complete Response After Neoadjuvant Chemotherapy: A Nonrandomized Controlled Trial.
No full textImportance: After neoadjuvant chemotherapy (NAC), pathologic complete response (pCR) is an optimal outcome and a surrogate end point for improved disease-free and overall survival. To date, surgical resection remains the only reliable method for diagnosing pCR. Objective: To evaluate the accuracy of magnetic resonance imaging (MRI)-guided biopsy for diagnosing a pCR after NAC compared with reference-standard surgical resection. Design, Setting, and Participants: Single-arm, phase 1, nonrandomized controlled trial in a single tertiary care cancer center from September 26, 2017, to July 29, 2019. The median follow-up was 1.26 years (interquartile range, 0.85-1.59 years). Data analysis was performed in November 2019. Eligible patients had (1) stage IA to IIIC biopsy-proven operable invasive breast cancer; (2) standard-of-care NAC; (3) MRI before and after NAC, with imaging complete response defined as no residual enhancement on post-NAC MRI; and (4) definitive surgery. Patients were excluded if they were younger than 18 years, had a medical reason precluding study participation, or had a prior history of breast cancer. Interventions: Post-NAC MRI-guided biopsy without the use of intravenous contrast of the tumor bed before definitive surgery. Main Outcomes and Measures: The primary end point was the negative predictive value of MRI-guided biopsy, with true-negative defined as negative results of the biopsy (ie, no residual cancer) corresponding to a surgical pCR. Accuracy, sensitivity, positive predictive value, and specificity were also calculated. Two clinical definitions of pCR were independently evaluated: definition 1 was no residual invasive cancer; definition 2, no residual invasive or in situ cancer. Results: Twenty of 23 patients (87%) had evaluable data (median [interquartile range] age, 51.5 [39.0-57.5] years; 20 women [100%]; 13 White patients [65%]). Of the 20 patients, pre-NAC median tumor size on MRI was 3.0 cm (interquartile range, 2.0-5.0 cm). Nineteen of 20 patients (95%) had invasive ductal carcinoma; 15 of 20 (75%) had stage II cancer; 11 of 20 (55%) had ERBB2 (formerly HER2 or HER2/neu)-positive cancer; and 6 of 20 (30%) had triple-negative cancer. Surgical pathology demonstrated a pCR in 13 of 20 (65%) patients and no pCR in 7 of 20 patients (35%) when pCR definition 1 was used. Results of MRI-guided biopsy had a negative predictive value of 92.8% (95% CI, 66.2%-99.8%), with accuracy of 95% (95% CI, 75.1%-99.9%), sensitivity of 85.8% (95% CI, 42.0%-99.6%), positive predictive value of 100%, and specificity of 100% for pCR definition 1. Only 1 patient had a false-negative MRI-guided biopsy result (surgical pathology showed <0.02 cm of residual invasive cancer). Conclusions and Relevance: This study's results suggest that the accuracy of MRI-guided biopsy to diagnose a post-NAC pCR approaches that of reference-standard surgical resection. MRI-guided biopsy may be a viable alternative to surgical resection for this population after NAC, which supports the need for further investigation. Trial Registration: ClinicalTrials.gov Identifier: NCT03289195
Sorafenib is associated with a reduced rate of tumour growth and liver function deterioration in HCV-induced hepatocellular carcinoma.
No full textPURPOSE: Sorafenib has been the standard of care for patients with advanced hepatocellular carcinoma and although immunotherapeutic approaches are now challenging this position, it retains an advantage in HCV seropositive patients. We aimed to quantify the rate of tumour progression in patients receiving sorafenib and relate this figure to survival, both overall, and according to viral status. PATIENTS AND METHODS: Using serial data from an international clinical trial we applied a joint model to combine survival and progression over time so as to estimate the rate of tumour growth as assessed by tumour burden and serum AFP, and the impact of treatment on liver function. RESULTS: High tumour burden at baseline was associated with an increased risk of death. In patients still alive at the end of the study, the progression in relation to tumour burden was very low compared to those who died within the study. Overall, the change in mean tumour burden was 0.12 mm per day or an absolute growth rate of 3.6mm/month. Median doubling time (DT) was 665 days. For those who progressed above 0.12mm per day or 12% rate, median survival was 234 days compared to 384 days if the rate was below 12%. Tumour growth rate and serum AFP rise were significantly lower in those who were HCV seropositive as was the rate of decline in liver function. These results were replicated in two independent patient groups. CONCLUSION: Our analysis suggests that sorafenib treatment is associated with improved survival in patients with advanced hepatocellular carcinoma mainly by decreasing the rate of tumour growth and liver function deterioration among patients with HCV infection. LAY SUMMARY: Among patients receiving sorafenib for advanced hepatocellular carcinoma the rate of tumour growth (as assessed by changes in tumour size and the biomarker AFP) and the deterioration of liver function is less in those who have the Hepatitis C virus, than those who do not. CLINICAL TRIALS DATA: The clinical trials data belongs to Bristol Myers Squibb and AbbVie Inc. The clinical data belongs to Cambridge University Hospitals NHS Foundation Trust
