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Abstract Background The purpose of this study is to assess the predictive accuracy of a multi-gene predictor of response to docetaxel, 5-fluorouracil, epirubicin and cyclophosphamide combination chemotherapy on gene expression data from patients who received these drugs as neoadjuvant treatment. Methods Tumor samples were obtained from patients with stage II-III breast cancer before starting neoadjuvant chemotherapy with four cycles of 5-fluorouracil/epirubicin/cyclophosphamide (FEC) followed by four cycles of docetaxel/capecitabine (TX) on US Oncology clinical trial 02-103. Most patients with HER-2-positive cancer also received trastuzumab (H). The chemotherapy predictor (TFEC-MGP) was developed from publicly available gene expression data of 42 breast cancer cell-lines with corresponding in vitro chemotherapy sensitivity results for the four chemotherapy drugs. No predictor was developed for treatment with trastuzumab. The predictive performance of TFEC-MGP in distinguishing cases with pathologic complete response from those with residual disease was evaluated for the FEC/TX and FEC/TX plus H group separately. The area under the receiver-operating characteristic curve (AU-ROC) was used as the metric of predictive performance. Genomic predictions were performed blinded to clinical outcome. Results The AU-ROC was 0.70 (95% CI: 0.57-0.82) for the FEC/TX group (n=66) and 0.43 (95% CI: 0.20-0.66) for the FEC/TX plus H group (n=25). Among the patients treated with FEC/TX, the AU-ROC was 0.69 (95% CI: 0.52-0.86) for estrogen receptor (ER)-negative (n=28) and it was 0.59 (95% CI: 0.36-0.82) for ER-positive cancers (n=37). ER status was not reported for one patient. Conclusions Our results indicate that the cell line derived 291-probeset genomic predictor of response to FEC/TX combination chemotherapy shows good performance in a blinded validation study, particularly in ER-negative patients.

Abstract Background To measure Methicillin-resistant Staphylococcus aureus (MRSA) nasal colonization prevalence in household contacts of children with current community associated (CA)-MRSA infections (study group) in comparison with a group of household contacts of children without suspected Staphylococcus aureus infection (a control group). Methods This is a cross sectional study. Cultures of the anterior nares were taken. Relatedness of isolated strains was tested using pulse field gel electrophoresis (PFGE). Results The prevalence of MRSA colonization in the study group was significantly higher than in the control group (18/77 (23%) vs 3/77 (3.9%); p ≤ 0.001). The prevalence of SA colonization was 28/77 (36%) in the study group and 16/77 (21%) in the control group (p = 0.032). The prevalence of SA nasal colonization among patients was 6/24 (25%); one with methicillin-susceptible S. aureus (MSSA) and 5 with MRSA. In the study (patient) group, 14/24 (58%) families had at least one household member who was colonized with MRSA compared to 2/29 (6.9%) in the control group (p = 0.001). Of 69 total isolates tested by PFGE, 40 (58%) were related to USA300. Panton-Valetine leukocidin (PVL) genes were detected in 30/52 (58%) tested isolates. Among the families with ≥1 contact colonized with MRSA, similar PFGE profiles were found between the index patient and a contact in 10/14 families. Conclusions Prevalence of asymptomatic nasal carriage of MRSA is higher among household contacts of patients with CA-MRSA disease than control group. Decolonizing such carriers may help prevent recurrent CA-MRSA infections.

Abstract Background Tomato yellow leaf curl virus (TYLCV) is a member of the family Geminiviridae, genus Begomovirus. To test the infectivity of TYLCV in tomato plants, an improved protocol for inoculation of in vitro-cultured tomato plants was developed. Results A TYLCV isolate was cloned, sequenced and used to construct a 1.8-mer infectious clone. Three weeks old microshoots of TYLCV-susceptible tomato plants were inoculated with Agrobacterium tumefaciens harboring the infectious clone for the TYLCV isolate. After two weeks, the TYLCV symptoms started to appear on the in vitro-inoculated plants and the symptoms became more severe and pronounced eight weeks post-inoculation. The method was used efficiently to uncover the resistance mechanism against TYLCV in Solanum habrochaites accession LA 1777, a wild tomato known for its high resistance to whitefly and TYLCV. Conclusions The reported in vitro-inoculation method can be used to screen tomato genotypes for their responses to TYLCV under controlled conditions and it will be a useful tool for better understanding of the TYLCV biology in tomato plants.

Undergraduate students participating in the UCLA Undergraduate Research Consortium for Functional Genomics (URCFG) have conducted a two-phased screen using RNA interference (RNAi) in combination with fluorescent reporter proteins to identify genes important for hematopoiesis in Drosophila. This screen disrupted the function of approximately 3500 genes and identified 137 candidate genes for which loss of function leads to observable changes in the hematopoietic development. Targeting RNAi to maturing, progenitor, and regulatory cell types identified key subsets that either limit or promote blood cell maturation. Bioinformatic analysis reveals gene enrichment in several previously uncharacterized areas, including RNA processing and export and vesicular trafficking. Lastly, the participation of students in this course-based undergraduate research experience (CURE) correlated with increased learning gains across several areas, as well as increased STEM retention, indicating that authentic, student-driven research in the form of a CURE represents an impactful and enriching pedagogical approach.

Reversible modification of proteins with linkage-specific ubiquitin chains is critical for intracellular signaling. Information on physiological roles and underlying mechanisms of particular ubiquitin linkages during human development are limited. Here, relying on genomic constraint scores, we identify 10 patients with multiple congenital anomalies caused by hemizygous variants in OTUD5, encoding a K48/K63 linkage-specific deubiquitylase. By studying these mutations, we find that OTUD5 controls neuroectodermal differentiation through cleaving K48-linked ubiquitin chains to counteract degradation of select chromatin regulators (e.g., ARID1A/B, histone deacetylase 2, and HCF1), mutations of which underlie diseases that exhibit phenotypic overlap with OTUD5 patients. Loss of OTUD5 during differentiation leads to less accessible chromatin at neuroectodermal enhancers and aberrant gene expression. Our study describes a previously unidentified disorder we name LINKED (LINKage-specific deubiquitylation deficiency-induced Embryonic Defects) syndrome and reveals linkage-specific ubiquitin cleavage from chromatin remodelers as an essential signaling mode that coordinates chromatin remodeling during embryogenesis.