Discovery and Structure-Based Design of Inhibitors of the WD Repeat-Containing Protein 5 (WDR5)-MYC Interaction.

WDR5 is a critical chromatin cofactor of MYC. WDR5 interacts with MYC through the WBM pocket and is hypothesized to anchor MYC to chromatin through its WIN site. Blocking the interaction of WDR5 and MYC impairs the recruitment of MYC to its target genes and disrupts the oncogenic function of MYC in cancer development, thus providing a promising strategy for the treatment of MYC-dysregulated cancers. Here, we describe the discovery of novel WDR5 WBM pocket antagonists containing a 1-phenyl dihydropyridazinone 3-carboxamide core that was identified from high-throughput screening and subsequent structure-based design. The leading compounds showed sub-micromolar inhibition in the biochemical assay. Among them, compound 12 can disrupt WDR5-MYC interaction in cells and reduce MYC target gene expression. Our work provides useful probes to study WDR5-MYC interaction and its function in cancers, which can also be used as the starting point for further optimization toward drug-like small molecules.

Discovery of berberine analogs as potent and highly selective p300/CBP HAT inhibitors.

The protein p300 is a positive regulator of cancer progression and is related to many human pathological conditions. To find effective p300/CBP HAT inhibitors, we screened an internal compound library and identified berberine as a lead compound. Next, we designed, synthesized, and screened a series of novel berberine analogs, and discovered that analog 5d was a potent and highly selective p300/CBP HAT inhibitor with IC50 values of 0.070 µM and 1.755 µM for p300 and CBP, respectively. Western blotting further proved that 5d specifically decreased H3K18Ac and interfere with the function of histone acetyltransferase. Although 5d had only a moderate inhibitory effect on the MDA-MB-231 cell line, 5d suppressed the growth of 4T1 tumor growth in mice with a tumor weight inhibition ratio (TWI) of 39.7%. Further, liposomes-encapsulated 5d increased its inhibition of tumor growth to 57.8 % TWI. In addition, 5d has no obvious toxicity to the main organ of mice and the pharmacokinetic study confirmed that 5d has good absorption properties in vivo.

BTH-induced joint regulation of wound healing at the wounds of apple fruit by JA and its downstream transcription factors.

Jasmonic acids (JAs) are important injury signaling molecules, which participate in the process of wound healing in plants. However, how JA and its downstream transcription factors involve in wound healing in apple fruit mediated by BTH has not been reported yet. In the present study, BTH treatment up-regulated gene expression of MdLOX3.1, MdAOS1, MdAOC, and MdOPR3, promoting JA synthesis at fruit wounds. Moreover, BTH up-regulated the gene expression of MdMYC2, MdGAIPB, and MdMYB108 transcription factors and increased MdPAL1, Md4CL2, MdCOMT1, and MdCAD6 expression. In addition, BTH facilitated the synthesis of phenylpropanoid metabolism products and accelerated suberin polyphenolics deposition at the wounds, which effectively reduced fruit weight loss and lesion diameter of apple fruit inoculated with Penicillium expansum during healing. It is suggested that BTH induced wound healing in apple fruit by the stimulating JA and its downstream transcription factors, and phenylpropanoid metabolism.

Health-related Quality of Life in Hormone Receptor-Positive Early Breast Cancer: Analyses From the Surveillance, Epidemiology, and End Results Medicare Health Outcomes Survey.

This study describes health-related quality of life (HRQoL) among older Medicare beneficiaries with hormone receptor-positive (HR+) early breast cancer (eBC). Women aged ≥65 years diagnosed with stage I-III HR+ eBC between 1997 and 2014 using the Surveillance, Epidemiology, and End Results Medicare Health Outcomes Survey Data Resource were included. HRQoL was measured using the Short Form Health Survey including physical/mental component summary (PCS/MCS) scores and subscales. Patient surveys ≤ 24 months post-diagnosis were matched to non-cancer controls. Mean differences in HRQoL were compared using analysis of covariance. Among 1880 HR+ eBC patients versus 5640 matched non-cancer controls, eBC patients surveyed ≤ 6 months post-diagnosis (n = 530) scored lower on component scores (PCS mean difference = 1.6 [95%CI: 0.6-2.6]; MCS mean difference = 2.0 [95%CI: 1.0-3.0]) and multiple subscales. Among women surveyed 19 to 24 months post-diagnosis (n = 402), mean differences in HRQoL were modest (PCS: 1.2 [95%CI: 0.1-2.4]; MCS: -1.5 [95%CI: -2.7 to -0.3]). Most differences in HRQoL following diagnosis of eBC did not indicate statistical significance or minimally important difference, emphasizing that preservation of HRQoL is an important and realistic goal among patients with eBC.

Impact of socioeconomic status and rurality on cancer-specific survival among women with de novo metastatic breast cancer by race/ethnicity.

PURPOSE: There are approximately 150,000 women living with metastatic breast cancer (mBC) in the United States. Disparities in de novo mBC incidence and mortality exist across race/ethnicity, socioeconomic status (SES), and rurality. However, how SES and rurality independently impact mBC outcomes across different racial/ethnic groups is not fully understood. The purpose of this study was to determine the impact of SES and rurality on cancer-specific mortality among women with mBC by race/ethnicity. METHODS: We conducted a large, population-based retrospective cohort study in women aged 18 + years diagnosed with de novo mBC using the Surveillance, Epidemiology and End Results Census Tract-level SES and Rurality Database (2000-2015). Associations between SES/rurality and cancer-specific mortality were determined using Fine and Gray regression models. Subdistribution hazard ratios (SHR) and 95% confidence intervals (CI) by race/ethnicity and hormone receptor (HR) status were calculated. RESULTS: A cohort of 33,976 women were included with the majority being White (67%), 17% Black, 0.4% American Indian/Alaskan Native, 6% Asian/Pacific Islander, and 10% Latina/Hispanic. We observed the greatest increased risk of BC mortality among Black women with HR-negative mBC residing in neighborhoods with lower SES (lowest versus highest quintile: SHR 1.38, 95% CI 1.00-1.90) and in rural areas compared to urban areas (SHR 1.27, 95% CI 1.01-1.59). CONCLUSION: Overall, BC-specific survival among women with de novo mBC differs by race/ethnicity, with the greatest adverse impacts of SES and rurality affecting Black women with HR-negative disease.

Coupling between Ribotypic and Phenotypic Traits of Protists across Life Cycle Stages and Temperatures.

Relationships between ribotypic and phenotypic traits of protists across life cycle stages remain largely unknown. Herein, we used single cells of two soil and two marine ciliate species to examine phenotypic and ribotypic traits and their relationships across lag, log, plateau, cystic stages and temperatures. We found that Colpoda inflata and Colpoda steinii demonstrated allometric relationships between 18S ribosomal DNA (rDNA) copy number per cell (CNPC), cell volume (CV), and macronuclear volume across all life cycle stages. Integrating previously reported data of Euplotes vannus and Strombidium sulcatum indicated taxon-dependent rDNA CNPC-CV functions. Ciliate and prokaryote data analysis revealed that the rRNA CNPC followed a unified power-law function only if the rRNA-deficient resting cysts were not considered. Hence, a theoretical framework was proposed to estimate the relative quantity of resting cysts in the protistan populations with total cellular rDNA and rRNA copy numbers. Using rDNA CNPC was a better predictor of growth rate at a given temperature than rRNA CNPC and CV, suggesting replication of redundant rDNA operons as a key factor that slows cell division. Single-cell high-throughput sequencing and analysis after correcting sequencing errors revealed multiple rDNA and rRNA variants per cell. Both encystment and temperature affected the number of rDNA and rRNA variants in several cases. The divergence of rDNA and rRNA sequence in a single cell ranged from 1% to 10% depending on species. These findings have important implications for inferring cell-based biological traits (e.g., species richness, abundance and biomass, activity, and community structure) of protists using molecular approaches. IMPORTANCE Based on phenotypic traits, traditional surveys usually characterize organismal richness, abundance, biomass, and growth potential to describe diversity, organization, and function of protistan populations and communities. The rRNA gene (rDNA) and its transcripts have been widely used as molecular markers in ecological studies of protists. Nevertheless, the manner in which these molecules relate to cellular (organismal) and physiological traits remains poorly understood, which could lead to misinterpretations of protistan diversity and ecology. The current research highlights the dynamic nature of cellular rDNA and rRNA contents, which tightly couple with multiple phenotypic traits in ciliated protists. We demonstrate that quantity of resting cysts and maximum growth rate of a population can be theoretically estimated using ribotypic trait-based models. The intraindividual sequence polymorphisms of rDNA and rRNA can be influenced by encystment and temperature, which should be considered when interpreting species-level diversity and community structure of microbial eukaryotes.

Improving the Acceptability of Human Papillomavirus Vaccines Among Men Who Have Sex With Men According to the Associated Factors: A Systematic Review and Meta-analysis.

Objectives: To investigate the acceptability of human papillomavirus (HPV) vaccination among men who have sex with men (MSM) and its associated factors. Methods: We searched studies written in English in PubMed, EMBASE, and Web of Science with no geographical or time restrictions. We evaluated the quality of the included literature. We calculated the pooled acceptability and performed meta-analysis of selected studies, including factors associated with the acceptability among MSM, using Review Manager (v5.3). Results: The acceptability among the 15 studies (n = 8,658) was 50% (95% CI: 0.27-0.72). The meta-analysis of seven articles (n = 4,200) indicated that having a college or higher degree (OR = 1.62, 95% CI: 1.35-1.95), disclosure of sexual orientation to healthcare professionals (HCPs; OR = 2.38, 95% CI: 1.47-3.86), vaccination with at least one dose for hepatitis A or B (OR = 2.10, 95% CI: 1.42-3.10), awareness of HPV (OR = 1.85, 95% CI: 1.21-2.83), knowledge of HPV (SMD = 0.28, 95% CI: 0.16-0.39), perceived susceptibility to HPV infection (SMD = 0.31, 95% CI: 0.11-0.50), and perceived severity of HPV-related disease (SMD = 0.40, 95% CI: 0.28-0.51) can promote acceptance of HPV vaccines. Meanwhile, people who have had unprotected anal sex or have more sex partners tend to have low acceptance of HPV vaccines. Conclusions: HPV education should be actively promoted according to the factors that influence the acceptability of HPV vaccines among the MSM population. HPV education should be especially aimed at people with low academic qualifications and people with risky sexual behaviors, and should emphasize the aspects of susceptibility to and severity of HPV-related disease. More intervention trials should be conducted to increase the credibility of the results.

Metabonomic studies of pancreatic cancer response to radiotherapy in a mouse xenograft model using magnetic resonance spectroscopy and principal components analysis.

AIM: To investigate the metabolic profiles of xenograft pancreatic cancer before and after radiotherapy by high-resolution magic angle spinning proton magnetic resonance spectroscopy (HRMAS (1)H NMR) combined with principal components analysis (PCA) and evaluate the radiotherapeutic effect. METHODS: The nude mouse xenograft model of human pancreatic cancer was established by injecting human pancreatic cancer cell SW1990 subcutaneously into the nude mice. When the tumors volume reached 800 mm(3), the mice received various radiation doses. Two weeks later, tumor tissue sections were prepared for running the NMR measurements. (1)H NMR and PCA were used to determine the changes in the metabolic profiles of tumor tissues after radiotherapy. Metabolic profiles of normal pancreas, pancreatic tumor tissues, and radiation- treated pancreatic tumor tissues were compared. RESULTS: Compared with (1)H NMR spectra of the normal nude mouse pancreas, the levels of choline, taurine, alanine, isoleucine, leucine, valine, lactate, and glutamic acid of the pancreatic cancer group were increased, whereas an opposite trend for phosphocholine, glycerophosphocholine, and betaine was observed. The ratio of phosphocholine to creatine, and glycerophosphocholine to creatine showed noticeable decrease in the pancreatic cancer group. After further evaluation of the tissue metabolic profile after treatment with three different radiation doses, no significant change in metabolites was observed in the (1)H NMR spectra, while the inhibition of tumor growth was in proportion to the radiation doses. However, PCA results showed that the levels of choline and betaine were decreased with the increased radiation dose, and conversely, the level of acetic acid was dramatically increased. CONCLUSION: The combined methods were demonstrated to have the potential for allowing early diagnosis and assessment of pancreatic cancer response to radiotherapy.

Discrimination of metabolic profiles of pancreatic cancer from chronic pancreatitis by high-resolution magic angle spinning 1H nuclear magnetic resonance and principal components analysis.

The metabolic profiles of Sprague-Dawley rat pancreases were investigated by high-resolution magic angle spinning proton magnetic resonance spectroscopy ((1)H NMR) combined with principal components analysis (PCA) to discriminate pancreatic cancer from chronic pancreatitis. Intact pancreatic tissue samples were obtained from Sprague-Dawley rats with histologically proven pancreatic cancer (n = 5), chronic pancreatitis (n = 5), and two matched controls (n = 5 per group). Two (1)H NMR experiments, single-pulse and Carr-Purcell-Meiboom-Gill, were carried out separately. Increases in phosphocholine and glycerophosphocholine levels and decreases in leucine, isoleucine, valine, lactate and alanine levels were observed in chronic pancreatitis, whereas the opposite trends were observed in pancreatic cancer. Increasing taurine and decreasing betaine were found both in chronic pancreatitis and in pancreatic cancer. Additionally, the lipid content in pancreatic cancer was higher than that in chronic pancreatitis. PCA was carried out for the single-pulse and Carr-Purcell-Meiboom-Gill (1)H NMR spectra, respectively, to visualize separation among the samples and to extract characteristic metabolites of pancreatic cancer and chronic pancreatitis. Decreased phosphocholine and glycerophosphocholine were suggested as unique metabolite indicators of pancreatic cancer. Furthermore, even with the disturbance of various quantities of lipid contents pancreatic cancer and chronic pancreatitis could be differentiated well by the combination of high-resolution magic angle spinning (1)H NMR and PCA. Thus this combination was demonstrated to have the potential to improve magnetic resonance spectroscopy for positive early diagnosis of pancreatic cancer in clinical settings.