Miracle-dz/UniFAR-FTUs huggingface dataset:
Novel Abscisic Acid Antagonists Identified with Chemical Array Screening

Abscisic acid (ABA) signaling is involved in multiple processes in plants, such as water stress control and seed dormancy. Major regulators of ABA signaling are the PYR/PYL/RCAR family receptor proteins, group A protein phosphatases 2C (PP2Cs), and subclass III of SNF1‐related protein kinase 2 (SnRK2). Novel ABA agonists and antagonists to modulate the functions of these proteins would not only contribute to clarification of the signaling mechanisms but might also be used to improve crop yields. To obtain small molecules that interact with Arabidopsis ABA receptor PYR1, we screened 24 275 compounds from a chemical library at the RIKEN Natural Products Depository by using a chemical array platform. Subsequent SnRK2 and PP2C assays narrowed down the candidates to two molecules. One antagonized ABA in a competitive manner and inhibited the formation of the PYR1‐ABA‐PP2C ternary complex. These compounds might have potential as bioprobes to analyze ABA signaling.
On power and sample size of the ANOVA-type rank test

ABSTRACT When using nonparametric methods to analyze factorial designs with repeated measures, the ANOVA-type rank test has gained popularity due to its robustness and appropriate type I error control. This article proposes power and sample size calculation formulas under two scenarios where the nonparametric regression coefficients are known or they are unknown but a pilot study is available. When a pilot study is available, the formulas do not need any assumption on the underlying population distributions. Simulation results confirm the accuracy of the proposed methods. An STZ rat excisional wound study is used to demonstrate the application of the methods.
Bioorthogonal Chemical Reporters for Monitoring Unsaturated Fatty‐Acylated Proteins

Dietary unsaturated fatty acids, such as oleic acid, have been shown to be covalently incorporated into a small subset of proteins, but the generality and diversity of this protein modification has not been studied. We synthesized unsaturated fatty‐acid chemical reporters and determined their protein targets in mammalian cells. The reporters can induce the formation of lipid droplets and be incorporated site‐specifically onto known fatty‐acylated proteins and label many proteins in mammalian cells. Quantitative proteomics analysis revealed that unsaturated fatty acids modify similar protein targets to saturated fatty acids, including several immunity‐associated proteins. This demonstrates that unsaturated fatty acids can directly modify many proteins to exert their unique and often beneficial physiological effects in vivo.
Ac‐LPFFD‐Th: A Trehalose‐Conjugated Peptidomimetic as a Strong Suppressor of Amyloid‐β Oligomer Formation and Cytotoxicity

The inhibition of amyloid formation is a promising therapeutic approach for the treatment of neurodegenerative diseases. Peptide‐based inhibitors, which have been widely investigated, are generally derived from original amyloid sequences. Most interestingly, trehalose, a nonreducing disaccharide of α‐glucose, is effective in preventing the aggregation of numerous proteins. We have determined that the development of hybrid compounds could provide new molecules with improved properties that might synergically increase the potency of their single moieties. In this work, the ability of Ac‐LPFFD‐Th, a C‐terminally trehalose‐conjugated derivative, to slow down the Aβ aggregation process was investigated by means of different biophysical techniques, including thioflavin T fluorescence, dynamic light scattering, ESI‐MS, and NMR spectroscopy. Moreover, we demonstrate that Ac‐LPFFD‐Th modifies the aggregation features of Aβ and protects neurons from Aβ oligomers' toxic insult.
A comparison of L-, LQ-, TL-moment and maximum likelihood high quantile estimates of the GPD and GEV distribution

ABSTRACT In this article, L-moments, LQ-moments and TL-moments of the generalized Pareto and generalized extreme-value distributions are derived up to the fourth order. The first three L-, LQ- and TL-moments are used to obtain estimators of their parameters. Performing a simulation study, high-quantile estimates based on L-, LQ-, and TL-moments are compared to the maximum likelihood estimate with respect to their sample mean squared error. This consists of identifying an optimal combination of parameters α and p both considered in the range [0, 0.5] for estimating quantiles by LQ-moments. The results show L-moment and maximum likelihood methods outperform other methods.
A Retrospective Study of Bifractionated CPT-11 With LF5FU Infusion (FOLFIRI-3) in Colorectal Cancer Patients Pretreated With Oxaliplatin and CPT-11 Containing Chemotherapies

Objective:The chemotherapy regimen suitable for advanced colorectal cancer patients previously treated with 5 fluorouracil (5FU); oxaliplatin and irinotecan remains an unresolved issue. The poor response rates and progression-free survival achieved with FOLFIRI in the second-line of therapy and the schedule-dependent activity of irinotecan, prompted us to assess the efficacy and tolerability of FOLFIRI3 regimen in patients with metastatic colorectal cancer (CRC) previously exposed to irinotecan and oxaliplatin. Methods:Twenty-seven metastatic CRC patients previously exposed to irinotecan and/or oxaliplatin were treated with the FOLFIRI3 regimen. They received an irinotecan injection at 100 mg/m2 before and at the end of a 2400 mg/m2 5FU continuous infusion. Two hundred and six cycles of chemotherapy were delivered in an outpatient basis. Results:FOLFIRI3 regimen was well tolerated. Grade 3 of 4 adverse events included nausea and vomiting (18%), diarrhea (11%), anemia (7%), and neutropenia (7%). Partial responses were observed in 2 patients and 10 patients achieved stable diseases. From the start of FOLFIRI3, time to progression was 4.47 months (0–11 months) and median overall survival was 8.9 months (0.72–21.4 months). Interestingly, FOLFIRI3 treatment was associated to a clinical benefit in 7 out of 17 patients who previously progressed “on-therapy” or less than 3 months after the completion of a previous FOLFIRI chemotherapy. Conclusion:These results suggest that fractionated irinotecan administration might restore the clinical benefit of this molecule in patients resistant to FOLFIRI.
Frequent Search for Sense by Long-Term Breast Cancer Survivors Associated with Reduced HRQOL

ABSTRACT This study examined breast cancer survivors' reports of continuing efforts to make sense of their breast cancer experience and associations of such efforts with post-traumatic stress symptomology (PTSS) and long-term health related quality of life (HRQOL). A cross-sectional survey was conducted with 636 women in 2002–2003 two, five and ten years after their diagnosis of breast cancer. Only a minority of women with breast cancer reported frequently searching for sense in their cancer experience, or wondering “why did this happen to me? ” two or more years after diagnosis. Controlling for key demographic and disease variables, greater involvement in search two, five and ten years post-diagnosis was associated with higher levels of PTSS (R2 = 0.26; p < 0.001) and with reduced HRQOL as measured using the SF-36 scale (p < 0.01 for all scales). It appears that continued efforts to search for sense in the cancer experience two or more years after cancer diagnosis are associated with PTSS and lower levels of HRQOL in long-term survivors of breast cancer.
Role Involvement and Well-Being in Middle-Aged Women

ABSTRACT Objectives: The aim of this research was to shed light on the relation of social role experiences and health to well-being outcomes of 198 middle-aged (40–55 years old) Swiss women living in various familial contexts (double-track women, i.e., partnered working mothers, homemakers, single mothers, single women). Results: Our results revealed that the way roles were experienced was primarily a function of a specific living context and satisfying social resources. Double-track women and homemakers showed the highest social role satisfaction rates and had better health and well-being outcomes than other women. Common to all groups was a considerable difference between actual and desired role investment. Discussion: The findings are discussed in terms of a resource-oriented model of well-being.
Aromatic Polyketide GTRI‐02 is a Previously Unidentified Product of the act Gene Cluster in Streptomyces coelicolor A3(2)

The biosynthesis of aromatic polyketides derived from type II polyketide synthases (PKSs) is complex, and it is not uncommon that highly similar gene clusters give rise to diverse structural architectures. The act biosynthetic gene cluster (BGC) of the model actinomycete Streptomyces coelicolor A3(2) is an archetypal type II PKS. Here we show that the act BGC also specifies the aromatic polyketide GTRI‐02 (1) and propose a mechanism for the biogenesis of its 3,4‐dihydronaphthalen‐1(2H)‐one backbone. Polyketide 1 was also produced by Streptomyces sp. MBT76 after activation of the act‐like qin gene cluster by overexpression of the pathway‐specific activator. Mining of this strain also identified dehydroxy‐GTRI‐02 (2), which most likely originated from dehydration of 1 during the isolation process. This work shows that even extensively studied model gene clusters such as act of S. coelicolor can still produce new chemistry, offering new perspectives for drug discovery.
A Phase I Trial of Oblimersen Sodium in Combination With Cisplatin and 5-Fluorouracil in Patients With Advanced Esophageal, Gastroesophageal Junction, and Gastric Carcinoma

Purpose:To determine the maximum tolerated dose of oblimersen, an antisense oligonucleotide directed to the Bcl-2 mRNA, in combination with cisplatin and 5-flourouracil in patients with advanced gastric and esophageal carcinoma. Methods:Patients were treated with escalating doses of oblimersen administered by continuous intravenous infusion (CIVI) days 1 to 7, CIVI 5-fluorouracil (5-FU) days 4 to 7, and cisplatin on day 4 every 3 weeks. Results:Fifteen patients received a total of 49 courses of oblimersen at doses of 3, 5, or 7 mg/kg/d given as a 7 day CIVI in combination with 4 or 5 day CIVI of 5-FU (1000 or 750 mg/m2/d) plus intravenous cisplatin (100 or 75 mg/m2 over 2 hours). The recommended phase II dose of oblimersen was 5 mg/kg/d in combination with 5-FU (750 mg/m2/d for 4 days) and cisplatin (75 mg/m2). The most common grade 3 to 4 adverse events that occurred in at least 10% of patients at all dose levels included neutropenia (33%), hypokalemia (27%), infection (20%), and mucositis, fatigue, dizziness, thrombosis, and dehydration (in 13% for each category). Conclusion:The combination of oblimersen with 5-FU and cisplatin chemotherapy is feasible in patients with advanced upper gastrointestinal cancer, with antitumor activity observed in gastric carcinoma.
The Association Between Employment Status and Metabolic Syndrome in Women: Modifying Effect of Education

The aim of the researchers in this study was to examine the relations of paid work versus housework and educational level to metabolic syndrome in women. The study sample consisted of women who participated in a baseline survey of the Heart of Balcova Project, which is an ongoing cohort study in Izmir, Turkey. A randomly selected subsample of women who were aged 30–64 years and who were not retired or unemployed was derived from the individuals who participated in the Heart of Balcova Project. All data were collected through face-to-face interviews with 191 workers and 342 housewives. The association between employment status and metabolic syndrome was explored using multiple logistic regression models. The prevalence of metabolic syndrome was significantly higher among housewives than among workers. Among the women with a high educational level, odds of metabolic syndrome were significantly higher for housewives than for those who were employed. An association between employment status and metabolic syndrome was not observed in the group with a low level of education. The findings revealed that educational level had a modifying effect on the relationship between employment status and metabolic syndrome among women and thus has implications for improving the understanding of the importance of health and educational opportunities for housewives.
A Multicenter Phase II Clinical Trial of Lapatinib (GW572016) in Hormonally Untreated Advanced Prostate Cancer

Objectives:Lapatinib (GW572016) is a selective and potent dual tyrosine kinase inhibitor of the epidermal growth factor 1 (EGFR) and 2 (HER2), approved in the treatment of HER2 positive breast cancer. Since EGFR and HER2 overexpression has also been seen in prostate cancer and appears to correlate with a worse clinical outcome, Lapatinib may represent a novel therapeutic strategy in prostate cancer. This Phase II multicenter clinical trial is the first to evaluate Lapatinib in early stage, hormonally untreated recurrent or metastatic prostate cancer. Methods:Eligible patients received lapatinib 1500 mg PO daily until progression. The primary end point was prostate specific antigen (PSA) response. Archival tumor tissue was collected for EGFR and HER2 analysis. Results:A total of 23 patients, median age 67, ECOG PS 0–2, mean baseline PSA 7.5, were evaluable for response. In total, 125 cycles were administered. The most frequent adverse events were lymphopenia, fatigue, rash, dyspepsia, and diarrhea. Grade 3+ increased alanine aminotransferase (ALT) was reported in 2 patients, and grade 4 blurry vision in 1 patient. No PSA responses were seen. Median time to progression (TTP) was 4.6 months and 6 months progression-free estimate was 44.5%. Conclusions:Lapatinib was well tolerated but like other EGFR- and HER2-targeted agents in advanced HRPC failed to show significant antitumor activity even in this very early stage hormonally untreated population.
Water-Based Exercise and Quality of Life in Women: The Role of Depressive Symptoms

Several studieshave evaluated the relation of exercise to quality of life (QoL). To our knowledge, no study has evaluated the relation of water-based exercise to depressive symptoms and QoL, or the association between improvement in QoL and depressive symptoms in healthy women. The purpose of this study was to evaluate the association of water-based exercise with changes in QoL. Forty-seven women performed water-based combined exercise for 12 weeks. All participants improved in the physical and psychological domains of QoL. Decreases in depressive symptoms and improvements in maximal strength and aerobic capacity were found for all participants. A regression model revealed that depressive symptoms were associated with improvements in physical and psychological domains of QoL. The results showed that moderate intensity, water-based exercise improved physical and psychological domains of QoL, depressive symptoms, aerobic capacity, and muscular strength of women. Furthermore, the improvement in physical and psychological domains of QoL appeared to be mediated by the antidepressant effects of exercise, but not by changes in aerobic capacity or muscular strength.
A Comparative Reengineering Study of cpADH5 through Iterative and Simultaneous Multisite Saturation Mutagenesis

Positions identified in directed evolution campaigns or by (semi)rational design can be recombined iteratively or simultaneously. Iterative recombination has yielded many success stories and is beneficially used if screening capabilities are limited (four iterative SSMs generate 20×4=80 different enzyme variants). Simultaneous site saturation mutagenesis offers significantly higher diversity (204=160 000 variants) and enables greater improvements to be found, especially if the selected positions are in close proximity to each other (cooperative effects). Here we report a first comprehensive comparison of iterative and simultaneous saturation of four residues in Candida parapsilosis alcohol dehydrogenase 5 (cpADH5) with methyl 3‐hydroxyhexanoate as substrate. Screening of 7200 clones from 33 site saturation mutagenesis libraries (exploring 17 recombination paths) yielded the cpADH5 W286A variant, with a 82‐fold improved initial activity toward methyl 3‐hydroxyhexanoate. Screening 3500 clones from a single OmniChange library with four positions (C57, W116, L119, and W286; 1.8 % of the generated sequence space) yielded the cpADH5 C57V/W286S variant, with a 108‐fold improvement in initial activity toward methyl 3‐hydroxyhexanoate. A 1.8 % coverage of the sequence space of the simultaneous multisite saturation library was, in comparison to the investigated 17 recombination paths, sufficient to identify a cpADH5 variant with improved activity.
Viewing Metastatic Colorectal Cancer as a Curable Chronic Disease

Improved survival of colorectal cancer has been made over the last 3 decades; reasons may be attributed to early detection through screening, and better treatment options. Advancements in modern systemic chemotherapy for colorectal cancer include oxaliplatin-based and irinotecan-based combination and the introduction of biological agents such as bevacizumab and cetuximab. Systemic therapies need to be used in patients with high risk stage II and stage III colorectal cancer and in patients with metastatic disease. Evidence for liver resection and ablation, pulmonary metastasectomy and/or radiofrequency ablation, and cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy for metastasis to sites of the liver, lung, and peritoneum respectively are well established. The biggest challenge is to select the right patients for metastasectomy and to pursue metastatic disease as a chronic disease to ensure appropriate personalized therapy, pursue second-line therapies or repeat surgeries, and minimize toxicities of therapies.
Epidemiologic Research: Principles and Quantitative Methods.

Key Issues in Epidemiologic Research: An Overview. OBJECTIVES AND METHODS OR EPIDEMIOLOGIC RESEARCH. Fundamentals of Epidemiologic Research. Types of Epidemiologic Research. Design Options in Observational Studies. Typology of Observational Study Designs. Measures of Disease Frequency: Incidence. Other Measures of Disease Frequency. Measures of Association. Measures of Potential Impact and Summary of the Measures. VALIDITY OF EPIDEMIOLOGIC RESEARCH. Validity: General Considerations. Selection Bias. Information Bias. Confounding. Confounding Involving Several Risk Factors. PRINCIPLES AND PROCEDURES OF EPIDEMIOLOGIC ANALYSIS. Statistical Inferences About Effect Measures: Simple Analysis. Overview of Options for Control of Extraneous Factors. Stratified Analysis. Matching in Epidemiologic Studies. Interaction, Effect Modification, and Synergism. Modeling: Theoretical Considerations. Modeling: Analysis Strategy. Applications of Modeling with No Interaction. Applications of Logistic Regression with Interaction, Using Unconditional ML Estimation. Applications of Modeling: Conditional Likelihood Estimation. Appendices. Index.
Comparative Effectiveness of Filgrastim, Pegfilgrastim, and Sargramostim as Prophylaxis Against Hospitalization for Neutropenic Complications in Patients With Cancer Receiving Chemotherapy

BackgroundComparative effectiveness of filgrastim, pegfilgrastim, and sargramostim in preventing hospitalization for febrile neutropenia (FN) during myelosuppressive chemotherapy has not been well characterized and is an important clinical question in oncology. MethodsThis study used a retrospective cohort design and US healthcare claims data. Source population included patients with solid tumors receiving filgrastim, pegfilgrastim, or sargramostim during their first observed course of chemotherapy between July 2001 and June 2007. For each patient, every unique chemotherapy cycle during the course was identified, along with each cycle in which filgrastim, pegfilgrastim, or sargramostim was administered by the fifth day of the cycle (ie, as prophylaxis). Risks of hospitalization for neutropenic complications (broad definition: admission with a diagnosis of neutropenia, fever, or infection; narrow definition: admission with a diagnosis of neutropenia) and for any reason were examined on a cycle-specific basis during all the cycles in which colony-stimulating factor prophylaxis was administered. Unadjusted and adjusted odds ratios (ORs) for hospitalization were estimated. ResultsRisk (unadjusted) of hospitalization for neutropenic complications (narrow definition) was 2.1% for filgrastim prophylaxis (n=8286), 1.1% for pegfilgrastim prophylaxis (n=67,247), and 2.5% for sargramostim prophylaxis (n=1736). Corresponding risks of hospitalization based on the broad definition were 4.0%, 2.6%, and 5.1%. Risks of all-cause hospitalization were 7.9%, 5.3%, and 9.6%, respectively. Adjusted odds of hospitalization were significantly higher for filgrastim [OR (range across the 3 alternative measures of hospitalization): 1.58-1.79; P<0.001] and sargramostim (OR: 1.89-2.68; P<0.001) versus pegfilgrastim. ConclusionsRisk of hospitalization for neutropenic complications during cancer chemotherapy is lower with pegfilgrastim prophylaxis than with filgrastim or sargramostim prophylaxis.
Factors associated with receiving Pap tests among married immigrant women of Vietnamese origin in southern Taiwan

ABSTRACT The purpose of this study was to explore the factors associated with Pap testing among married immigrant women of Vietnamese origin residing in Taiwan, including demographics, knowledge of cervical cancer, knowledge of Pap tests, fatalism, attitudes toward cervical cancer, and barriers to receiving Pap tests. A cross-sectional correlational design was used. Data were collected from July 2012 to January 2013. Participants were recruited through snowball sampling in two communities in Southern Taiwan. A total of 451 married immigrant women of Vietnamese origin aged 30 years and over were invited to participate in the study and 427 participated. Data analysis included descriptive statistics and multivariate logistic regression. Participants with no children were significantly less likely to have received a Pap test (odds ratio = 0.278, 95% confidence interval [CI] = 0.135–0.569); each additional point of knowledge about Pap tests increased the likelihood of having a Pap test by 19% (odds ratio = 1.190, 95% CI = 1.093–1.297), and each additional point in barriers to receiving Pap tests decreased the chances of having received a Pap test (odds ratio = 0.714, 95% CI = 0.637–0.800). The results can provide governments with a reference for developing policies for cervical cancer prevention among married immigrant Vietnamese women.
Environmental and personal correlates of physical activity and sedentary behavior in African American women: An ecological momentary assessment study

ABSTRACT The authors of this study examined within-person associations of environmental factors (weather, built and social environmental barriers) and personal factors (daily hassles, affect) with moderate-to-vigorous physical activity (MVPA) and sedentary behavior (SB) in African American women aged 25–64 years living in metropolitan Chicago (n = 97). In 2012–13, for seven days, women wore an accelerometer and were signaled five times per day to complete a survey covering environmental and personal factors on a study-provided smartphone. Day-level measures of each were derived, and mixed regression models were used to test associations. Poor weather was associated with a 27.3% reduction in daily MVPA. Associations between built and social environmental barriers and daily MVPA or SB were generally not statistically significant. Negative affect at the first daily signal was associated with a 38.6% decrease in subsequent daily MVPA and a 33.2-minute increase in subsequent daily SB. Each one-minute increase in MVPA during the day was associated with a 2.2% higher likelihood of positive affect at the end of the day. SB during the day was associated with lower subsequent positive affect. Real-time interventions that address overcoming poor weather and negative affect may help African American women increase MVPA and/or decrease SB.