Miracle-dz/UniFAR-FTUs huggingface dataset:
Proteomic approaches for investigation of therapy resistance in cancer

Resistance to anticancer therapy is a major obstacle for successful management of patients in oncology. Although in the past, various biological mechanisms involved in therapy resistance, in particular multidrug resistance, have been identified, cancer patients did not really benefit. The mechanisms include the enhanced activity of drug extrusion pumps, modulation of cellular death pathways, alteration and repair of target molecules and various other mechanisms. Together they build a complex network mediating an individual therapy‐resistant phenotype. The improved description of this multifactorial network should be useful for prediction of treatment response and would allow to design an individual‐tailored therapy regiment. Proteome analyzing technologies appear as powerful tools for identifying new factors and protein expression profiles associated with anticancer therapy resistance. In the last years, the application of proteomic techniques identified multiple new factors or protein expression signatures in drug‐resistant cell models and cancerous tissues. However, the functional role and the clinical impact of these findings are not yet clarified. So far, none of the proteomic data were useful for the development of improved diagnostic tests, for prediction of individual therapy response or for development of updated chemosensitizers. Here, the previous therapy resistance‐related proteome data and future perspectives will be discussed.
Stimulation of Sirt1-Regulated FoxO Protein Function by the Ligand-Bound Vitamin D Receptor

ABSTRACT Hormonal vitamin D, 1,25-dihydroxyvitamin D (1,25D), signals through the nuclear vitamin D receptor (VDR). 1,25D regulates cell proliferation and differentiation and has been identified as a cancer chemopreventive agent. FoxO proteins are transcription factors that control cell proliferation and survival. They function as tumor suppressors and are associated with longevity in several organisms. Accumulating data have revealed that 1,25D and FoxO proteins regulate similarly common target genes. We show here that the ligand-bound VDR regulates the posttranslational modification and function of FoxO proteins. 1,25D treatment enhances binding of FoxO3a and FoxO4 within 4 h to promoters of FoxO target genes and blocks mitogen-induced FoxO protein nuclear export. The VDR associates directly with FoxO proteins and regulators, the sirtuin 1 (Sirt1) class III histone deacetylase (HDAC), and protein phosphatase 1. In addition, phosphatase activity and trichostatin A-resistant HDAC activity coimmunoprecipitate with the VDR. 1,25D treatment rapidly (in <4 h) induces FoxO deacetylation and dephosphorylation, consistent with activation. In contrast, ablation of VDR expression enhances FoxO3a phosphorylation, as does knockdown of Sirt1, consistent with the coupling of FoxO acetylation and phosphorylation. 1,25D regulation of common VDR/FoxO target genes is attenuated by blockade of phosphatase activity or by small interfering RNA (siRNA)-mediated knockdown of Sirt1 or FoxO protein expression. Finally, 1,25D-dependent cell cycle arrest is blocked in FoxO3a-deficient cells, indicating that FoxO proteins are key downstream mediators of the antiproliferative actions of 1,25D. These studies link 1,25D signaling through the VDR directly to Sirt1 and FoxO function and provide a molecular basis for the cancer chemopreventive actions of 1,25D.
Phosphonic acid: preparation and applications

The phosphonic acid functional group, which is characterized by a phosphorus atom bonded to three oxygen atoms (two hydroxy groups and one P=O double bond) and one carbon atom, is employed for many applications due to its structural analogy with the phosphate moiety or to its coordination or supramolecular properties. Phosphonic acids were used for their bioactive properties (drug, pro-drug), for bone targeting, for the design of supramolecular or hybrid materials, for the functionalization of surfaces, for analytical purposes, for medical imaging or as phosphoantigen. These applications are covering a large panel of research fields including chemistry, biology and physics thus making the synthesis of phosphonic acids a determinant question for numerous research projects. This review gives, first, an overview of the different fields of application of phosphonic acids that are illustrated with studies mainly selected over the last 20 years. Further, this review reports the different methods that can be used for the synthesis of phosphonic acids from dialkyl or diaryl phosphonate, from dichlorophosphine or dichlorophosphine oxide, from phosphonodiamide, or by oxidation of phosphinic acid. Direct methods that make use of phosphorous acid (H3PO3) and that produce a phosphonic acid functional group simultaneously to the formation of the P–C bond, are also surveyed. Among all these methods, the dealkylation of dialkyl phosphonates under either acidic conditions (HCl) or using the McKenna procedure (a two-step reaction that makes use of bromotrimethylsilane followed by methanolysis) constitute the best methods to prepare phosphonic acids.
Differential effects of NT‐3 on reinnervation of the fast extensor digitorum longus (EDL) and the slow soleus muscle of rat

Previous studies of gastrocnemius muscle reinnervation showed specific normalization of the proportion and diameter of fast type 2b muscle fibres following NT‐3 delivery to the proximal stump of the cut sciatic nerve. Here, we investigate if normalization was related to greater improvement of muscle reinnervation of fast (extensor digitorum longus; EDL) than slow (soleus) motor units. NT‐3‐impregnated (NT‐3 group) or plain fibronectin (FN group) mats were inserted into a sciatic nerve gap. Neuromuscular junctions (NMJs) labelled with TRITC‐α‐bungarotoxin were colabelled with calcitonin gene‐related peptide (CGRP) or 4E2 antisera and imaged using confocal microscopy. CGRP and 4E2 were used as markers for newly reinnervated and structurally mature NMJs, respectively. At 40 days postsurgery, denervated NMJs in EDL and soleus muscles of both groups presented a 50% decrease of surface area due to decreased width. At day 80 in EDL, more NMJs were reinnervated by CGRP‐immunoreactive terminals in the NT‐3 (7.1%) than in the FN group (4.2%); there was no difference between groups for soleus. At 120 days, 4E2‐immunoreactive NMJs were more numerous in EDL of the NT‐3 (40.0%) than in the FN group (7.3%), unlike in soleus (NT‐3, 1.6%; FN, 1.8%), and presented a partial size recovery. These results indicate that NT‐3 preferentially improves reinnervation of fast muscles over slow muscle, although the mechanism of this improvement is still unclear.
Modeling of receptor mimics that inhibit superantigen pathogenesis

Staphylococcal enterotoxins SEB and SEC3 and toxic shock syndrome toxin TSST‐1 act as superantigens by overstimulating the human immune system and thereby compromise host defense. The mechanism of pathogenesis is explained on the basis of superantigen binding to the MHC class II receptor on the antigen presenting cell and to the T cell receptor (TcR) on the T cell. SEB, SEC3 and TSST‐1 bind as intact proteins and make contacts with the α1 subdomain (DRα) of MHC class II and Vβ subdomain of TcR. SEB, SEC3 and TSST‐1 show specificities for different TcRVβ isoforms. We have designed three different chimeras linking the same DRα with different TcRVβ isoforms to specifically target SEB, SEC3 and TSST‐1 and inhibit their pathogenesis. Here, we show by molecular modeling that the DRα, TcRVβ and linker of a given chimera interact with the target superantigen in a type‐specific manner. An initial model of the complex is constructed on the basis of observed inter‐molecular contacts between DRα/TcRVβ and the superantigens. A constant temperature (300 K) 200 ps molecular dynamics is performed to sample different conformations of a chimera‐superantigen complex by utilizing the flexibility of the (GSTAPPA)2 linker while maintaining the native folds of superantigen, DRα and TcRVβ and the observed intermolecular contacts. After equilibration, 100 molecular dynamic snapshots are minimized and analyzed. This provides descriptions of various pairwise interactions at the contact interface in the complex and important clues on single site mutations on the chimera that may enhance the stability of a given superantigen–chimera complex. Copyright © 2004 John Wiley & Sons, Ltd.
The PTSD interview: rationale, description, reliability, and concurrent validity of a DSM-III-based technique.

This paper describes the PTSD Interview (PTSD-I). It was developed to meet four specifications: (a) close correspondence to DSM-III standards; (b) binary present/absent and continuous severity/frequency outputs on each symptom and the entire syndrome; (c) administrable by trained subprofessionals; and (d) substantial reliability and validity. It was written to meet the first three criteria. It demonstrated very high internal consistency (alpha = .92) and test-retest reliability (Total score r = .95; diagnostic agreement = 87%). It correlated strongly with parallel DIS criteria (Total score vs. DIS diagnosis rbis = .94, sensitivity = .89, specificity = .94, overall hit rate = .92, and kappa = .84). Earlier studies revealed correlations with a military stress scale and Keane et al.'s MMPI PTSD subscale. It is apparently the only PTSD instrument that meets all of the above criteria.
Defining the relationship of oxygen delivery and consumption: use of biologic system models.

To determine the most appropriate mathematical description of the relationship between oxygen consumption and oxygen delivery, we compared the statistical validity of a piecewise linear model to two different biologic system models--Michaelis-Menten (MM) kinetics (used for enzyme systems) and the exponential dose-response relationship (used to describe drug administration and induced response). Nine rabbits underwent five incremental steps of normovolemic hemodilution to progressively decrease DO2. VO2 was measured concurrently by a metabolic gas monitor. All three models (piecewise linear, Michaelis-Menten, and exponential) provided a very close population curve fit to the data points (r2 = 0.88, 0.91, and 0.92). However, there were significant differences in maximum predicted VO2 (VO2max)--6.8, 9.9, 7.2 ml O2.kg-1.min-1 (P < 0.0002)--and a wide range in the model-specific parameters for individual rabbits (critical DO2 6.5-11.8 ml O2.kg-1.min-1, Km 4.2-11.4 ml O2.kg-1.min-1, and kappa 0.12-0.23 ml O2-1.kg.min). In the curvilinear models, average and population parameters were not significantly different. However, in the piecewise linear model, population critical DO2 (10.9 ml O2.kg-1.min-1) was 30% more than the average critical DO2 (8.4 ml O2.kg-1.min-1) for the nine rabbits (P < 0.005). VO2max values predicted by the piecewise linear and exponential dose-response model were more consistent with those in previous publications than was the higher VO2max predicted by the MM model. The difference in the average versus population critical DO2 in the piecewise linear model meant that population modeling was inaccurate because it yielded a critical DO2 higher than that demonstrated by eight of nine individual rabbits. (ABSTRACT TRUNCATED AT 250 WORDS)
The GAB2 and BDNF polymorphisms and the risk for late-onset Alzheimer's disease in an elderly Brazilian sample

ABSTRACT Background: Evidences suggest that GAB2 and BDNF genes may be associated with Alzheimer's disease (AD). We aimed to investigate the GAB2 rs2373115 and BDNF rs6265 polymorphisms and the risk of AD in a Brazilian sample. Methods: 269 AD patients and 114 controls were genotyped with Real-time PCR. Multifactor dimensionality reduction (MDR) was employed to explore the effects of gene–gene interactions. Results: GAB2 and BDNF were not associated with AD in our sample. Nevertheless BDNF Val allele (rs6265) presented a synergic association with the APOE ε4 allele. A multiple logistic regression demonstrated that the APOE ε4 allele and years of education were the best predictors for AD. In ε4 non-carriers sex, education and hypertension were independently correlated with AD, while in ε4 carriers we did not observe any association. The findings were further confirmed by bootstrapping method. Conclusions: Our data suggest that the interaction of BDNF and APOE has significant effect on AD. Moreover in absence of ε4, female sex, low level of education and hypertension are independently associated with AD. Interventions aimed to prevent AD should focus on these factors and also taking into account the APOE alleles.
Population health significance of gestational diabetes.

OBJECTIVE Women who have had gestational diabetes mellitus (GDM) have a high risk of subsequently developing diabetes. However, the contribution of GDM toward the total population of people with diabetes, or its population health impact, has not been examined. Therefore, the aim of this study is to determine the population health significance of GDM by estimating the proportion of cases of diabetes in women that would have been preceded by a pregnancy complicated by GDM. RESEARCH DESIGN AND METHODS A MEDLINE search was conducted to identify controlled follow-up studies of women with GDM. Meta-analysis of these studies, using the Mantel-Haenszel method for pooling relative risks (RRs), provided an overall RR for the development of diabetes in women with GDM versus control women who had been pregnant without GDM. Recent large studies examining the prevalence of GDM were also reviewed. This enabled the calculation of the population-attributable risk (PAR) for these populations. In this case, the PAR represents the proportion of cases of diabetes among parous women that were associated with previous GDM. RESULTS From six controlled follow-up studies, the overall RR for developing diabetes after GDM was calculated to be 6.0 (95% CI 4.1-8.8). Applying this to the studies of GDM prevalence, the PAR for GDM ranged from 0.10 to 0.31 (i.e., 10-31% of parous women with diabetes would have experienced a GDM pregnancy earlier). CONCLUSIONS In some populations, women who have had GDM comprise a substantial proportion of subjects who ultimately develop diabetes. Effective measures to prevent women with GDM from progressing to frank diabetes could therefore have a significant population health impact.
MicroRNAs regulate synthesis of the neurotransmitter substance P in human mesenchymal stem cell-derived neuronal cells

MicroRNAs (miRNAs) are a class of 19- to 23-nt, small, noncoding RNAs, which bind the 3′ UTR of target mRNAs to mediate translational repression in animals. miRNAs have been shown to regulate developmental processes, such as self-renewal of stem cells, neuronal differentiation, myogenesis, and cancer. A functional role of miRNAs in the regulation of neurotransmitter synthesis has yet to be ascribed. We used mesenchymal stem cells (MSCs) as a model to study miRNA-mediated neurotransmitter regulation in developing neuronal cells. MSCs are mesoderm-derived cells, primarily resident in adult bone marrow, which can generate functional neuronal cells. We have previously shown that human MSC-derived neuronal cells express the neurotransmitter gene, Tac1, but do not synthesize the gene's encoded peptide, the neurotransmitter substance P (SP), unless stimulated with the inflammatory mediator IL-1α. These findings suggested a potential role for miRNAs in the regulation of SP synthesis. Here, we report on the miRNA profile of undifferentiated human MSCs and MSC-derived neuronal cells by using miRNA-specific bioarrays. miRNAs that were increased in the neuronal cells and decreased after IL-1α stimulation were analyzed by the miRanda algorithm to predict Tac1 mRNA targets. Putative miR-130a, miR-206, and miR-302a binding sites were predicted within the 3′ UTR of Tac1. Target validation using a luciferase reporter system confirmed the miR-130a and miR-206 sites. Specific inhibition of miR-130a and miR-206 in the neuronal cells resulted in SP synthesis and release. The studies provide a different approach in ascribing a new regulatory role for miRNAs in regulating neurotransmitter synthesis.
Increasing copayments and adherence to diabetes, hypertension, and hyperlipidemic medications.

OBJECTIVE To examine the impact of a medication copayment increase on adherence to diabetes, hypertension, and hyperlipidemic medications. STUDY DESIGN Retrospective pre-post observational study. METHODS This study compared medication adherence at 4 Veterans Affairs medical centers between veterans who were exempt from copayments and propensity-matched veterans who were not exempt. The diabetes sample included 1069 exempt veterans and 1069 nonexempt veterans, the hypertension sample included 3545 exempt veterans and 3545 nonexempt veterans, and the sample of veterans taking statins included 2029 exempt veterans and 2029 nonexempt veterans. The main outcome measure was medication adherence 12 months before and 23 months after the copayment increase. Adherence differences were assessed in a difference-in-difference approach by using generalized estimating equations that controlled for time, copayment exemption, an interaction between time and copayment exemption, and patient demographics, site, and other factors. RESULTS Adherence to all medications increased in the short term for all veterans, but then declined in the longer term (February-December 2003). The change in adherence between the preperiod and the postperiod was significantly different for exempt and nonexempt veterans in all 3 cohorts, and nonadherence increased over time for veterans required to pay copayments. The impact of the copayment increase was particularly adverse for veterans with diabetes who were required to pay copayments. CONCLUSION A $5 copayment increase (from $2 to $7) adversely impacted medication adherence for veterans subject to copayments taking oral hypoglycemic agents, antihypertensive medications, or statins.
First Marriage Dissolution, Divorce, and Remarriage: United States

Objectives —This report presents national estimates of the duration of first and second marriages for women 15–44 years of age in 1995. National estimates of the probability of divorce given separation and of the probability of remarriage given divorce are also presented. Methods —The life- table estimates are based on a nationally representative sample of women 15–44 years of age in the United States in 1995 from the National Survey of Family Growth, Cycle 5. Results —One fifth of first marriages end within 5 years and one third end within 10 years. First marriages of teenagers disrupt faster than the first marriages of women who were ages 20 years and older at marriage. First marriages of black non-Hispanic women dissolve at a faster rate: 47 percent end within 10 years compared with 34 percent for Hispanic, 32 percent for white non-Hispanic, and 20 percent for Asian non-Hispanic women. Virtually all separations among white non-Hispanic women (98 percent) end in divorce within 6 years, compared with only 80 percent of separations among Hispanic women and 72 percent of separations among black non-Hispanic women. Women under age 25 years at divorce are more likely to remarry than women at least age 25 years at divorce. White non-Hispanic and Hispanic women are much more likely to remarry than black non-Hispanic women. White non-Hispanic women are slightly more likely than Hispanic women to remarry. The data suggest that women who remarry before age 25 years are more likely to experience a second marital disruption than women who remarry at ages older than 25 years, although the difference is only significant at late marital durations. Black nonHispanic remarriages are more likely to disrupt than Hispanic or white non-Hispanic remarriages.
Effects and Feasibility of the “Traffic Light Method for Somatic Screening and Lifestyle” in Patients With Severe Mental Illness: A Pilot Study

PURPOSE: To study the preliminary effects and feasibility of the “Traffic Light Method for somatic screening and lifestyle” (TLM) in patients with severe mental illness. DESIGN AND METHODS: A pilot study using a quasi-experimental mixed method design with additional content analyses of lifestyle plans and logbooks. FINDINGS: Significant improvements were found in body weight and waist circumference. Positive trends were found in patients’ subjective evaluations of the TLM. The implementation of the TLM was considered feasible. PRACTICE IMPLICATIONS: The TLM may contribute to a higher quality of care regarding somatic screening and lifestyle training.
Decreased half‐life time of plasma von Willebrand factor collagen binding activity in essential thrombocythaemia: normalization after cytoreduction of the increased platelet count

Patients with essential thrombocythaemia (ET) exhibit a decrease of large von Willebrand factor (VWF) multimers in plasma, which is inversely related to the platelet count. In the present study we investigated whether the decrease of large VWF multimers in plasma with increasing platelet counts is the consequence of increased turnover of large VWF multimers in vivo. To that end we measured the half‐life times of endogenously released VWF:Ag and VWF:CBA (collagen binding activity) after intravenous administration of desmopressin (DDAVP) to nine ET patients and nine control subjects (N). In addition, the half‐life times of VWF:Ag and VWF:CBA were also measured in four ET patients after cytoreduction of the increased platelet count to normal or nearly normal values. Estimated half‐life times of VWF:Ag did not differ between ET patients and normals (11.0 ± 4.0 h v 12.4 ± 2.5 h, P > 0.05). Estimated half‐life times of VWF:CBA were significantly lower in ET patients as compared with normal individuals (6.1 ± 2.0 h v 8.4 ± 2.5 h, P < 0.05). After cytoreduction of the increased platelet count to (nearly) normal values in all four ET patients the half‐life time of VWF:CBA significantly (P = 0.014) increased from 5.2 ± 1.2 h to 8.7 ± 2.0 h. Our data suggest that platelets may play a role in the homeostasis of circulating von Willebrand factor, which may compromise normal haemostasis at fairly increased platelet counts.
Design Evaluation of DBR Fiber Laser Sensor for Directional Lateral Force Monitoring

This letter reports an analysis of the potential of distributed Bragg reflector (DBR) fiber laser sensor designed to monitor the force orientation information, and with the birefringence characteristics of optical fiber, enabling the measurement of a directional lateral force applied to the fiber. In system design, to interrogate birefringence variation of the sensor according to the change of applied force angles, a reference lasing signal was employed following the results of an analysis using heterodyning theory. Agreement between theoretical and experimental results was obtained for a constant lateral force loading from different directions corresponding to the variation of sensitivity in beat signals. The design created in this letter is based on fundamental principles and generic, thus suitable for use with any DBR fiber laser structure for vector sensor applications.