Miracle-dz/UniFAR-FTUs huggingface dataset:
Serum Proteomics Based Discovery Of Predictive Biomarkers Of Response To Androgen Deprivation Therapy In Advanced Prostate Cancer

Background: We investigated the serum proteome of hormone-sensitive prostate cancer patients to determine candidate biomarkers associated with androgen deprivation therapy (ADT) efficacy. Methods: Serum proteomes generated using isobaric mass tags for relative and absolute quantitation (iTRAQ) were analyzed by reverse-phase liquid chromatography coupled to tandem mass spectrometry. The advanced hormone-sensitive prostate cancer cohorts studied were 1) untreated “paired” pre-ADT and 4-month post-ADT hormone-sensitive patients (n=15); 2) “early ADT failure” patients (n=10) failing ADT with-in a short period of time; 3) “late ADT failure” patients (n=10) failing ADT after a prolonged response time. Differential abundance was assessed, and Ingenuity Pathway Analysis (IPA) was used to identify interaction networks in selected candidates from these comparisons. Results: Between “post-ADT” and combined “early” and “late” ADT failure 149 differentially detected candidates were observed, and between “early” and “late” ADT failure 98 candidates were observed; 47 candidates were common in both comparisons. IPA network enrichment analysis of the 47 candidates identified three interaction networks (p<0.01) including estradiol (E1), NfKB complex P38-MAPK as pathways with potential markers of response to ADT. Conclusions: A global proteomic analysis identified pathways with markers of ADT response, which will need validation in independent datasets. Microabstract: A global serum proteomic analysis was analyzed using liquid chromatography coupled with tandem mass spectrometry to identify predictive biomarkers in hormone sensitive prostate cancer patients undergoing androgen deprivation therapy. We identified 47 candidates and then performed network enrichment analysis which implicated beta estradiol, NfKB complex and P38-MAPK complex pathways as candidate pathways with potential predictive biomarkers of androgen deprivation. that serum based candidates of ADT response could be identified by comparing global serum proteomic signatures in advanced prostate cancer patients initiating ADT and failing the treatment after variable durations of response. We profiled serum samples taken from multiple advanced stage hormone sensitive prostate cancer patient cohorts to test this hypothesis.
Molecular Dynamics Simulations of Asymmetric NaCl and KCl Solutions Separated by Phosphatidylcholine Bilayers: Potential Drops and Structural Changes Induced by Strong Na 1 -Lipid Interactions and Finite Size Effects

Differences of ionic concentrations across lipid bilayers are some of the primary energetic driving forces for cellular electrophysiology. Whilemacroscopic models of asymmetric ionic solutionsare well-developed, their connection toion, water, and lipid interactions at the atomic scale are much more poorly understood. In this study, we used molecular dynamics to examine a systemoftwochambers ofequalionicstrength,butdiffering amountsofNaClandKCl,separatedbyalipidbilayer.Ourexpectation was that the net electrostatic potential difference between the two chambers should be small or zero. Contrary to our expectation, a large potential difference ( (cid:2) 70 mV) slowly evolved across the two water chambers over the course of our 172-ns simulation. This potentialprimarilyoriginatedfromstrongNa 1 bindingtothecarbonylsofthephosphatidylcholinelipids.Thisionadsorptionalsoled to signiﬁcant structural and mechanical changes in the lipid bilayer. We discuss this surprising result in the context of indirect experimental evidence for Na 1 interaction with bilayers as well as potential caveats in current biomembrane simulation methodology, including force-ﬁeld parameters and ﬁnite size effects.
NF- (cid:2) B/Rel Regulates Inhibitory and Excitatory Neuronal Function and Synaptic Plasticity

Changes in synaptic plasticity required for memory formation are dynamically regulated through opposing excitatory and inhibitory neurotransmissions. To explore the potential contribution of NF- (cid:1) B/Rel to these processes, we generated transgenic mice conditionally expressing a potent NF- (cid:1) B/Rel inhibitor termed I (cid:1) B (cid:2) superrepressor (I (cid:1) B (cid:2) -SR). Using the prion promoter-enhancer, I (cid:1) B (cid:2) -SR is robustly expressed in inhibitory GABAergic interneurons and, at lower levels, in excitatory neurons but not in glia. This neuronal pattern of I (cid:1) B (cid:2) -SR expression leads to decreased expression of glutamate decarboxylase 65 (GAD65), the enzyme required for synthesis of the major inhibitory neurotransmitter, (cid:3) -aminobutyric acid (GABA) in GABAergic interneurons. I (cid:1) B (cid:2) -SR expression also results in diminished basal GluR1 levels and impaired synaptic strength (input/output function), both of which are fully restored following activity-based task learning. Consistent with diminished GAD65-derived inhibitory tone and enhanced excitatory ﬁring, I (cid:1) B (cid:2) -SR (cid:4) mice exhibit increased late-phase long-term potentiation, hyperactivity, seizures, increased exploratory activity, and enhanced spatial learning and memory. I (cid:1) B (cid:2) -SR (cid:4) neurons also express higher levels of the a ctivity- r egulated, c ytoskeleton-associated (Arc) protein, consistent with neuronal hyperexcitability. These ﬁndings suggest that NF- (cid:1) B/Rel transcription factors act as pivotal regulators of activity-dependent inhibitory and excitatory neuronal function regulating synaptic plasticity and memory.
Impact of polymorphisms within genes involved in regulating DNA methylation in metastatic colorectal cancer patients enrolled in three independent, randomized, open-label clinical trials: a meta-analysis from TRIBE, MAVERICC, and FIRE-3. pathways on outcomes in

Background— CpG island DNA hypermethylation and global DNA hypomethylation are hallmark characteristics of CRC. Therefore, we aim to explore the effect of genetic variations within the genes that regulate the DNA methylation and demethylation metastatic CRC (mCRC) patients treated with first-line therapy and enrolled in three independent, randomized, open-label clinical trials. Methods— A total of 884 mCRC patients enrolled in TRIBE, MAVERICC, and FIRE-3 trials were included. Single nucleotide Polymorphisms (SNPs) within genes involved in DNA methylation and demethylation pathways were analyzed. The prognostic value of each SNP across all treatment arms was quantified using the inverse-variance-weighted effect size, a meta-analysis approach implemented in the METASOFT software. Results— In the meta-analysis, DNMT3A rs11681717 was significantly associated with OS (HR=1.26; 95%CI 1.08–1.46; P=0.002; FDR=0.016), accounting for seven tests in the DNA methylation pathway. In addition, there was suggestive evidence of association for TET genes variance with tumor response (TET1 rs3814177, OR=0.76, 95%CI 0.59–0.97, P=0.025, FDR=0.087; TET3 rs7560668, OR=1.44; 95%CI 1.10–1.89; P=0.009; FDR=0.062). Conclusions— We showed that polymorphisms within the genes responsible for the DNA methylation and demethylation machineries are correlated with outcomes in mCRC patients enrolled in three independent, randomized, open label, phase II/III clinical trials. In addition, we demonstrated the feasibility of a meta-analysis approach to identify stronger and more convincing association between gene polymorphisms and outcome, potentially leading the way to a new method of analysis for similar dataset.
Growth Factors, Cytokines, Cell Cycle Molecules SCF Controls Smad4 Protein Stability in Pancreatic Cancer Cells

Smad4, also known as deleted in pancreatic carcinoma locus 4 (DPC4), is a critical co-factor in signal transduction pathways activated by transforming growth factor (TGF)- (cid:1) -related ligands that regulate cell growth and differentiation. Mutations in Smad4/ DPC4 have been identified in (cid:1) 50% of pancreatic adenocarcinomas. Here we report that SCF (cid:1) -TrCP1 , a ubiquitin (E3) ligase, is a critical determinant for Smad4 protein degradation in pancreatic cancer cells. We found that F-box protein (cid:1) -TrCP1 in this E3 ligase interacted with Smad4 and that SCF (cid:1) -TrCP1 inhibited TGF- (cid:1) biological activity in pancreatic cancer cells by decreasing Smad4 stability. Very low Smad4 protein levels in human pancreatic ductal adenocarcinoma cells were observed by immunohistochemistry. By analyzing pancreatic tumor-derived Smad4 mutants, we found that most point-mutated Smad4 proteins, except those within or very close to a mutation cluster region, exhibited higher interaction affinity with (cid:1) -TrCP1 and significantly elevated protein ubiquitination by SCF (cid:1) -TrCP1 . Furthermore, AsPC-1 and Caco-2, two cancer cell lines harboring Smad4 point mutations, exhibited rapid Smad4 protein degradation due to the effect of SCF (cid:1) -TrCP1 . Both Smad4 levels and
Simulation of Spontaneous Ca 2 þ Oscillations in Astrocytes Mediated by Voltage-Gated Calcium Channels

The purpose of this computational study was to investigate the possible role of voltage-gated Ca 2 þ channels in spontaneous Ca 2 þ oscillations of astrocytes. By incorporating different types of voltage-gated Ca 2 þ channels and a previous model, this study reproduced typical Ca 2 þ oscillations in silico. Our model could mimic the oscillatory phenomenon under a wide range of experimental conditions, including resting membrane potential ( (cid:2) 75 to (cid:2) 60 mV), extracellular Ca 2 þ concentration (0.1 to 1500 m M), temperature (20 to 37 (cid:3) C), and blocking speciﬁc Ca 2 þ channels. By varying the experimental conditions, the amplitude and duration of Ca 2 þ oscillations changed slightly (both < 25%), while the frequency changed signiﬁcantly (~400%). This indicates that spontaneous Ca 2 þ oscillations in astrocytes might be an all-or-none process, which might be frequency-encoded in signaling. Moreover, the properties of Ca 2 þ oscillations were found to be related to the dynamics of Ca 2 þ inﬂux, and not only to a constant inﬂux. Therefore, calcium channels dynamics should be used in studying Ca 2 þ oscillations. This work provides a platform to explore the still unclear mechanism of spontaneous Ca 2 þ oscillations in astrocytes.
Cdc1 and the Vacuole Coordinately Regulate Mn 2 (cid:49) Homeostasis in the Yeast Saccharomyces cerevisiae

The yeast CDC1 gene encodes an essential protein that has been implicated in the regulation of cytosolic [Mn 2 (cid:49) ]. To identify factors that impinge upon Cdc1 or the Cdc1-dependent process, we isolated second-site suppressors of the conditional cdc1-1 (Ts) growth defect. Recessive suppressors deﬁne 15 COS ( C dc O ne S uppressor) genes. Seven of the ﬁfteen COS genes are required for biogenesis of the vacuole, an organelle known to sequester intracellular Mn 2 (cid:49) . An eighth gene, COS16 , encodes a vacuolar membrane protein that seems to be involved in Mn 2 (cid:49) homeostasis. These results suggest mutations that block vacuolar Mn 2 (cid:49) sequestration compensate for defects in Cdc1 function. Interestingly, Cdc1 is dispensable in a cos16 (cid:68) deletion strain, and a cdc1 (cid:68) cos16 (cid:68) double mutant exhibits robust growth on medium supplemented with Mn 2 (cid:49) . Thus, the single, essential function of Cdc1 is to regulate intracellular, probably cytosolic, Mn 2 (cid:49) .
Treatment response assessment for bladder cancer on CT based on computerized volume analysis, WHO and RECIST Criteria

Purpose— To evaluate the accuracy of our Auto-Initialized Cascaded Level Set (AI-CALS) 3D segmentation system, the World Health Organization (WHO), and the Response Evaluation Criteria In Solid Tumors (RECIST) criteria for estimation of treatment response of bladder cancer in CT urography. Materials and Methods— Pre- and post- neoadjuvant chemotherapy treatment CT of 18 patients with muscle invasive localized or locally advanced bladder cancers were collected. The disease pathological stage determined by cystectomy after chemotherapy was available as reference standard of treatment response. Two radiologists measured the longest diameter and its perpendicular on the pre- and post-treatment scans. Full 3D contours for all tumors were manually outlined by one radiologist. AI-CALS was used to automatically extract 3D tumor boundary. The prediction accuracy of pT0 stage (complete response) at cystectomy by the manual, AI-CALS, WHO, and RECIST methods was estimated by the area under the receiver operating characteristic curve (AUC). Results— The AUC for prediction of pT0 disease at cystectomy was 0.78±0.11 for AI-CALS compared to 0.82±0.10 for manual segmentation. The difference did not reach statistical significance (p=0.67). The prediction using RECIST criteria by radiologists with AUCs of 0.62±0.16 and 0.71±0.12, preliminary study is to evaluate the potential usefulness of a computerized system developed in our laboratory for segmenting bladder cancers imaged in CTU and estimating the GTV to assist radiologists in monitoring the GTV change in response to neoadjuvant chemotherapy, and to compare the automatic estimation to results based on the WHO and RECIST criteria.
Signaling Lymphocyte Activated Molecule (SLAM)/SLAM-associated Protein (SAP) Pathway Regulates Human B-cell Tolerance

Background— SAP can mediate the function of SLAM molecules, which have been proposed to be involved in the development of autoimmunity in mice. Objective— We sought to determine if the SLAM/SAP pathway regulates the establishment of human B-cell tolerance and what mechanisms of B-cell tolerance could be affected by SAP deficiency. Methods— We tested the reactivity of antibodies isolated from single B cells from SAP-deficient X-linked lymphoproliferative disease (XLP) patients. The expressions of SAP and SLAM family members were assessed in human bone marrow developing B cells. We also analyzed regulatory T cell (Treg) function in XLP patients and healthy controls. Results— We found that new emigrant/transitional B cells from XLP patients were enriched in autoreactive clones, revealing a defective central B-cell tolerance checkpoint in the absence of functional SAP. In agreement with a B-cell intrinsic regulation of central tolerance, we identified SAP expression in a discrete subset of bone marrow immature B cells. SAP colocalized with SLAMF6 only in association with clustered B-cell receptors (BCRs) likely recognizing self-antigens, suggesting that SLAM/SAP regulate BCR-mediated central tolerance. In addition, XLP patients displayed defective peripheral B-cell tolerance, which is normally controlled by Tregs. Tregs in XLP patients seem functional but SAP-deficient T cells were resistant to Treg-mediated suppression. Indeed, SAP-deficient T cells were hyper-responsive to TCR stimulation, which resulted in increased secretion of interleukin-2, IFN γ and TNF α . Conclusions— SAP expression is required for the counterselection of developing autoreactive B cells and prevents their T-cell dependent accumulation in the periphery. The monoclonal anti-SAP antibody (clone1C9, Abnova) was biotinylated using the Fluoreporter Mini-biotin-XX protein labeling kit (Molecular Probes). Intracellular staining for FOXP3-AlexaFluor488 (clone PCH101, eBioscience) and Helios-AlexaFluor647 (Biolegend) were performed using the FOXP3/Transcription Factor Staining Buffer Set (eBioscience), according to the manufacturer’s instructions. For intracellular cytokine detection, CD4+ T responder cells activated for 4 days in vitro were then stimulated with nM and 200 nM for hours in the presence of GolgiStop Biosciences) and intracellular staining of cytokines γ , TNF was performed staining buffers and the donkey anti-rabbit AlexaFluor350 (Invitrogen Molecular Probes). The percentage of cells presenting a clustered pattern of either IgM or Ig κ /Ig λ was estimated by counting the number of cells with clustered vs diffuse/non-clustered IgM or Ig κ /Ig λ cells in the SAP + cells and in the SAP − cells. Slides were visualized under a Zeiss AxioObserver.Z1 microscope.
The socialization of civilians and militia members

When the Guatemalan civil war ended in 1996, the Peace Accords required the demobilization of the civil patrols. Yet, nearly two decades after the end of the war, the ex-patrollers remain organized and active. At first glance, the persistence of Guatemala’s civil patrols sounds like a triumph of socialization: the men enrolled in the civil patrols were effectively socialized during the war, so they continue patrolling today. This argument is seductively simple, but it is incorrect. Using process tracing to analyze historical documents and interviews with former civil patrollers, I show that the military did not succeed in socializing most of its patrollers. The military was, however, remarkably successful at socializing civilians in conflict zones. After enduring a ferocious scorched earth campaign followed by re-education, civilians either learned to fear and comply with the military and the civil patrols, or they internalized the military-promulgated narrative that repression is necessary to guarantee security. Both these outcomes facilitate patrolling in postwar Guatemala, where many civilians in war-affected areas either embrace or tolerate extralegal security patrolling as a means of preventing crime from spreading to their communities. Theoretically, the case of Guatemala’s civil patrols expands our knowledge of socialization in militias and civil defense forces. Mass socialization of group members is not necessary for an armed group to retain its influence in the long term, even after a conflict has ended. Additionally, socialization occurs not just within groups, but also dynamically and interactively across group boundaries. To fully understand the trajectories of armed groups, it is important to analyze both socialization within armed groups and the socialization of the broader civilian population.
Patterns and Loss of Sexual Activity in the Year Following Hospitalization for Acute Myocardial Infarction (A U.S. National, Multi-Site Observational Study)

A multi-site, observational study of sexual activity-related outcomes among patients enrolled in the TRIUMPH Registry during hospitalization for an acute myocardial infarction (AMI) was conducted to identify patterns and loss of sexual activity 1 year following hospitalization for AMI. Gender-specific multivariable hierarchical models were used to identify correlates of loss of sexual activity, including physician counseling. Main outcome measures included “loss of sexual activity” (less frequent or no sexual activity one year after an AMI in those who were sexually active in the year before the AMI) and 1-year mortality. Mean age (years) was 61.1 for women (n=605) and 58.6 for men (n=1274). Many were sexually active in the year before and 1 year after hospitalization (44% and 40% of women, 74% and 68% of men, respectively). A third of women and 47% of men reported receiving hospital discharge instructions about resuming sex. Those who did not receive instructions were more likely to report loss of sexual activity (women: adjusted RR 1.44, 95% CI 1.16–1.79; men: adjusted RR 1.27, 95% CI 1.11–1.46). One year post-AMI mortality was similar among those who reported sexual activity in the first month after their AMI (2.1%) and those who were sexually inactive (4.1%) (p=0.08). In conclusion, although many patients were sexually active prior to AMI, only a minority received discharge counseling about resuming sexual activity. Lack of counseling was associated with loss of sexual activity 1 year later. Mortality was not significantly elevated among individuals who were sexually active soon after their AMI.
Ca 2 1 -Dependent Gating Mechanisms for dSlo, a Large-Conductance Ca 2 1 -Activated K 1 (BK) Channel

The Ca 2 1 -dependent gating mechanism of cloned BK channels from Drosophila ( dSlo ) was studied. Both a natural variant (A1/C2/E1/G3/IO) and a mutant (S942A) were expressed in Xenopus oocytes, and single-channel currents were recorded from excised patches of membrane. Stability plots were used to define stable segments of data. Unlike native BK channels from rat skeletal muscle in which increasing internal Ca 2 1 concentration (Ca i2 1 ) in the range of 5 to 30 m M increases mean open time, increasing Ca i2 1 in this range for dSlo had little effect on mean open time. However, further increases in Ca i2 1 to 300 or 3000 m M then typically increased dSlo mean open time. Kinetic schemes for the observed Ca 2 1 -dependent gating kinetics of dSlo were evaluated by fitting two-dimensional dwell-time distributions using maximum likelihood techniques and by comparing observed dependency plots with those predicted by the models. Previously described kinetic schemes that largely account for the Ca 2 1 -dependent kinetics of native BK channels from rat skeletal muscle did not adequately describe the Ca 2 1 dependence of dSlo . An expanded version of these schemes which, in addition to the Ca 2 1 -activation steps, permitted a Ca 2 1 -facilitated transition from each open state to a closed state, could approximate the Ca 2 1 -dependent kinetics of dSlo , suggesting that Ca 2 1 may exert dual effects on gating.
The Impact of the Smiling Sun Health Communication Campaign on the Demand for Family Planning and Antenatal Care Services in Rural Bangladesh with Controls for Program Targeting and Endogenous Message Recall

We examine the effectiveness of the Smiling Sun multimedia health communication campaign in encouraging women to use family health services in rural Bangladesh. We control for endogenous program placement and address the potential endogeneity of self-reported campaign exposure in health behavior equations by estimating a set of exposure, contraceptive use, and antenatal care equations by full information maximum likelihood (FIML). Relative to the exposure effect of 3.7 percentage points in the simple model of contraceptive use, the exposure effect in the FIML model is a larger 5.1 percentage points, corresponding to as many as 40,000 additional users of family planning.
Racial/Ethnic Differences in ADL Disability among Older Adults with Arthritis: A Longitudinal Study

Objective— To investigate racial/ethnic differences in disability onset among older Americans with arthritis. We examined factors amenable to clinical and public health intervention that may explain racial/ethnic differences in incident disability. Methods— Longitudinal data (1998 − 2004) from a national representative sample of 5818 non-Hispanic Whites, 1001 African Americans, 228 Hispanics interviewed in Spanish (Hispanic/ Spanish), and 210 Hispanics interviewed in English (Hispanic/English), ages 51 or older with arthritis who did not have baseline disability were analyzed. Disability in activities of daily living (ADL) was identified from report of inability, avoidance, or needing assistance to perform one or more ADL tasks. Results— Over six years, 28.0% African Americans, 28.5% Hispanic/Spanish, 19.1% Hispanic/ English, and 16.2% Whites developed disability. The demographic-adjusted disability hazard ratio (AHR) were significantly greater among African Americans (AHR=1.94, 95% CI: 1.51 − 2.38) and Hispanic/Spanish (AHR=2.03, 95% CI: 1.35 − 2.71), but not significantly increased for Hispanic/ English (AHR=1.41, 95% CI: 0.82 − 2.00) compared to Whites. Differences in health factors (comorbid conditions, functional limitations, and behaviors) explained over half the excess risk among African Americans and Hispanic/Spanish. Medical access factors (education, income, wealth, and health insurance) were substantial mediators of racial/ethnic differences in all minority groups. Conclusion— Racial/ethnic differences in the development of disability among older adults with arthritis were largely attenuated by health and medical access factors. Lack of health insurance was particularly problematic. At the clinical level, treatment of comorbid conditions, functional limitations, and promotion of physical activity and weight maintenance should be a priority to prevent the development of disability, especially in minority populations.