Miracle-dz/UniFAR-FTUs huggingface dataset:
EB1089 inhibits the parathyroid hormone–related protein–enhanced bone metastasis and xenograft growth of human prostate cancer cells

Parathyroid hormone–related protein (PTHrP) plays a major role in prostate carcinoma progression and bone metastasis. Once prostate cancers become androgen-independent, treatment options become limited. Vitamin D analogues represent a potentially valuable class of agents in this clinical context. Using the prostate cancer cell line C4-2 as a model, we studied the effects of PTHrP and the noncalcemic vitamin D analogue EB1089 on markers of prostate cancer cell progression in vitro and in vivo. C4-2 is a second-generation androgen-independent LNCaP subline that metastasizes to the lymph nodes and bone when injected into nude mice and produces mixed lytic/blastic lesions, mimicking the in vivo situation. We report that PTHrP increases cell migration and invasion, and that a pathway via which EB1089 inhibits these processes is through down-regulation of PTHrP expression. PTHrP also increases anchorage-independent cell growth in vitro and xenograft growth in vivo; EB1089 reverses these effects. The in vivo PTHrP effects are accompanied by increased tumor cell proliferation and survival. Treatment with EB1089 reverses the proliferative but not the antiapoptotic effects of PTHrP. PTHrP also increases intratumor vessel density and vascular endothelial growth factor expression; EB1089 reverses these effects. Intracardially injected C4-2 cells produce predominantly osteoblastic lesions; PTHrP overexpression decreases the latency, increases the severity and alters the bone lesion profile to predominantly osteolytic. EB1089 largely reverses these PTHrP effects. A direct correlation between PTHrP immunoreactivity and increasing tumor grade is observed in human prostate cancer specimens. Thus, decreasing PTHrP production by treatment with vitamin D analogues may prove therapeutically beneficial for prostate cancer. [Mol Cancer Ther 2009;8(7):1787–98]
Improving access to Indigenous medicine for patients in hospital-based settings: a challenge for health systems in northern Canada

ABSTRACT In this commentary, we argue that Indigenous patients in the Northwest Territories (NWT) have a right to access traditional medicine and related practitioners as a part of the continuum of medical care. Indigenous people make up over half of the NWT population, spread over vast geographic areas with representation from First Nations, Inuit and Métis (FNIM) people. Ensuring barrier-free access to traditional medicine and providers in a culturally respectful environment is a challenge that requires structural transformation in the territorial health system. The ongoing transmission of knowledge about Indigenous traditional medicine in Northern Canada and the collective survival of Northern peoples is a testament to the applicability of traditional medicines in a self-determined wellness system. Through a discussion of the barriers to policy development and implementation, this commentary aims to elevate Indigenous perspectives and offer recommendations for integrating traditional medicines into Northern health systems.
Adalimumab Effectiveness Up to Six Years in Adalimumab-naïve Patients with Crohn’s Disease: Results of the PYRAMID Registry

Abstract Background PYRAMID was an international multicenter, noninterventional, postmarketing registry assessing long-term safety and effectiveness of adalimumab (Humira), as used in routine clinical practice. Methods Adult patients with moderately to severely active Crohn’s disease with or without prior adalimumab experience were enrolled in the registry and followed for up to 6 years. Effectiveness measurements included the Physician’s Global Assessment (PGA, a composite of Harvey Bradshaw Index [HBI] and rectal bleeding score), clinical remission (HBI < 5), Short Inflammatory Bowel Disease Questionnaire (SIBDQ), and Work Productivity and Activity Impairment (WPAI) questionnaire. Data were reported for adalimumab-naïve patients and analyzed by baseline immunomodulator use and disease duration. Results This study evaluated 2057 adalimumab-naïve patients. Mean PGA improved from 7.5 (baseline) to 3.9 (year 1) and 3.3 (year 6). The proportion of patients in HBI remission increased from 29% (573 of 1969; baseline) to 68% (900 of 1331; year 1) and 75% (625 of 831; year 6). Patients stratified by baseline immunomodulator use had similar HBI remission rates; patients with disease duration <2 years achieved numerically higher HBI remission rates than patients with longer disease duration. Patient-reported SIBDQ and WPAI scores improved at year 1; all WPAI subscore improvements were clinically meaningful (≥7% point change) at year 1 and maintained through year 6. Serious infections were reported in 11.1% of patients; incidence rates of malignancies, lymphoma, and demyelinating disorders were low. Conclusion Adalimumab therapy, as used in routine clinical practice, improved physician-reported and patient-reported disease outcomes and remission rates for up to 6 years. No new safety signals were observed.
Matrix Metalloproteinases and Their Inhibitors and Proteoglycan 4 in Patients Undergoing Total Joint Arthroplasty

Osteoarthritis, a degenerative disease of the joints, is the most common form of arthritis in the knee. Total joint arthoplasty is a commonly used treatment for joint degeneration and osteoarthritis, and due to these factors, TJA for hip and knee joints is projected to grow by 137% and 601% between 2005 and 2030. Matrix metalloproteases are enzymes found in the extracellular matrix that cleave matrix components. Normally MMPs are downregulated in tissues by Tissue Inhibitors of Metalloproteases, or TIMPs. The relative concentration of TIMPs also may denote some of the activity of the MMPs found in serum. Lubricin (proteoglycan 4) is a molecule found in the synovial fluid that protects joints by dissipating strain energy during locomotion. Lubricin synovial fluid concentration is also diminished in many patients with osteoarthritis, but not all. Given the importance of these three sets of molecules, our lab investigated the correlation between circulating lubricin, MMP levels and TIMPs levels. Blood plasma samples were obtained from de-identified subjects undergoing total joint arthroplasty at Loyola University Medical Center and the University of Utah. Normal blood plasma from pooled healthy individuals served as a control. We analyzed biomarker levels in plasma using ELISA. Our data show that MMP-1 and 9 were increased in TJA patients compared to normal controls, while MMP-2 and 13 were decreased. We also found decreased lubricin and tissue factor in surgical patients relative to controls. These data support the idea that lubricin is vital in protecting the synovial joint and that MMPs play a complex role in the destruction of the joint.
Effect of dislocation timing following primary total hip arthroplasty on the risk of redislocation and revision

Introduction: There is little data regarding timing of index dislocation in patients who undergo primary total hip arthroplasty (THA) and subsequent risk of redislocation and revision. Methods: Between 1992 and 2013, 21,490 primary THAs were performed at a single institution. 189 patients (190 hips) had a first episode of dislocation within one year of index surgery (0.9 %). 32 patients (32 hips) were excluded for the following reasons: complex THA secondary to fracture malunion, Crowe III/IV developmental hip dysplasia, periprosthetic fracture, prior hip surgery, incomplete information, and hip abductor avulsion. The final cohort consisted of 157 patients (158 hips) who experienced dislocation within 1 year of primary non-complex THA. 88 patients were female (56%), mean age was 61 years (SD = 14), and mean follow-up was 76 months (range 0–229). Multivariable Cox proportional-hazards regression models with fractional polynomial models were used to estimate the association between timing of index dislocation and subsequent redislocation and revision surgery. Results: 69 patients (44%) redislocated at final follow-up. Revision for any cause occurred in 26 out of 157 hips (17%). Time lapse from index THA to first dislocation was significantly associated with the risk of redislocation (p = 0.004) and with the risk of revision (p = 0.04). For every additional 7 days from surgery, risk of redislocation increased by a factor of 1.1 and risk of revision was increased by a factor of 1.13. Conclusion: This study demonstrates there is a lower risk of redislocation and revision in patients who have a first episode of dislocation closer to primary THA.
Electrical Properties and Electromagnetic Interference Shielding Effectiveness of Interlayered Systems Composed by Carbon Nanotube Filled Carbon Nanofiber Mats and Polymer Composites

The demand for multifunctional requirements in aerospace, military, automobile, sports, and energy applications has encouraged the investigation of new composite materials. This study focuses on the development of multiwall carbon nanotube (MWCNT) filled polypropylene composites and carbon nanofiber composite mats. The developed systems were then used to prepare interlayered composites that exhibited improved electrical conductivity and electromagnetic interference (EMI) shielding efficiency. MWCNT-carbon nanofiber composite mats were developed by centrifugally spinning mixtures of MWCNT suspended in aqueous poly(vinyl alcohol) solutions. The developed nanofibers were then dehydrated under sulfuric acid vapors and then heat treated. Interlayered samples were fabricated using a nanoreinforced polypropylene composite as a matrix and then filled with carbon fiber composite mats. The in-plane and through-plane electrical conductivity of an eight-layered flexible carbon composite (0.65 mm thick) were shown to be 6.1 and 3.0 × 10−2 S·cm−1, respectively. The EMI shielding effectiveness at 900 MHz increased from 17 dB for the one-layered composite to 52 dB for the eight-layered composite. It was found that the reflection of the electromagnetic waves was the dominating mechanism for EMI shielding in the developed materials. This study opens up new opportunities for the fabrication of novel lightweight materials that are to be used in communication systems.
Cold and Exercise: Therapeutic Tools to Activate Brown Adipose Tissue and Combat Obesity

The rise in obesity over the last several decades has reached pandemic proportions. Brown adipose tissue (BAT) is a thermogenic organ that is involved in energy expenditure and represents an attractive target to combat both obesity and type 2 diabetes. Cold exposure and exercise training are two stimuli that have been investigated with respect to BAT activation, metabolism, and the contribution of BAT to metabolic health. These two stimuli are of great interest because they have both disparate and converging effects on BAT activation and metabolism. Cold exposure is an effective mechanism to stimulate BAT activity and increase glucose and lipid uptake through mitochondrial uncoupling, resulting in metabolic benefits including elevated energy expenditure and increased insulin sensitivity. Exercise is a therapeutic tool that has marked benefits on systemic metabolism and affects several tissues, including BAT. Compared to cold exposure, studies focused on BAT metabolism and exercise display conflicting results; the majority of studies in rodents and humans demonstrate a reduction in BAT activity and reduced glucose and lipid uptake and storage. In addition to investigations of energy uptake and utilization, recent studies have focused on the effects of cold exposure and exercise on the structural lipids in BAT and secreted factors released from BAT, termed batokines. Cold exposure and exercise induce opposite responses in terms of structural lipids, but an important overlap exists between the effects of cold and exercise on batokines. In this review, we will discuss the similarities and differences of cold exposure and exercise in relation to their effects on BAT activity and metabolism and its relevance for the prevention of obesity and the development of type 2 diabetes.
Effect of Alpha-Lipoic Acid Supplementation on Endothelial Function and Cardiovascular Risk Factors in Overweight/Obese Youths: A Double-Blind, Placebo-Controlled Randomized Trial

Endothelial dysfunction is recognized as an early sign of systemic atherosclerosis, and it represents a therapeutic target to prevent long-term cardiovascular (CV) consequences. Alpha-lipoic acid (ALA) is a commonly used dietary supplement exerting anti-oxidant and anti-inflammatory effects. We investigated whether a three-month treatment with ALA improves endothelial function, as assessed by flow-mediated dilation (FMD) of the brachial artery, and clinical and metabolic risk factors in overweight/obese youths. We enrolled 67 overweight/obese children, and 22 normal-weight metabolically healthy controls. Overweight/obese youths were randomly allocated in a double-blinded manner to receive ALA (n = 34) or placebo (n = 33). Of these, 64 (32 ALA, 32 placebo) completed the follow-up. At baseline, in ALA and placebo groups, FMD was similar, but lower as compared with that in controls (p = 0.045). At three months, within the ALA and placebo groups, FMD did not change significantly. However, the basal and peak diameter of brachial artery significantly increased after ALA treatment as compared to placebo (p = 0.036 and p = 0.01, respectively). There were no significant within- and between-group changes for anthropometric and metabolic variables. The results show that ALA supplementation improves vascular tone and may have a beneficial effect on CV health in overweight/obese youths.
Associations of dietary intake with cardiometabolic risk in a multi-ethnic cohort: a longitudinal analysis of the Determinants of Adolescence, now young Adults, Social well-being and Health (DASH) study

Abstract Unfavourable dietary habits, such as skipping breakfast, are common among ethnic minority children and may contribute to inequalities in cardiometabolic disease. We conducted a longitudinal follow-up of a subsample of the UK multi-ethnic Determinants of Adolescent Social well-being and Health cohort, which represents the main UK ethnic groups and is now aged 21–23 years. We aimed to describe longitudinal patterns of dietary intake and investigate their impact on cardiometabolic risk in young adulthood. Participants completed a dietary behaviour questionnaire and a 24 h dietary intake recall; anthropometry, blood pressure, total cholesterol and HDL-cholesterol and HbA1c were measured. The cohort consisted of 107 White British, 102 Black Caribbean, 132 Black African, 98 Indian, 111 Bangladeshi/Pakistani and 115 other/mixed ethnicity. Unhealthful dietary behaviours such as skipping breakfast and low intake of fruits and vegetables were common (56, 57 and 63 %, respectively). Rates of skipping breakfast and low fruit and vegetable consumption were highest among Black African and Black Caribbean participants. BMI and cholesterol levels at 21–23 years were higher among those who regularly skipped breakfast at 11–13 years (BMI 1·41 (95 % CI 0·57, 2·26), P=0·001; cholesterol 0·15 (95 % CI –0·01, 0·31), P=0·063) and at 21–23 years (BMI 1·05 (95 % CI 0·22, 1·89), P=0·014; cholesterol 0·22 (95 % CI 0·06, 0·37), P=0·007). Childhood breakfast skipping is more common in certain ethnic groups and is associated with cardiometabolic risk factors in young adulthood. Our findings highlight the importance of targeting interventions to improve dietary behaviours such as breakfast consumption at specific population groups.
Comparative Effectiveness of Antihypertensive Therapeutic Classes and Treatment Strategies in the Initiation of Therapy in Primary Care Patients: A Distributed Ambulatory Research in Therapeutics Network (DARTNet) Study

Background: Few comparative effectiveness studies of treatment strategies using antihypertensive therapeutic classes in hypertension control have been assessed in a primary care environment. The objectives are to compare the effectiveness of common antihypertensive therapeutic classes initiated as monotherapy and of fixed-dose combinations (FDCs), free-equivalent combinations (FECs), and monotherapy on hypertension control. Methods: This article reports observational comparative effectiveness analyses of data electronically extracted from electronic health records. The study population consisted of 8,676 patients with an incident prescription for an antihypertensive agent of a total of 79,176 patients receiving antihypertensive therapy in 33 geographically diverse primary care clinics. The main measures were reductions in systolic blood pressure (SBP) and diastolic blood pressure (DBP) and rates of attaining goals per the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7). Results: There were small, clinically insignificant differences in blood pressure reductions between the monotherapy classes. Higher rates of blood pressure control were obtained when patients were initiated on an angiotensin-converting enzyme inhibitor than a thiazide or thiazide-like diuretic (47.8% vs 39.9%) or a β-blocker versus a thiazide (45.9% vs 39.9%). Patients initiated on FDCs had significantly larger reductions in blood pressure than patients initiated on FECs (−17.3 vs −12.0 mm Hg SBP; −10.1 vs −6.0 mm Hg DBP) or monotherapy (−17.3 vs −13.6 mm Hg SBP; −10.1 vs −7.9 mm Hg DBP). Rates of attaining JNC7 goals also were better for FDCs than FECs (57.2% vs 42.5%) and for FDCs versus monotherapy (57.2% vs 44.9%). Conclusions: Patients initiated on angiotensin-converting enzyme inhibitors and β-blockers had slightly higher rates of blood pressure control. The use of FDCs as initial therapy is more effective in the control of hypertension than monotherapy or FECs.
Brain metastases and treatment: multiplying cognitive toxicities

ABSTRACT Introduction: Thirty per cent of cancer patients develop brain metastases, with multiple combination or sequential treatment modalities available, to treat systemic or central nervous system (CNS) disease. Most patients experience toxicities as a result of these treatments, of which cognitive impairment is one of the adverse events most commonly reported, causing major impairment of the patient’s quality of life. Areas covered: This article reviews the role of cancer treatments in cognitive decline of patients with brain metastases: surgery, radiotherapy, chemotherapy, targeted therapies, immunotherapies and hormone therapy. Pathological and molecular mechanisms, as well as future directions for limiting cognitive toxicities are also presented. Other causes of cognitive impairment in this population are discussed in order to refine the benefit-risk balance of each treatment modality. Expert opinion: Cumulative cognitive toxicity should be taken into account, and tailored to the patient’s cognitive risk in the light of the expected survival benefit. Standardization of cognitive assessment in this context is needed in order to better appreciate each treatment’s responsibility in cognitive impairment, keeping in mind disease itself impacts cognition in this context.
Intensification of the O_3/TiO_2/UV advanced oxidation process using a modified flotation cell

The present work reports the use of a flotation cell as a prospective reactor for ozonation and the intensification of ozonation (catalytic ozonation and photocatalytic ozonation). The effect of the pH, ozone concentration and loading catalyst was investigated. The performance of the flotation cell was compared with that of conventional reactors used in ozonation through the ozone utilized index (OUI), which was proposed in this work and relates the amount of ozone supplied to the system per milligram of degraded pollutant. The flotation cell has the lowest OUI, which indicates that the ozone supplied is highly consumed. It was found that the modified flotation cell is an efficient reactor for ozonation, catalytic ozonation and photocatalytic ozonation processes because total diclofenac degradation was achieved in a short time, mass transfer limitations were not found (Ha = 7.26), and it presented a relatively low energy consumption (1.15 kW h m^−3).
Developing scalable cultivation systems of hepatic spheroids for drug metabolism via genomic and functional analyses

Spheroids, a widely used three‐dimensional (3D) culture model, are standard in hepatocyte culture as they preserve long‐term hepatocyte functionality and enhance survivability. In this study, we investigated the effects of three operation modes in 3D culture — static, orbital shaking, and under vertical bidirectional flow using spheroid forming units (SFUs) on hepatic differentiation and drug metabolism to propose the best for mass production of functionally enhanced spheroids. Spheroids in SFUs exhibited increased hepatic gene expression, albumin secretion, and cytochrome P450 3A4 (CYP3A4) activity during the differentiation period (12 days). SFUs advantages include facilitated mass production and a relatively earlier peak of CYP3A4 activity. However, CYP3A4 activity was not well maintained under dimethyl sulfoxide (DMSO)‐free conditions (13–18 days), dramatically reducing drug metabolism capability. Continued shear stimulation without differentiation stimuli in assay conditions markedly attenuated CYP3A4 activity, which was less severe in static conditions. In this condition, SFU spheroids exhibited dedifferentiation characteristics, such as increased proliferation and Notch signaling genes. We found that the dedifferentiation could be overcome by using the serum‐free medium formulation. Therefore, we suggest that SFUs represent the best option for the mass production of functionally improved spheroids and so the serum‐free conditions should be maintained during drug metabolism analysis.
A Scale Mixture-Based Stochastic Model of Surface EMG Signals With Variable Variances

Objective: Surface electromyogram (EMG) signals have typically been assumed to follow a Gaussian distribution. However, the presence of non-Gaussian signals associated with muscle activity has been reported in recent studies, and there is no general model of the distribution of EMG signals that can explain both non-Gaussian and Gaussian distributions within a unified scheme. Methods: In this paper, we describe the formulation of a non-Gaussian EMG model based on a scale mixture distribution. In the model, an EMG signal at a certain time follows a Gaussian distribution, and its variance is handled as a random variable that follows an inverse gamma distribution. Accordingly, the probability distribution of EMG signals is assumed to be a mixture of Gaussians with the same mean but different variances. The EMG variance distribution is estimated via marginal likelihood maximization. Results: Experiments involving nine participants revealed that the proposed model provides a better fit to recorded EMG signals than conventional EMG models. It was also shown that variance distribution parameters may reflect underlying motor unit activity. Conclusion: This study proposed a scale mixture distribution-based stochastic EMG model capable of representing changes in non-Gaussianity associated with muscle activity. A series of experiments demonstrated the validity of the model and highlighted the relationship between the variance distribution and muscle force. Significance: The proposed model helps to clarify conventional wisdom regarding the probability distribution of surface EMG signals within a unified scheme.
Attitudes of Older Adults and Caregivers in Australia toward Deprescribing

Use of harmful and/or unnecessary medications in older adults is common. Understanding older adult and caregiver attitudes toward deprescribing will contribute to medication optimization in practice. The aims of this study were to capture the attitudes and beliefs of older adults and caregivers toward deprescribing and determine what participant characteristics and/or attitudes (if any) predicted reported willingness to have a medication deprescribed.