Miracle-dz/UniFAR-FTUs huggingface dataset:
In Vitro Drug-Drug Interaction Evaluation of GalNAc Conjugated siRNAs Against CYP450 Enzymes and Transporters

Small interfering RNAs (siRNAs) represent a new class of medicines that are smaller (∼16,000 Da) than biologic therapeutics (>150,000 Da) but much larger than small molecules (<900 Da). Current regulatory guidance on drug-drug interactions (DDIs) from the European Medicines Agency, Food and Drug Administration, and Pharmaceutical and Medical Devices Agency provides no recommendations for oligonucleotide therapeutics including siRNAs; therefore, small molecule guidance documents have historically been applied. Over ∼10 years, in vitro DDI investigations with siRNAs conjugated to a triantennary N-acetylgalactosamine [(GalNAc)-siRNA] ligand have been conducted during nonclinical drug development to elucidate the potential clinical DDI liability. GalNAc siRNAs were evaluated as substrates, inhibitors, or inducers of major cytochrome P450s (P450s) and as substrates and inhibitors of transporters. Aggregate analysis of these data demonstrates a low potential for DDI against P450s. Zero of five, 10, and seven are inducers, time-dependent inhibitors, or substrates, respectively, and nine of 12 do not inhibit any P450 isoform evaluated. Three GalNAc siRNAs inhibited CYP2C8 at supratherapeutic concentrations, and one mildly inhibited CYP2B6. The lowest Ki value of 28 µM is >3000-fold above the therapeutic clinical Cmax at steady state, and importantly no clinical inhibition was projected. Of four GalNAc siRNAs tested none were substrates for transporters and one caused inhibition of P-glycoprotein, calculated not to be clinically relevant. The pharmacological basis for DDIs, including consideration of the target and/or off-target profiles for GalNAc siRNAs, should be made as part of the overall DDI risk assessment. If modulation of the target protein does not interfere with P450s or transporters, then in vitro or clinical investigations into the DDI potential of the GalNAc siRNAs are not warranted. SIGNIFICANCE STATEMENT Recommendations for evaluating DDI potential of small molecule drugs are well established; however, guidance for novel modalities, particularly oligonucleotide-based therapeutics are lacking. Given the paucity of published data in this field, in vitro DDI investigations are often conducted. The aggregate analysis of GalNAc-siRNA data reviewed herein demonstrates that, like new biological entities, these oligonucleotide-based therapeutic drugs are unlikely to result in DDIs; therefore, it is recommended that the need for in vitro or clinical investigations similarly be determined on a case-by-case basis. Given the mechanism of siRNA action, special consideration should be made in cases where there may be a pharmacological basis for DDIs.
The effect of aging in primary human dermal fibroblasts

Skin aging is a complex process, and alterations in human skin due to aging have distinct characteristic as compared to other organs. The aging of dermal cells and the biological mechanisms involved in this process are key areas to understand skin aging. A large number of biological mechanisms, such as decreasing of protein synthesis of extracellular matrix or increasing of degradation, are known to be altered through skin aging. However, environmental influence can accelerate this characteristic phenotype. In this study, we analyzed primary human dermal fibroblasts in three different in-vitro aging models—UVB irradiation and accelerated proliferation of human dermal fibroblasts from young donors as well as from elderly donors—for the gene expression of COL1A1, COL1A2, COL3A1, COL4A1, COL7A1, MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP12, MMP13, MMP14, TIMP1, TIMP2, TIMP3, TIMP4, IL1B, IL1A, IL6, IL8, IL10, PTGS2, TP53, CASP3, LMNA, SIRT1. We compared the gene expression levels with young control. Furthermore, the behavior of skin fibroblasts was also evaluated using cell growth rate. The findings reveal that the gene expression levels in skin fibroblasts was altered in the process of aging in all three in-vitro aging models, and the cell growth rate was reduced, suggesting that these methods can be employed to understand skin aging mechanisms as well as drug discovery screening method.
Induction Therapy in Localized Pancreatic Cancer.

OBJECTIVES Pancreatic cancer (PDAC) with localized stage includes resectable (RPC), borderline resectable (BRPC), or locally advanced unresectable (LAPC). Standard of care for RPC is adjuvant chemotherapy. There are no prospective randomized trials for best treatment of BRPC and LAPC. We evaluate the impact of induction chemotherapy on localized PDAC. METHODS Charts of PDAC patients treated at Emory University between 2009 and 2016 were reviewed. The primary end point was overall survival (OS). RESULTS A total of 409 localized PDACs were identified. Resectability was prospectively determined at a multidisciplinary tumor conference. Median age was 67 years (range, 30-92 years), 49% were male, 66% were white, 171 had RPC, 131 had BRPC, and 107 had LAPC. Median OSs for RPC, BRPC, and LAPC were 19.5, 16.1, and 12.7 months, respectively. Type of chemotherapy and age were predictors of OS. Induction chemotherapy was used in 106 with BRPC (81%) and 74 with RPC (56.5%); patients with BRPC who received combination chemotherapy and resection had a median OS of 31.5 compared with 19.5 months in patients with RPC (P = 0.0049). Patients with LAPC had a median OS of 12.7 months. CONCLUSIONS In patients with BRPC who undergo resection after induction treatment, the OS was significantly better than in patients with RPC. Neoadjuvant treatment should be considered for all localized PDACs.
Exposure to Hyperchloremia Is Associated with Poor Early Recovery of Kidney Graft Function after Living-Donor Kidney Transplantation: A Propensity Score-Matching Analysis

The effects of hyperchloremia on kidney grafts have not been investigated in patients undergoing living-donor kidney transplantation (LDKT). In this study, data from 200 adult patients undergoing elective LDKT between January 2016 and December 2017 were analyzed after propensity score (PS) matching. The patients were allocated to hyperchloremia and non-hyperchloremia groups according to the occurrence of hyperchloremia (i.e., ≥110 mEq/L) immediately after surgery. Poor early graft recovery was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 during the first 48 hours after surgery. After PS matching, no significant differences in perioperative recipient or donor graft parameters were observed between groups. Although the total amount of crystalloid fluid infused during surgery did not differ between groups, the proportions of main crystalloid fluid type used (i.e., 0.9% normal saline vs. Plasma Solution-A) did. The eGFR increased gradually during postoperative day (POD) 2 in both groups. However, the proportion of patients with eGFR > 60 mL/min/1.73 m2 on POD 2 was higher in the non-hyperchloremia group than in the hyperchloremia group. In this PS-adjusted analysis, hyperchloremia was significantly associated with poor graft recovery on POD 2. In conclusion, exposure to hyperchloremia may have a negative impact on early graft recovery in LDKT.
Retinol binding protein 3 is increased in the retina of patients with diabetes resistant to diabetic retinopathy

Retinol binding protein 3 may protect against the progression of diabetic retinopathy by inhibiting glucose uptake into retinal cells. Endogenous protection Diabetic retinopathy (DR) is one of the most common consequences of diabetes affecting more than 35% of patients. Endogenous protective factors could explain why only a fraction of patients with diabetes develop DR. In this study, Yokomizo et al. analyzed data from a large cohort of patients with diabetes (Mendalist cohort) and showed that retinol binding protein 3 (RBP3) expression was negatively correlated with DR severity. Intravitreal RBP3 injection or retinal RBP3 overexpression in rodents protected against vascular endothelial growth factor– and diabetes-induced vascular retinal permeability. The protective effects were mediated by inhibition of glucose uptake in retinal endothelial and Müller cells. The Joslin Medalist Study characterized people affected with type 1 diabetes for 50 years or longer. More than 35% of these individuals exhibit no to mild diabetic retinopathy (DR), independent of glycemic control, suggesting the presence of endogenous protective factors against DR in a subpopulation of patients. Proteomic analysis of retina and vitreous identified retinol binding protein 3 (RBP3), a retinol transport protein secreted mainly by the photoreceptors, as elevated in Medalist patients protected from advanced DR. Mass spectrometry and protein expression analysis identified an inverse association between vitreous RBP3 concentration and DR severity. Intravitreal injection and photoreceptor-specific overexpression of RBP3 in rodents inhibited the detrimental effects of vascular endothelial growth factor (VEGF). Mechanistically, our results showed that recombinant RBP3 exerted the therapeutic effects by binding and inhibiting VEGF receptor tyrosine phosphorylation. In addition, by binding to glucose transporter 1 (GLUT1) and decreasing glucose uptake, RBP3 blocked the detrimental effects of hyperglycemia in inducing inflammatory cytokines in retinal endothelial and Müller cells. Elevated expression of photoreceptor-secreted RBP3 may have a role in protection against the progression of DR due to hyperglycemia by inhibiting glucose uptake via GLUT1 and decreasing the expression of inflammatory cytokines and VEGF.
Developmental control of convergent floral pigmentation across evolutionary timescales

Convergent phenotypic evolution has been widely documented across timescales, from populations, to species, to major lineages. The extent to which convergent phenotypes arise from convergent genetic and developmental mechanisms remains an open question, although studies to‐date reveal examples of both similar and different underlying mechanisms. This variation likely relates to a range of factors, including the genetic architecture of the trait and selective filtering of mutations over time. Here we focus on floral pigmentation, and examine the degree of developmental convergence between white‐flowered lineages and white morphs within pigmented species.
Evolution of Meniere’s Disease from MD 1.0, via MD 1.5, to MD 2.0

Abstract Background: Elder Meniere’s disease (MD) patients ultimately lose their vestibular function. Objective: This study utilized an inner ear test battery to investigate evolution of MD. Methods: Total 278 elder MD patients aged >65 years were divided into three groups. Ninety-four patients with bilateral MD (188 ears) were assigned to Group A. The remaining 184 patients with unilateral MD were further divided into two groups. Group B consisted of 20 affected ears with normal vestibular function on the opposite ears, while Group C indicated 184 unaffected ears. All patients underwent an inner ear test battery. Results: Inner ear deficits in Group B declined from the cochlea via the saccule, utricle to semicircular canals. In contrast, Groups A and C did not significantly differ in the abnormality rates of cervical vestibular-evoked myogenic potential (cVEMP), ocular VEMP and caloric tests, indicating that Group C (unaffected ears) may partly share the same mechanism like Group A (affected ears), namely aging and hydropic effects. Conclusion and significance: Evolution of MD may progress from unilateral MD (MD 1.0), via unilateral MD coupled with asymptomatic hydrops on opposite ear (MD 1.5), toward bilateral MD (MD 2.0), where the number 1.0-2.0 means the number of clinically affected ears.
Top 10 Research Priorities in Spatial Lifecourse Epidemiology

Summary: The International Initiative on Spatial Lifecourse Epidemiology (ISLE) convened its first International Symposium on Lifecourse Epidemiology and Spatial Science at the Lorentz Center in Leiden, Netherlands, 16–20 July 2018. Its aim was to further an emerging transdisciplinary field: Spatial Lifecourse Epidemiology. This field draws from a broad perspective of scientific disciplines including lifecourse epidemiology, environmental epidemiology, community health, spatial science, health geography, biostatistics, spatial statistics, environmental science, climate change, exposure science, health economics, evidence-based public health, and landscape ecology. The participants, spanning 30 institutions in 10 countries, sought to identify the key issues and research priorities in spatial lifecourse epidemiology. The results published here are a synthesis of the top 10 list that emerged out of the discussion by a panel of leading experts, reflecting a set of grand challenges for spatial lifecourse epidemiology in the coming years. https://doi.org/10.1289/EHP4868
Plant domestication disrupts biodiversity effects across major crop types

Abstract Plant diversity fosters productivity in natural ecosystems. Biodiversity effects might increase agricultural yields at no cost in additional inputs. However, the effects of diversity on crop assemblages are inconsistent, probably because crops and wild plants differ in a range of traits relevant to plant–plant interactions. We tested whether domestication has changed the potential of crop mixtures to over‐yield by comparing the performance and traits of major crop species and those of their wild progenitors under varying levels of diversity. We found stronger biodiversity effects in mixtures of wild progenitors, due to larger selection effects. Variation in selection effects was partly explained by within‐mixture differences in leaf size. Our results indicate that domestication might disrupt the ability of crops to benefit from diverse neighbourhoods via reduced trait variance. These results highlight potential limitations of current crop mixtures to over‐yield and the potential of breeding to re‐establish variance and increase mixture performance.
Reliability of the 30 s Chair Stand Test in Women with Fibromyalgia

Background: The 30 s chair stand test is often used to evaluate physical fitness in chronic pain populations. In patients with fibromyalgia, physical fitness is closely related to pain, quality of life, and fear of falling. However, the reliability of this test has only been evaluated concerning the number of repetitions. Objective: To evaluate the test–retest reliability of the 30 s chair stand test in women with fibromyalgia (n = 30), using data from the contact and non-contact time registered with an automatic chronometer (chronojump). Methods: Participants carried out the 30 s chair stand test twice with five minutes as a rest period, while an automatic chronometer recorded the time elapsed in contact with the chair (impulse phase) and not in contact (non-contact phase). Number and fear of falls in the last year and in the last six weeks were also recorded. Results: The reliability of duration of both phases was good. A relationship between these results and the number and fear of falling was also found. Conclusion: The analysis of movement phases in the 30 s chair stand test showed a good reliability in females with fibromyalgia, providing further useful information about the onset of muscle fatigue during the test.
Intravenous iron delivers a sustained (8‐week) lowering of pulmonary artery pressure during exercise in healthy older humans

In older individuals, pulmonary artery pressure rises markedly during exercise, probably due in part to increased pulmonary vascular resistance and in part to an increase in left‐heart filling pressure. Older individuals also show more marked pulmonary vascular response to hypoxia at rest. Treatment with intravenous iron reduces the rise in pulmonary artery pressure observed during hypoxia. Here, we test the hypothesis that intravenous iron administration may also attenuate the rise in pulmonary artery pressure with exercise in older individuals. In a randomized double‐blind placebo‐controlled physiology study in 32 healthy participants aged 50–80 years, we explored the hypothesis that iron administration would deliver a fall in systolic pulmonary artery pressure (SPAP) during moderate cycling exercise (20 min duration; increase in heart rate of 30 min−1) and a change in maximal cycling exercise capacity ( V˙O2max ). Participants were studied before, and at 3 h to 8 weeks after, infusion. SPAP was measured using Doppler echocardiography. Iron administration resulted in marked changes in indices of iron homeostasis over 8 weeks, but no significant change in hemoglobin concentration or inflammatory markers. Resting SPAP was also unchanged, but SPAP during exercise was lower by ~3 mmHg in those receiving iron (P < 0.0001). This effect persisted for 8 weeks. Although V˙O2max remained unaffected in the iron‐replete healthy participants studied here, this study demonstrates for the first time the ability of intravenous iron supplementation to reduce systolic pulmonary artery pressure during exercise.
Observation of irrigation‐induced climate change in the Midwest United States

Irrigated agriculture alters near‐surface temperature and humidity, which may mask global climate change at the regional scale. However, observational studies of irrigation‐induced climate change are lacking in temperate, humid regions throughout North America and Europe. Despite unknown climate impacts, irrigated agriculture is expanding in the Midwest United States, where unconfined aquifers provide groundwater to support crop production on coarse soils. This is the first study in the Midwest United States to observe and quantify differences in regional climate associated with irrigated agricultural conversion from forests and rainfed agriculture. To this end, we established a 60 km transect consisting of 28 stations across varying land uses and monitored surface air temperature and relative humidity for 31 months in the Wisconsin Central Sands region. We used a novel approach to quantify irrigated land use in both space and time with a database containing monthly groundwater withdrawal estimates by parcel for the state of Wisconsin. Irrigated agriculture decreased maximum temperatures and increased minimum temperatures, thus shrinking the diurnal temperature range (DTR) by an average of 3°C. Irrigated agriculture also decreased the vapor pressure deficit (VPD) by an average of 0.10 kPa. Irrigated agriculture significantly decreased evaporative demand for 25% and 66% of study days compared to rainfed agriculture and forest, respectively. Differences in VPD across the land‐use gradient were highest (0.21 kPa) during the peak of the growing season, while differences in DTR were comparable year‐round. Interannual variability in temperature had greater impacts on differences in DTR and VPD across the land‐use gradient than interannual variability in precipitation. These regional climate changes must be considered together with increased greenhouse gas emissions, changes to groundwater quality, and surface water degradation when evaluating the costs and benefits of groundwater‐sourced irrigation expansion in the Midwest United States and similar regions around the world.
Understanding the training and education needs of homecare workers supporting people with dementia and cancer: A systematic review of reviews

Many people with dementia, supported by family carers, prefer to live at home and may rely on homecare support services. People with dementia are also often living with multimorbidities, including cancer. The main risk factor for both cancer and dementia is age and the number of people living with dementia and cancer likely to rise. Upskilling the social care workforce to facilitate more complex care is central to national workforce strategies and challenges. Training and education development must also respond to the key requirements of a homecare workforce experiencing financial, recruitment and retention difficulties. This systematic review of reviews provides an overview of dementia and cancer training and education accessible to the homecare workforce. Findings reveal there is a diverse range of training and education available, with mixed evidence of effectiveness. Key barriers and facilitators to effective training and education are identified in order to inform future training, education and learning development for the homecare workforce supporting people with dementia and cancer.
The joint effect of aging and HIV infection on microstructure of white matter bundles

Recent evidence suggests the aging process is accelerated by HIV. Degradation of white matter (WM) has been independently associated with HIV and healthy aging. Thus, WM may be vulnerable to joint effects of HIV and aging. Diffusion‐weighted imaging (DWI) was conducted with HIV‐seropositive (n = 72) and HIV‐seronegative (n = 34) adults. DWI data underwent tractography, which was parcellated into 18 WM tracts of interest (TOIs). Functional Analysis of Diffusion Tensor Tract Statistics (FADTTS) regression was conducted assessing the joint effect of advanced age and HIV on fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) along TOI fibers. In addition to main effects of age and HIV on WM microstructure, the interactive effect of age and HIV was significantly related to lower FA and higher MD, AD, and RD across all TOIs. The location of findings was consistent with the clinical presentation of HIV‐associated neurocognitive disorders. While older age is related to poorer WM microstructure, its detrimental effect on WM is stronger among HIV+ relative to HIV− individuals. Loss of WM integrity in the context of advancing age may place HIV+ individuals at increased risk for brain and cognitive compromise.
Considering smoking status, coexpression network analysis of non–small cell lung cancer at different cancer stages, exhibits important genes and pathways

Non–small cell lung cancer (NSCLC) is the most common subtype of lung cancer among smokers, nonsmokers, women, and young individuals. Tobacco smoking and different stages of the NSCLC have important roles in cancer evolution and require different treatments. Existence of poorly effective therapeutic options for the NSCLC brings special attention to targeted therapies by considering genetic alterations. In this study, we used RNA‐Seq data to compare expression levels of RefSeq genes and to find some genes with similar expression levels. We utilized the “Weighted Gene Co‐expression Network Analysis” method for three different datasets to create coexpressed genetic modules having relations with the smoking status and different stages of the NSCLC. Our results indicate seven important genetic modules having important associations with the smoking status and cancer stages. Based on investigated genetic modules and their biological explanation, we then identified 13 newly candidate genes and 7 novel transcription factors in association with the NSCLC, the smoking status, and cancer stages. We then examined those results using other datasets and explained our results biologically to illustrate some important genes in relation with the smoking status and metastatic stage of the NSCLC that can bring some crucial information about cancer evolution. Our genetic findings also can be used as some therapeutic targets for different clinical conditions of the NSCLC.