Miracle-dz/UniFAR-FTUs huggingface dataset:
Longitudinal Molecular Imaging of Progesterone Receptor Reveals Early Differential Response to Endocrine Therapy in Breast Cancer with an Activating ESR1 Mutation

Visual Abstract Activating mutations in the estrogen receptor (ER) α-gene (ESR1) result in constitutive transcriptional activity in the absence of estrogen and are associated with endocrine resistance in metastatic ER-positive (+) breast cancer. It is not known how activating ESR1 mutations may alter the predictive values of molecular imaging agents for endocrine therapy response. This study investigated the effect of an activating ESR1 mutation on pretreatment 18F-fluoroestradiol (18F-FES) uptake and early assessment of endocrine therapy response using 18F-FDG and 18F-fluorofuranylnorprogesterone (18F-FFNP) PET/CT imaging of tumor glucose metabolism and progesterone receptor (PR) expression, respectively. Methods: ER+, PR+ T47D breast cancer cells expressing wild-type (WT) ER or an activating ESR1 mutation, Y537S-ER, were used to generate tumor xenografts in ovariectomized female immunodeficient mice supplemented with 17β-estradiol. Tumor growth curves were determined in the presence or absence of estrogen and for ethanol vehicle control or fulvestrant treatment, a selective ER degrader. Pretreatment 18F-FES uptake was compared between Y537S-ER and WT-ER tumors. Longitudinal PET/CT imaging with 18F-FFNP and 18F-FDG was performed before and 7–9 d after the start of endocrine therapy with fulvestrant. Radiopharmaceutical uptake in Y537S-ER and WT-ER tumors was compared between baseline and follow-up scans. Statistical significance was determined using paired t testing for longitudinal imaging and 2-way ANOVA for the 18F-FFNP tissue biodistribution assay. Results: Y537S-ER xenografts showed estrogen-independent growth, whereas WT-ER tumors grew only with estrogen. Fulvestrant treatment for 28 d significantly reduced tumor volumes for WT-ER but only stabilized volumes for Y537S-ER. Baseline 18F-FES uptake did not significantly differ between WT-ER and Y537S-ER tumors. Fulvestrant treatment induced a similar early metabolic response for both WT-ER and Y537S-ER tumors. 18F-FFNP uptake in WT-ER tumors was significantly reduced after 7 d of fulvestrant treatment; however, this reduction did not occur in Y537S-ER tumors, which showed no significant change between baseline and follow-up PET/CT. Conclusion: Molecular imaging of PR expression dynamics could be a noninvasive approach for early identification of reduced effectiveness of endocrine therapy resulting from activating ESR1 mutations.
Microencapsulation of Fluticasone Propionate and Salmeterol Xinafoate in Modified Chitosan Microparticles for Release Optimization

Chitosan (CS) is a natural polysaccharide, widely studied in the past due to its unique properties such as biocompatibility, biodegradability and non-toxicity. Chemical modification of CS is an effective pathway to prepare new matrices with additional functional groups and improved properties, such as increment of hydrophilicity and swelling rate, for drug delivery purposes. In the present study, four derivatives of CS with trans-aconitic acid (t-Acon), succinic anhydride (Succ), 2-hydroxyethyl acrylate (2-HEA) and acrylic acid (AA) were prepared, and their successful grafting was confirmed by FTIR and 1H-NMR spectroscopies. Neat chitosan and its grafted derivatives were fabricated for the encapsulation of fluticasone propionate (FLU) and salmeterol xinafoate (SX) drugs, used for chronic obstructive pulmonary disease (COPD), via the ionotropic gelation technique. Scanning electron microscopy (SEM) micrographs demonstrated that round-shaped microparticles (MPs) were effectively prepared with average sizes ranging between 0.4 and 2.2 μm, as were measured by dynamic light scattering (DLS), while zeta potential verified in all cases their positive charged surface. FTIR spectroscopy showed that some interactions take place between the drugs and the polymeric matrices, while X-ray diffraction (XRD) patterns exhibited that both drugs were encapsulated in MPs’ interior with a lower degree of crystallinity than the neat drugs. In vitro release studies of FLU and SX exposed a great amelioration in the drugs’ dissolution profile from all modified CS’s MPs, in comparison to those of neat drugs. The latter fact is attributed to the reduction in crystallinity of the active substances in the MPs’ interior.
High efficiency preparation of skinned mouse cardiac muscle strips from cryosections for contractility studies

What is the central question of this study? Can frozen cardiac papillary muscles and cryosectioning be used to reliably obtain uniform cardiac muscle strips with high yields? What is the main finding and its importance? A new method was developed using frozen cardiac papillary muscles and cryosectioning to reliably obtain uniform cardiac muscle strips with high yields. Experimental results demonstrate that this new methodology significantly increases the efficiency and application of quantitative biomechanical studies using skinned muscle fibres with an additional advantage of no need for transferring live animals.
Multi-agent approach to sequence structure simulation in the RNA World hypothesis

The origins of life on Earth have been the subject of inquiry since the early days of philosophical thought and are still intensively investigated by the researchers around the world. One of the theories explaining the life emergence, that gained the most attention recently is the RNA World hypothesis, which assumes that life on Earth was sparked by replicating RNA chains. Since wet lab analysis is time-consuming, many mathematical and computational approaches have been proposed that try to explain the origins of life. Recently proposed one, based on the work by Takeuchi and Hogeweg, addresses the problem of interplay between RNA replicases and RNA parasitic species, which is crucial for understanding the first steps of prebiotic evolution. In this paper, the aforementioned model has been extended and modified by introducing RNA sequence (structure) information and mutation rate close to real one. It allowed to observe the simple evolution mechanisms, which could have led to the more complicated systems and eventually, to the formation of the first cells. The main goal of this study was to determine the conditions that allowed the spontaneous emergence and evolution of the prebiotic replicases equipped with simple functional domains within a large population. Here we show that polymerase ribozymes could have appeared randomly and then quickly started to copy themselves in order for the system to reach equilibrium. It has been shown that evolutionary selection works even in the simplest systems.
Qualitative Analysis of Health Systems Utilizing Non-Face-to-Face Chronic Care Management for Medicare-Insured Patients With Diabetes

Chronic diseases impact 117 million adults in the United States and account for $3.3 trillion in health care spending. This qualitative study investigated experiences with reimbursement structure for non-face-to-face (NFF) chronic care management (CCM) through diverse health system approaches in primary care settings in Southeastern Louisiana. In-depth interviews were conducted with 16 purposively selected key informants, and reflexive thematic analysis was utilized to explore findings. Variation in health system approaches for implementing and quality of NFF CCM programs were identified. Results included differences in health system motivation and methods for financial structuring and quality of third-party vendor and alternative models.
A pilot study investigating the effects of voluntary exercise on capillary stalling and cerebral blood flow in the APP/PS1 mouse model of Alzheimer’s disease

Exercise exerts a beneficial effect on the major pathological and clinical symptoms associated with Alzheimer’s disease in humans and mouse models of the disease. While numerous mechanisms for such benefits from exercise have been proposed, a clear understanding of the causal links remains elusive. Recent studies also suggest that cerebral blood flow in the brain of both Alzheimer’s patients and mouse models of the disease is decreased and that the cognitive symptoms can be improved when blood flow is restored. We therefore hypothesized that the mitigating effect of exercise on the development and progression of Alzheimer’s disease may be mediated through an increase in the otherwise reduced brain blood flow. To test this idea, we performed a pilot study to examine the impact of three months of voluntary wheel running in a small cohort of ~1-year-old APP/PS1 mice on short-term memory function, brain inflammation, amyloid deposition, and baseline cerebral blood flow. Our findings that exercise led to a trend toward improved spatial short-term memory, reduced brain inflammation, markedly increased neurogenesis in the dentate gyrus, and a reduction in hippocampal amyloid-beta deposits are consistent with other reports on the impact of exercise on the progression of Alzheimer’s related symptoms in mouse models. Notably, we did not observe any impact of wheel running on overall baseline blood flow nor on the incidence of non-flowing capillaries, a mechanism we recently identified as one contributing factor to cerebral blood flow deficits in mouse models of Alzheimer’s disease. Overall, our findings add to the emerging picture of differential effects of exercise on cognition and blood flow in Alzheimer’s disease pathology by showing that capillary stalling is not decreased following exercise.
On the Clinical Pharmacology of Reactive Oxygen Species

Reactive oxygen species (ROS) have been correlated with almost every human disease. Yet clinical exploitation of these hypotheses by pharmacological modulation of ROS has been scarce to nonexistent. Are ROS, thus, irrelevant for disease? No. One key misconception in the ROS field has been its consideration as a rather detrimental metabolic by-product of cell metabolism, and thus, any approach eliminating ROS to a certain tolerable level would be beneficial. We now know, instead, that ROS at every concentration, low or high, can serve many essential signaling and metabolic functions. This likely explains why systemic, nonspecific antioxidants have failed in the clinic, often with neutral and sometimes even detrimental outcomes. Recently, drug development has focused, instead, on identifying and selectively modulating ROS enzymatic sources that in a given constellation cause disease while leaving ROS physiologic signaling and metabolic functions intact. As sources, the family of NADPH oxidases stands out as the only enzyme family solely dedicated to ROS formation. Selectively targeting disease-relevant ROS-related proteins is already quite advanced, as evidenced by several phase II/III clinical trials and the first drugs having passed registration. The ROS field is expanding by including target enzymes and maturing to resemble more and more modern, big data–enhanced drug discovery and development, including network pharmacology. By defining a disease based on a distinct mechanism, in this case ROS dysregulation, and not by a symptom or phenotype anymore, ROS pharmacology is leaping forward from a clinical underperformer to a proof of concept within the new era of mechanism-based precision medicine. Significance Statement Despite being correlated to almost every human disease, nearly no ROS modulator has been translated to the clinics yet. Here, we move far beyond the old-fashioned misconception of ROS as detrimental metabolic by-products and suggest 1) novel pharmacological targeting focused on selective modulation of ROS enzymatic sources, 2) mechanism-based redefinition of diseases, and 3) network pharmacology within the ROS field, altogether toward the new era of ROS pharmacology in precision medicine.
Lower Mortality and Morbidity with Low-Molecular-Weight Heparin for VTE Prophylaxis in Spine Trauma.

STUDY DESIGN Retrospective review of prospectively collected data. OBJECTIVE The objective of this study was to evaluate outcomes between patients receiving LMWH vs. UH in a retrospective cohort of patients with spine trauma. SUMMARY OF BACKGROUND DATA Although multiple clinical trials have been conducted, current guidelines do not have enough evidence to suggest low molecular weight heparin (LMWH) or unfractionated heparin (UH) for venous thromboembolism (VTE) prophylaxis in spine trauma. METHODS Patients with spine trauma in the Trauma Quality Improvement Program datasets were identified. Those who died, were transferred within 72 hours, were deemed to have a fatal injury, were discharged within 24 hours, suffered from polytrauma, or were missing data for VTE prophylaxis were excluded. A propensity score was created using age, sex, severity of injury, time to prophylaxis, presence of a cord injury, and altered mental status or hypotension upon arrival, and inverse probability weighted logistic regression modeling was used to evaluate mortality, venous thromboembolic, return to operating room, and total complication rates. E-values were used to calculate the likelihood of unmeasured confounders. RESULTS Those receiving UH (n = 7,172) were more severely injured (p < 0.0001), with higher rates of spinal cord injury (32.26% vs. 25.32%, p < 0.0001) and surgical stabilization (29.52% vs. 22.94%, p < 0.0001) compared to those receiving LMWH (n = 20,341). Patients receiving LMWH had lower mortality (OR: 0.47; 95% CI: 0.42 - 0.53; p < 0.001; E = 3.68), total complication (OR: 0.92; 95% CI: 0.88 - 0.95; p < 0.001; E = 1.39), and VTE event (OR: 0.80; 95% CI: 0.72 - 0.88; p < 0.001; E = 1.81) rates than patients receiving UH. There were no differences in rates of unplanned return to the operating room (OR: 1.01; 95% CI: 0.80 - 1.27; p = 0.93; E = 1.11). CONCLUSIONS There is an association between lower mortality and receiving LMWH for VTE prophylaxis in patients with spine trauma. A large randomized clinical trial is necessary to confirm these findings. LEVEL OF EVIDENCE 3.
Cutaneous Radiation Injuries: Models, Assessment and Treatments

Many cases of human exposures to high-dose radiation have been documented, including individuals exposed during the detonation of atomic bombs in Hiroshima and Nagasaki, nuclear power plant disasters (e.g., Chernobyl), as well as industrial and medical accidents. For many of these exposures, injuries to the skin have been present and have played a significant role in the progression of the injuries and survivability from the radiation exposure. There are also instances of radiation-induced skin complications in routine clinical radiotherapy and radiation diagnostic imaging procedures. In response to the threat of a radiological or nuclear mass casualty incident, the U.S. Department of Health and Human Services tasked the National Institute of Allergy and Infectious Diseases (NIAID) with identifying and funding early- to mid-stage medical countermeasure (MCM) development to treat radiation-induced injuries, including those to the skin. To appropriately assess the severity of radiation-induced skin injuries and determine efficacy of different approaches to mitigate/treat them, it is necessary to develop animal models that appropriately simulate what is seen in humans who have been exposed. In addition, it is important to understand the techniques that are used in other clinical indications (e.g., thermal burns, diabetic ulcers, etc.) to accurately assess the extent of skin injury and progression of healing. For these reasons, the NIAID partnered with two other U.S. Government funding and regulatory agencies, the Biomedical Advanced Research and Development Authority (BARDA) and the Food and Drug Administration (FDA), to identify state-of-the-art methods in assessment of skin injuries, explore animal models to better understand radiation-induced cutaneous damage and investigate treatment approaches. A two-day workshop was convened in May 2019 highlighting talks from 28 subject matter experts across five scientific sessions. This report provides an overview of information that was presented and the subsequent guided discussions.
Antioxidant and Cytoprotective Properties of Cyanobacteria: Potential for Biotechnological Applications

Antioxidant compounds from cyanobacteria may constitute a natural alternative to current synthetic antioxidants, which contain preservatives and suspected toxicity. In this work, we evaluate the antioxidant potential of cyanobacterial strains of distinct species/genus isolated from freshwater (n = 6), soil (n = 1) and wastewater (n = 1) environments. Lyophilized biomass obtained from in-vitro cultures of those strains was extracted with ethanol and methanol. The antioxidant potential was evaluated by chemical (DPPH scavenging method, β-carotene bleaching assay, determination of total phenolic and total flavonoid compounds) and biological (H2O2-exposed HEK293T cell line model) approach. Some strains showed high yields of antioxidant activity by the DPPH assay (up to 10.7% IP/20.7 TE μg/mL) and by the β-carotene bleaching assay (up to 828.94 AAC), as well as significant content in phenolic (123.16 mg EAG/g DW) and flavonoid (900.60 mg EQR/g DW) compounds. Normalization of data in a “per cell” or “per cell volume” base might facilitate the comparison between strains. Additionally, most of the cyanobacterial extracts conferred some degree of protection to HEK293T cells against the H2O2-induced cytotoxicity. Freshwater Aphanizomenon gracile (LMECYA 009) and Aphanizomenon flos-aquae (LMECYA 088), terrestrial Nostoc (LMECYA 291) and wastewater Planktothrix mougeotii (LEGE 06224) seem to be promising strains for further investigation on cyanobacteria antioxidant potential.
The effects of low temperatures on the vegetative growth and flowering of the primocane fruiting raspberry ‘Autumn Bliss’

Summary The effects of low temperatures on subsequent vegetative growth and flowering in the raspberry ‘AutumnBliss’ were investigated. In the first experiment, a number of lifting dates were used to determine the seasonal pattern of dormancy and the effect of natural chilling on plant development. In the second, different durations of artificial chilling(0, 2, 4, 6, 8 and 10 weeks at 0˚C) were combined with two lifting dates to investigate the effect of natural and artificial chilling. In these experiments, plants which received little chilling grew slowly and failed to develop beyond short rosettes of leaves but as chilling increased, the rate of vegetative growth increased. This coincided with a decline in the time toflowering. These two responses, however, were distinct. In a third experiment, the effect of vernalization of actively growing canes was tested in an attempt to separate the effects of cold on time to flowering, and on the removalof dormancy. The plants responded significantly to cold treatment and flowering was advanced, indicating a distinct vernalizing effect
Syntaxin 1B regulates synaptic GABA release and extracellular GABA concentration, and is associated with temperature‐dependent seizures

De novo heterozygous mutations in the STX1B gene, encoding syntaxin 1B, cause a familial, fever‐associated epilepsy syndrome. Syntaxin 1B is an essential component of the pre‐synaptic neurotransmitter release machinery as a soluble N‐ethylmaleimide‐sensitive factor attachment protein receptor protein that regulates the exocytosis of synaptic vesicles. It is also involved in regulating the functions of the SLC6 family of neurotransmitter transporters that reuptake neurotransmitters, including inhibitory neurotransmitters, such as γ‐aminobutyric acid (GABA) and glycine. The purpose of the present study was to elucidate the molecular mechanisms underlying the development of febrile seizures by examining the effects of syntaxin 1B haploinsufficiency on inhibitory synaptic transmission during hyperthermia in a mouse model. Stx1b gene heterozygous knockout (Stx1b+/−) mice showed increased susceptibility to febrile seizures and drug‐induced seizures. In cultured hippocampal neurons, we examined the temperature‐dependent properties of neurotransmitter release and reuptake by GABA transporter‐1 (GAT‐1) at GABAergic neurons using whole‐cell patch‐clamp recordings. The rate of spontaneous quantal GABA release was reduced in Stx1b+/− mice. The hyperthermic temperature increased the tonic GABAA current in wild‐type (WT) synapses, but not in Stx1b+/− synapses. In WT neurons, recurrent bursting activities were reduced in a GABA‐dependent manner at hyperthermic temperature; however, this was abolished in Stx1b+/− neurons. The blockade of GAT‐1 increased the tonic GABAA current and suppressed recurrent bursting activities in Stx1b+/− neurons at the hyperthermic temperature. These data suggest that functional abnormalities associated with GABA release and reuptake in the pre‐synaptic terminals of GABAergic neurons may increase the excitability of the neural circuit with hyperthermia.
The Effectiveness and Value of Oral Semaglutide for Type 2 Diabetes Mellitus

DISCLOSURES Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from Aetna, America's Health Insurance Plans, Anthem, Allergan, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, and United Healthcare. Fazioli, Rind, and Pearson are employed by ICER. Gazauskas and Hansen have nothing to disclose.
Vitamin D Doses from Solar Ultraviolet and Dietary Intakes in Patients with Depression: Results of a Case-Control Study

The purpose of this study to estimate cumulative vitamin D doses from solar ultraviolet and dietary intakes in patients with depression and compare it to healthy controls. Using a case-control research design, a sample of 96 patients with depression were age- and sex-matched with 96 healthy controls. Dietary vitamin D dose was estimated from diet analysis. Vitamin D-weighted ultraviolet solar doses were estimated from action spectrum conversion factors and geometric conversion factors accounting for the skin type, the fraction of body exposed, and age factor. Patients with depression had a lower dose of vitamin D (IU) per day with 234, 153, and 81 per day from all sources, sunlight exposure, and dietary intake, respectively. Controls had a higher intake of vitamin D (IU) per day with 357, 270, and 87 per day from all sources, sunlight exposure, and dietary intake, respectively. Only 19% and 30% met the minimum daily recommended dose of ≥400 IU per day for cases and controls, respectively. The sensitivity, specificity, percentage correctly classified and receiver operating characteristic (ROC) Area for the estimated vitamin D against serum vitamin D as reference were 100%, 79%, 80%, and 89%. Physical activity level was the only predictor of daily vitamin D dose. Vitamin D doses are lower than the recommended dose of ≥400 IU (10 mcg) per day for both cases with depression and healthy controls, being much lower in the former.