Miracle-dz/UniFAR-FTUs huggingface dataset:
Impact of repeated remote ischemic conditioning on diabetic foot ulcers: A proof‐of‐concept study

Patients with a diabetic foot ulcer (DFU) suffer disabilities and are at increased risk for lower extremity amputation. Current standard of care includes debridement, topical antibiotics, and weight off‐loading—still resulting in low rates of healing. Previous small‐scale research has indicated that repeated remote ischemic conditioning (rRIC) is a novel modality that delivers significantly higher DFU healing rates. This proof‐of‐concept study was performed to expand the research on the utility of rRIC as an adjunctive treatment in the healing of chronic DFUs. Forty subjects (41 wounds) received rRIC treatment three times weekly in addition to standard of care for 12 weeks. Subjects that did not heal in this time frame but had a significant reduction in wound size were eligible to continue for an 8‐week extension period. By the end of the extension period, 31 of the 41 DFU wounds (75.6%) in this study were determined to be healed. This compares favourably to the 25–30% standard of care average healing rate. For additional comparison, another group of patients receiving standard of care alone, by the same investigator, was selected and matched by wound size at baseline and wound location. For this matching cohort, after 20 weeks of treatment, only 15 of the 41 DFU comparison wounds (36.6%) were determined to be healed, in line with other standard of care results. In the rRIC treatment group, the 10 wounds that did not heal, experienced an average reduction in wound area of 54.3%. The results of this proof‐of‐concept study reinforce earlier evidence that the addition of rRIC to local wound care significantly improves the healing of chronic diabetic foot ulcers.
Pioglitazone improves skeletal muscle functions in reserpine-induced fibromyalgia rat model

Abstract Background Fibromyalgia (FM) is characterized by musculoskeletal pain, fatigue, sleep and memory disturbance. There is no definitive cure yet for FM-related health problems. Peroxisome proliferator-activated receptor’s (PPAR’s) activation is associated with insulin sensitisation and improved glucose metabolism. PPAR-γ was reported to alleviate FM allodynia. Limited data are discussing its effect on motor disorders. Objective To investigate the potential effect of PPAR-γ agonists (pioglitazone, as one member of thiazolidinediones (TZD)) on motor dysfunction in reserpine-induced FM in a rat model. Materials and methods Thirty-six male Wistar rats were divided into negative control (n = 9) and reserpine-induced FM (n = 27) groups. The latter was subdivided into three equal subgroups (n = 9), positive control (untreated FM model), pioglitazone-treated and GW9662-treated. We evaluated muscle functions and activity of chloramphenicol acetyltransferase, superoxide dismutase, malondialdehyde, and serum levels of interleukin-8 and monocyte chemoattractant protein-1. Results Pioglitazone significantly relieved fatigue, improved muscle performance, reduced inflammatory cytokines and enhanced antioxidant’s activity, while GW9662, a known PPAR-γ antagonist, aggravated the FM manifestations in the rat model. Conclusion PPAR-γ agonists show a promising role against FM-associated motor dysfunctions.
Patterns in Serum Toxicokinetics in Peromyscus Exposed to Per‐ and Polyfluoroalkyl Substances

Per‐ and polyfluoroalkyl substances (PFAS) are compounds manufactured for use in paints, cleaning agents, fire suppressants, nonstick cookware, food containers, and water‐resistant products. Concerns about PFAS stem from their ubiquitous presence in the environment, persistence, and variable/uncertain bioaccumulation and toxicity. In the present study, 5 perfluoroalkyl acids and one polyfluoroalkyl substance were administered to white‐footed mice (Peromyscus leucopus) to elucidate the kinetics of each chemical over 28 d of exposure. Perfluorooctanoate, perfluorohexane sulfonate (PFHxS), and perfluorobutane sulfonate were administered to male and female mice via drinking water. Perfluorooctane sulfonate, perfluorononanoate, 6:2 fluorotelomer sulfonate, and PFHxS were administered to male and female mice via oral gavage. Blood samples collected after 14 or 21 and 28 d of exposure were analyzed for individual PFAS concentrations via liquid chromatography‐tandem mass spectrometry. In general, a plateau in serum concentration in this toxicity test–relevant timeline depended on interactions between 1) the type of PFAS (i.e., perfluoroalkyl sulfonic acids [PFSAs] vs perfluoroalkyl carboxylic acids [PFCAs] vs polyfluorinated), 2) continuous versus bolus dosing, and 3) to a lesser extent, sex. Specifically, PFCAs were detected at higher concentration in females than males, whereas PFSAs were generally detected at similar levels across sex. An exception occurred when PFHxS yielded higher serum levels in males than females through bolus, but not continuous, dosing. Type of PFAS had the largest impact on serum concentrations, whereas sex had the lowest. As such, future work on the toxicokinetics of PFAS in common ecological receptors would be valuable to further explore these patterns. Environ Toxicol Chem 2021;40:2886–2898. © 2021 SETAC. This article has been contributed to by US Government employees and their work is in the public domain in the USA.
In-vivo impact of common cosmetic preservative systems in full formulation on the skin microbiome

Preservatives play an essentially role in ensuring that cosmetic formulations remain safe for use via control of microbial contamination. Commonly used preservatives include organic acids, alcohols and phenols and these play an essential role in controlling the growth of bacteria, fungi and moulds in substrates that can potentially act as a rich food source for microbial contaminants. Whilst the activity of these compounds is clear, both in vitro and in formulation, little information exists on the potential impact that common preservative systems, in full formulation, have on the skin’s resident microbiome. Dysbiosis of the skin’s microbiome has been associated with a number of cosmetic conditions but there currently are no in vivo studies investigating the potential for preservative ingredients, when included in personal care formulations under normal use conditions, to impact the cutaneous microbiome. Here we present an analysis of four in vivo studies that examine the impact of different preservation systems in full formulation, in different products formats, with varying durations of application. This work demonstrates that despite the antimicrobial efficacy of the preservatives in vitro, the skin microbiome is not impacted by preservative containing products in vivo.
MRI investigation of vascular remodeling for heterogeneous edema lesions in subacute ischemic stroke rat models: Correspondence between cerebral vessel structure and function

The spatial heterogeneity in the temporal occurrence of pseudo-normalization of MR apparent diffusion coefficient values for ischemic lesions may be related to morphological and functional vascular remodeling. As the area of accelerated pseudo-normalization tends to expand faster and more extensively into the chronic stage, detailed vascular characterization of such areas is necessary. During the subacute stage of transient middle cerebral artery occlusion rat models, the morphological size of the macrovasculature, microvascular vessel size index (VSI), and microvessel density (MVD) were quantified along with functional perfusion measurements of the relative cerebral blood flow (rCBF) and mean transit time (rMTT) of the corresponding areas (33 cases for each parameter). When compared with typical pseudo-normalization lesions, early pseudo-normalization lesions exhibited larger VSI and rCBF (p < 0.001) at reperfusion days 4 and 7, along with reduced MVD and elongated rMTT (p < 0.001) at reperfusion days 1, 4, and 7. The group median VSI and rCBF exhibited a strong positive correlation (r = 0.92), and the corresponding MVD and rMTT showed a negative correlation (r = −0.48). Light sheet fluorescence microscopy images were used to quantitatively validate the corresponding MRI-derived microvascular size, density, and cerebral blood volume.
Megestrol acetate drives endometrial carcinoma cell senescence via interacting with progesterone receptor B/FOXO1 axis

Megestrol acetate is a common and efficient anticancer progesterone. To explore the activity and the therapeutic mechanisms of megestrol acetate in endometrial cancer, human endometrial cancer cell lines Ishikawa and HHUA overexpressing progesterone receptor A (PR-A) and progesterone receptor B (PR-B) were treated with megestrol acetate. Cell viability, apoptosis, cycle arrest, and senescence, as well as the expressions of p21 and p16, two hallmarks of cellular senescence, were evaluated. Compared with the control, >10 nmol/L megestrol acetate treatment could significantly reduce endometrial cancer cell growth, and induce the irreversible G1 arrest and cell senescence. The expression of cyclin D1 in megestrol acetate treated cells was downregulated, while the expressions of p21 and p16 were upregulated via PR-B isoform. FOXO1 inhibitor AS1842856 could significantly abrogate megestrol acetate-induced cell senescence, suggesting that FOXO1 was involved in megestrol acetate/PR-B axis. These findings may provide a new understanding for the treatment of human endometrial cancer.
A Novel Use of NEMSIS to Create a PECARN-Specific EMS Patient Registry

Abstract Background: Research networks need access to EMS data to conduct pilot studies and determine feasibility of prospective studies. Combining data across EMS agencies is complicated and costly. Leveraging the National EMS Information System (NEMSIS) to extract select agencies’ data may be an efficient and cost-effective method of providing network-level data. Objective: Describe the process of creating a Pediatric Emergency Care Applied Research Network (PECARN) specific NEMSIS data set and determine if these data were nationally representative. Methods: We established data use agreements (DUAs) with EMS agencies participating in PECARN to allow for agency identification through NEMSIS. Using 2019 NEMSIS version 3.4. 0 data for EMS events with patients 18 years old and younger, we compared PECARN NEMSIS data to national NEMSIS data. Analyzed variables were selected for their ability to characterize events. No statistical analyses were utilized due to the large sample, instead, differences of ±5% were deemed clinically meaningful. Results: DUAs were established for 19 EMS agencies, creating a PECARN data set with 305,188 EMS activations of which 17,478 (5.7%) were pediatric. Of the pediatric activations, 17,140 (98.1%) were initiated through 9-1-1 and 9,487 (55.4%) resulted in transport by the documenting agency. The national data included 36,288,405 EMS activations of which 2,152,849 (5.9%) were pediatric. Of the pediatric activations 1,704,141 (79.2%) were initiated through 9-1-1 and 1,055,504 (61.9%) were transported by the documenting agency. Age and gender distributions were similar between the two groups, but the PECARN-specific data under-represents Black and Latinx patients. Comparison of EMS provider primary impressions revealed that three of the five most common were similar with injury being the most prevalent for both data sets along with mental/behavioral health and seizure. Conclusion: We demonstrated that NEMSIS can be leveraged to create network specific data sets. PECARN’s EMS data were similar to the national data, though racial/ethnic minorities and some primary impressions may be under-represented. Additionally, more EMS activations in PECARN study areas originated through 9-1-1 but fewer were transported by the documenting agency. This is likely related to the type of participating agencies, their ALS response level, and the diversity of the communities they serve.
The finer details? The predictability of life outcomes from Big Five domains, facets, and nuances.

Associations between personality traits and life outcomes are usually studied using the Big Five domains and, occasionally, their facets. But recent research suggests these associations may be driven by the items (reflecting nuances) chosen to measure these traits. Using a large dataset (N = 6,126), we examined associations with 53 self-reported outcomes using domains, facets and items (markers for nuances), training and validating models in different sample partitions. Facets better predicted outcomes than domains (on average, 18.0% vs 16.6% of variance explained), but items provided the most accurate predictions (on average 20.9%). Removing domain and facet variance from items had no effect on their predictive validity, suggesting that outcome-related information was often in items' unique variances (i.e., nuance-specific). Item-based prediction also showed the highest discriminant validity. These observations, replicating previous findings, suggest that personality traits' associations with outcomes are often driven by narrow personality nuances.
Carcinoembryonic Antigen, the Most Accessible Test for Predicting Colorectal Cancer Prognosis: Exploring Alternative Roles

A tumor marker, which is produced by cancer tissues or surrounding cells, expresses information regarding the current state of cancer. Tumor markers can be used to predict cancer malignancy, prognosis, and treatment response, which is essential for cancer treatment. In particular, given the various modalities utilized for cancer treatment, the role of tumor markers becomes critical. Notably, the accurate prediction of therapeutic effects using tumor markers allows one to measure the usefulness of the modality and make a future treatment plan. Carcinoembryonic antigen (CEA), one of the most widely used serum biomarkers for colorectal cancer, is not only easily accessible through serum but also has already been confirmed to be useful [1]. In patients with newly diagnosed colorectal cancer, elevated CEA before surgery indicates a poor prognosis. Moreover, failure of the increased CEA after surgery to normalize could indicate the possibility of residual cancer and the requirement of additional treatment. Continuous assessment of serum CEA levels after surgery can also help to detect recurrence. On the other hand, CEA has some limitations in colorectal cancer. First, the diagnostic power of CEA to detect early-stage colorectal cancer has remained low. A meta-analysis showed that CEA had a sensitivity of only 46% in colorectal cancer, as well as a specificity of 89%, which is not particularly high [2]. This raises doubts regarding the usefulness of CEA, which drives the need for identifying alternative tests for circulating DNA and bloodbased microRNAs. Nonetheless, CEA still undoubtedly remains a non-expensive and readily available approach for diagnosing colorectal cancer. However, most of the existing studies on CEA have focused on colorectal cancer surgery and chemotherapy instead of neoadjuvant chemoradiotherapy (nCRT). In advanced rectal cancer, nCRT has become an essential treatment modality that should be provided before surgery. Given that the effects of radiation appear in very diverse categories, predicting the effects of treatment remains difficult. This makes the prediction crucial for the appropriate treatment for rectal cancer. Although some studies have suggested the usefulness of CEA for predicting treatment effects after surgery with nCRT, studies on this are still lacking [3-5]. As such, more studies on this matter will certainly help clinicians establish treatment plans for rectal cancer. The present study suggests that CEA plays a particularly meaningful role in predicting prognosis after nCRT in patients with rectal cancer [6]. As discussed in the limitations of the present study, it is unfortunate that the relationship between tumor response after nCRT and CEA level could not be studied. However, the present study offers valuable insights into the treatment and follow-up of rectal cancer, notwithstanding the limitations. We believe that this alternative role of CEA in patients receiving nCRT will inspire and help many clinicians care for patients with rectal cancer.
Can placebo and nocebo effects generalize within pain modalities and across somatosensory sensations?

ABSTRACT Pain and other somatosensory sensations, such as itch, can be effectively decreased by placebo effects and increased by nocebo effects. There are indications that placebo effects on pain generalize to other sensations and that nocebo effects generalize within itch modalities. However, it has not yet been investigated whether learned effects can generalize within pain stimulus modalities or from pain to itch. Our aims were to test whether placebo and nocebo effects can generalize within pain modalities, i.e., from heat pain to pressure pain, and across somatosensory sensations with psychophysiological similarities, i.e., from heat pain to cowhage-evoked itch. For this purpose, sixty-five healthy participants were randomized to either a placebo or nocebo group. All participants firstly underwent a conditioning and verbal suggestion procedure with heat pain stimuli. Subsequently, responses to heat pain, pressure pain, and cowhage-evoked itch stimuli were tested. Results showed that altered levels of heat and pressure pain with the conditioned cue in both placebo and nocebo groups in the expected directions, but no significant difference in itch in both groups. In conclusion, placebo and nocebo effects on pain may generalize within but not across stimulus modalities. This study provides a novel perspective on the role that response generalization plays in physical symptoms.
Green coffee: economic relevance and a systematic review of the effects on human health

Abstract Coffee is probably the most popular beverage after water and is an important component in diet and health since its consumption is high worldwide. Globally, it is the most relevant food commodity being just behind crude oil. Besides its pleasant flavor, it is an antioxidant source due to polyphenols, which are protective compounds against several diseases. This study aimed to evaluate the economic relevance and perform a systematic review of green coffee’s effects on human health. Databases such as MEDLINE–PubMed, EMBASE, COCHRANE, and GOOGLE SCHOLAR were searched, and PRISMA guidelines were followed. Green coffee is considered a novel food product because consumers usually consume only roasted coffee. It can be marketed as such or as an extract. Due to the content of bioactive compounds, which are partially lost during the roasting process, the extracts are usually marketed concerning the potential regarding health effects. Green coffee can be used as dietary supplements, cosmetics, and pharmaceuticals, as a source of antioxidants. It can benefit human health, such as improvement in blood pressure, plasma lipids, and body weight (thus contributing to the improvement of risk components of Metabolic Syndrome). Moreover, benefits for cognitive functions may also be included.
Structural and interaction studies on the carboxy-terminus of filamin, an actin-binding protein

Filamins are large dimeric proteins that cross-link actin into three-dimensional bundles or orthogonal networks. In addition to an actin-binding domain, each filamin monomer contains 24 immunoglobulin-like domains separated by flexible regions between domains 15–16 and 23–24. Dimerisation of filamin occurs through the Ig-like domain 24. Filamins bind to a variety of molecules. They provide a link between the plasma membrane and the cytoskeleton through interactions with transmembrane receptors, and at the same time, serve as a platform for signalling molecules. Filamins are involved in several human diseases affecting the central nervous system, vascular system and muscle. In this study the structure of the the carboxy-terminus of filamin was resolved and details of filamins interaction with a platelet surface protein important in haemostasis were analysed. An x-ray structure of the Ig-like domain 24 of human filamin C was solved at the resolution of 1.43 Å. The asymmetric unit of the crystal contains one monomer; a crystallographic dimer is formed by 2-fold axis symmetry. Point mutation studies confirmed that the dimer seen in the crystal is also present in solution. The structure showed that the dimerisation mode of human filamin is completely different from that in the Dictyostelium discoideum amoeba filamin analogue. Human filamin dimerises through β-strands C and D, and the Dictyostelium protein through β-strands B and G located on the opposite edge of the β-sandwich. Based on the sequence homology between vertebrate filamins it was proposed that the interface seen in human filamin is common for all vertebrate filamins. The structure of human filamin C Ig-like domains 23–24 was solved by combining the techniques of x-ray crystallography and small angle x-ray scattering (SAXS). This structure provides further insight into the organization of the domains in the carboxy-terminal part of filamin molecule. One of the first structural examples of the interaction of filamin with a ligand was provided by this study. The x-ray structure of filamin A domain 17 in complex with the alpha subunit of the GPIb-VIX receptor was solved at a resolution of 2.3 Å. The interaction between filamin and the GPIbα-V-IX receptor is important for maintaining the integrity and shape of blood platelets, as well as for regulating the receptor adhesive function. This study also revealed that the Ig-like domain 17 represents a major binding site of filamin to GPIbα. The Kd of the interaction, determined by calorimetric studies, was 11 μM. The specificity of the filamin A 17 GPIbα interaction is mainly determined by hydrophobic contacts.
Crosstalk between repair pathways elicits double-strand breaks in alkylated DNA and implications for the action of temozolomide

Temozolomide (TMZ), a DNA methylating agent, is the primary chemotherapeutic drug used in glioblastoma treatment. TMZ induces mostly N-alkylation adducts (N7-methylguanine and N3-methyladenine) and some O6-methylguanine (O6mG) adducts. Current models propose that during DNA replication, thymine is incorporated across from O6mG, promoting a futile cycle of mismatch repair (MMR) that leads to DNA double-strand breaks (DSBs). To revisit the mechanism of O6mG processing, we reacted plasmid DNA with N-methyl-N-nitrosourea (MNU), a temozolomide mimic, and incubated it in Xenopus egg-derived extracts. We have shown that in this system, MMR proteins are enriched on MNU-treated DNA and we observed robust, MMR-dependent, repair synthesis. Our evidence also suggests that MMR, initiated at O6mG:C sites, is strongly stimulated in cis by repair processing of other lesions, such as N-alkylation adducts. Importantly, MNU-treated plasmids display DSBs in extracts, the frequency of which increases linearly with the square of alkylation dose. We suggest that DSBs result from two independent repair processes, one involving MMR at O6mG:C sites and the other involving base excision repair acting at a nearby N-alkylation adduct. We propose a new, replication-independent mechanism of action of TMZ, which operates in addition to the well-studied cell cycle-dependent mode of action.