Miracle-dz/UniFAR-FTUs huggingface dataset:
Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitor

No approved therapy exists for cancer‐associated cachexia. The colon‐26 mouse model of cancer cachexia mimics recent late‐stage clinical failures of anabolic anti‐cachexia therapy and was unresponsive to anabolic doses of diverse androgens, including the selective androgen receptor modulator (SARM) GTx‐024. The histone deacetylase inhibitor (HDACi) AR‐42 exhibited anti‐cachectic activity in this model. We explored combined SARM/AR‐42 therapy as an improved anti‐cachectic treatment paradigm. A reduced dose of AR‐42 provided limited anti‐cachectic benefits, but, in combination with GTx‐024, significantly improved body weight, hindlimb muscle mass, and grip strength versus controls. AR‐42 suppressed the IL‐6/GP130/STAT3 signaling axis in muscle without impacting circulating cytokines. GTx‐024‐mediated β‐catenin target gene regulation was apparent in cachectic mice only when combined with AR‐42. Our data suggest cachectic signaling in this model involves catabolic signaling insensitive to anabolic GTx‐024 therapy and a blockade of GTx‐024‐mediated anabolic signaling. AR‐42 mitigates catabolic gene activation and restores anabolic responsiveness to GTx‐024. Combining GTx‐024, a clinically established anabolic therapy, with AR‐42, a clinically evaluated HDACi, represents a promising approach to improve anabolic response in cachectic patients.
Endothelial Immune Activation by Medin: Potential Role in Cerebrovascular Disease and Reversal by Monosialoganglioside‐Containing Nanoliposomes

Background The function of medin, one of the most common human amyloid proteins that accumulates in the vasculature with aging, remains unknown. We aim to probe medin's role in cerebrovascular disease by comparing cerebral arterial medin content between cognitively normal and vascular dementia (VaD) patients and studying its effects on endothelial cell (EC) immune activation and neuroinflammation. We also tested whether monosialoganglioside‐containing nanoliposomes could reverse medin's adverse effects. Methods and Results Cerebral artery medin and astrocyte activation were measured and compared between VaD and cognitively normal elderly brain donors. ECs were exposed to physiologic dose of medin (5 μmol/L), and viability and immune activation (interleukin‐8, interleukin‐6, intercellular adhesion molecule‐1, and plasminogen activator inhibitor‐1) were measured without or with monosialoganglioside‐containing nanoliposomes (300 μg/mL). Astrocytes were exposed to vehicle, medin, medin‐treated ECs, or their conditioned media, and interleukin‐8 production was compared. Cerebral collateral arterial and parenchymal arteriole medin, white matter lesion scores, and astrocyte activation were higher in VaD versus cognitively normal donors. Medin induced EC immune activation (increased interleukin‐8, interleukin‐6, intercellular adhesion molecule‐1, and plasminogen activator inhibitor‐1) and reduced EC viability, which were reversed by monosialoganglioside‐containing nanoliposomes. Interleukin‐8 production was augmented when astrocytes were exposed to medin‐treated ECs or their conditioned media. Conclusions Cerebral arterial medin is higher in VaD compared with cognitively normal patients. Medin induces EC immune activation that modulates astrocyte activation, and its effects are reversed by monosialoganglioside‐containing nanoliposomes. Medin is a candidate novel risk factor for aging‐related cerebrovascular disease and VaD.
Use of autologous platelet-rich plasma in healing skin graft donor sites.

OBJECTIVE To demonstrate that the use of platelet-rich plasma (PRP) enhances both the quality of healing and the time required for wound healing at a skin graft donor site. METHODS Patients who had dermo-epidermal skin grafts taken from the thigh area were included in a prospective, randomised clinical study. PRP was applied to one donor site and then covered with Vaseline-impregnated, open-weave gauze and gauze, while the contralateral donor site on the other thigh served as a control and was covered with the open-weave gauze and gauze without PRP. RESULTS A total of 24 patients took part in the study, of which three developed infections and were thus removed from the study. Use of PRP reduced the wound healing time of the dermo-epidermal graft donor sites by a mean 17.8% and median 18 days. On average, the treated donor sites healed in 14.9 days compared with 18.4 days for the control group. The median was 14 days compared with 18 days in the control group (p=0.026). In one patient, healing was slower on the side where PRP was applied. In 20 patients, healing of the donor site was accelerated where PRP was applied. CONCLUSION The study demonstrated a beneficial effect of PRP, as healing time was shortened. Using PRP to heal wounds could be beneficial for patients for whom commonly available wound healing therapies have failed, as well as for high-risk patient groups for whom problematic wound healing may be expected.
Detection of a High Ratio of Soluble to Membrane‐Bound LOX‐1 in Aspirated Coronary Thrombi From Patients With ST‐Segment–Elevation Myocardial Infarction

Background The circulating level of soluble lectin‐like oxidized low‐density lipoprotein receptor‐1 (sLOX‐1) is a valuable biomarker of acute myocardial infarction (AMI). The most electronegative low‐density lipoprotein, L5, signals through LOX‐1 to trigger atherogenesis. We examined the characteristics of LOX‐1 and the role of L5 in aspirated coronary thrombi of AMI patients. Methods and Results Intracoronary thrombi were aspirated by performing interventional thrombosuction in patients with ST‐segment–elevation myocardial infarction (STEMI; n=32) or non–ST‐segment–elevation myocardial infarction (n=12). LOX‐1 level and the ratio of sLOX‐1 to membrane‐bound LOX‐1 were higher in thrombi of STEMI patients than in those of non–ST‐segment–elevation myocardial infarction patients. In all aspirated thrombi, LOX‐1 colocalized with apoB100. When we explored the role of L5 in AMI, deconvolution microscopy showed that particles of L5 but not L1 (the least electronegative low‐density lipoprotein) quickly formed aggregates prone to retention in thrombi. Treating human monocytic THP‐1 cells with L5 or L1 showed that L5 induced cellular adhesion and promoted the differentiation of monocytes into macrophages in a dose‐dependent manner. In a second cohort of AMI patients, the L5 percentage and plasma concentration of sLOX‐1 were higher in STEMI patients (n=33) than in non–ST‐segment–elevation myocardial infarction patients (n=25), and sLOX‐1 level positively correlated with L5 level in AMI patients. Conclusions The level of LOX‐1 and the ratio of sLOX‐1 to membrane‐bound LOX‐1 in aspirated thrombi, as well as the circulating level of sLOX‐1 were higher in STEMI patients than in non–ST‐segment–elevation myocardial infarction patients. L5 may play a role in releasing a high level of sLOX‐1 into the circulation of STEMI patients.
Correlation between Health-Related Quality of Life and Hand Grip Strength among Older Adults

ABSTRACT Background: With advanced age, the progressive loss of muscle strength estimated by the handgrip strength (HGS) may result in a poorer health-related quality of life (HRQoL). Studying this association becomes a vital area of research for promoting aging-well. The aim of this study was to examine the correlation between HRQoL and HGS among community-dwelling older adults above 60 years old. Methods: Participants comprised of 176 older adults (mean age: 68.15 ± 6.74). The HGS was tested with Jamar® Dynamometer, and the EuroQuol-5 Dimensions 5Levels (EQ-5D-5L) questionnaire was used to assess HRQoL. Results: Both HGS and HRQoL were negatively correlated with age (p < .001). Lower values of HGS and HRQoL were recorded among older adults who had diagnosed with one or more chronic diseases (p < .001). Significant correlations were recorded between HGS and functioning, and subjective well-being domains of EQ-5D-5L. A relatively higher association was recorded between the functioning variables of EQ-5D-5L and HGS compared to subjective well- being variables. Conclusion: Handgrip strength is a simple and practical measure in identifying older adults at risk of physical decline. Maintaining handgrip strength may contribute to improving HRQoL, and can add an imperative dimension to promote aging-well in older adults ≥60 years old.
Metabolite‐based genome‐wide association study enables dissection of the flavonoid decoration pathway of wheat kernels

Summary The marriage of metabolomic approaches with genetic design has proven a powerful tool in dissecting diversity in the metabolome and has additionally enhanced our understanding of complex traits. That said, such studies have rarely been carried out in wheat. In this study, we detected 805 metabolites from wheat kernels and profiled their relative contents among 182 wheat accessions, conducting a metabolite‐based genome‐wide association study (mGWAS) utilizing 14 646 previously described polymorphic SNP markers. A total of 1098 mGWAS associations were detected with large effects, within which 26 candidate genes were tentatively designated for 42 loci. Enzymatic assay of two candidates indicated they could catalyse glucosylation and subsequent malonylation of various flavonoids and thereby the major flavonoid decoration pathway of wheat kernel was dissected. Moreover, numerous high‐confidence genes associated with metabolite contents have been provided, as well as more subdivided metabolite networks which are yet to be explored within our data. These combined efforts presented the first step towards realizing metabolomics‐associated breeding of wheat.
Redefining migraine phases – a suggestion based on clinical, physiological, and functional imaging evidence

Migraine is defined by attacks of headache with a specific length and associated symptoms such as photophobia, phonophobia and nausea. It is long recognized that migraine is more than just the attacks and that migraine should be understood as a cycling brain disorder with at least 4 phases: interictal, preictal, ictal and postictal. However, unlike the pain phase, the other phases are less well defined, which renders studies focusing on these phases susceptible to bias. We herewith review the available clinical, electrophysiological, and neuroimaging data and propose that the preictal phase should be defined as up to 48 hours before the headache attack and the postictal phase as up to 24 hours following the ictal phase. This would allow future studies to specifically investigate these migraine phases and to make study results more comparable.
A Social Ties-based Approach to Breast Cancer Patients’ Quality of Life: Examining Group Ties and Individual Ties across Offline and Online Settings

ABSTRACT Supportive social ties positively impact cancer patients’ health; however, little is known about the intertwined links between both offline and online ties, and individual and group ties. Using the common-identity/common-bond approach, we empirically tested the critical difference that individual and group ties exert on health across offline and online settings. Results from 356 female breast cancer patients showed group ties affect quality of life through sequential group identification and social support, while individual ties affect quality of life through sequential interpersonal bonds and social support. Offline group and online individual ties are stronger predictors of quality of life than online group and offline individual ties. A cluster analysis categorized participants into four distinguishable segments. People with stronger offline interpersonal bonds and online group identification reported a better quality of life. This offers insight into the social dynamics that are most consequential for health, and the potential theoretical pathways through which they operate.
Spinal astrocytic FGFR3 activation leads to mechanical hypersensitivity by increased TNF-α in spared nerve injury.

BACKGROUND Accumulated studies indicated a crucial role of astrocytes in neuropathic pain (NPP) development, spread and potentiation by a communication with the nervous system. Increased GFAP expression in dorsal horn of the spinal cord indicated the participation of astrocyte in NPP. However, the underlying mechanism is still in need of further investigations. METHODS In our study, the spared nerve injury (SNI) model was established with partial sciatic nerve ligation. The expression status of FGFR3 was studied in spinal dorsal horn of SNI models. The molecular mechanism of spinal astrocytic FGFR3 activation in mechanical hypersensitivity was investigated. RESULTS SNI rats showed with hind paw mechanical hypersensitivity and increased GFAP expression in their spinal cords. Increased FGFR3 expression was observed in spinal dorsal horn of SNI models, which was consistent with increased GFAP expression. Elevated FGFR3 upregulates GFAP and TNF-α expression in astrocytes in vivo and in vitro. FGFR3 inhibition by PD173074 lead to downregulation of GFAP and TNF-α and increased withdrawal threshold of SNI models. Mechanically, FGFR3-TBX3 axis activation enhanced TNF-α expression in cultured primary spinal astrocytes. Spinal TNF-α synthesis induced mechanical hypersensitivity in SNI rat models. CONCLUSION FGFR3 is involved in NPP maintenance via FGFR3-TBX3 axis activation induced TNF-α synthesis. FGFR3 and correlated signaling pathways of astrocytes are potential molecular targets for NPP administration.
Antileishmanial activity of Urtica dioica extract against zoonotic cutaneous leishmaniasis

Background Neglected parasitic diseases (NTDs) like cutaneous leishmaniasis (CL) have caused high mortality and morbidity rate in developing countries. This disease is considered as one of the six major tropical diseases, and has a great importance in HIV infected individuals as an opportunistic infection in those areas that both infections are endemic. This study evaluated the therapeutic effects of the Urtica dioica L (U. dioica) aqueous extract as an anti-leishmanial herbal drug in-vitro and in-vivo, and in addition to that, evaluated two vital immune system cytokines including gamma interferon (IFN-γ) and interleukin-4 (IL-4) plus nitric oxide (NO) and arginase activity against Leishmania major (L. major) infected mice. Methodology/Principal findings In-vitro anti-leishmanial activity of U. dioica aqueous extract was determined using MTT method and also Parasite Rescue Transformation Assay. Also, the footpad lesion size and parasite load in BALB/c mice infected with L. major were quantified for in-vivo assessment. Furthermore, for evaluating the immune responses, the levels of IFN-γ, IL-4, NO and arginase were measured in the BALB/c mice. These results indicated that U. dioica extract significantly reduced the L. major promastigotes viability. According to the in-vitro cytotoxicity assay of the extract on Leishmania parasites (CC50) and infected macrophages (EC50), the extract had no toxicity to the macrophages, however it efficiently killed the L. major amastigotes. In addition, the lesion size, parasite load, IL-4, and ARG were decreased in the treated infected mice, however IFN-γ and NO were significantly increased. Conclusions/Significance This study established satisfactory results in Leishmania parasite clearing both in-vivo and in-vitro. Therefore, U. dioica extract can be considered as an effective and harmless herbal compound for killing the parasite without toxicity to the host macrophages. Furthermore, it also can treat the CL by switching the mouse immune response towards a cell-mediated response (Th1); hence, it may be identified as a perfect therapeutic herbal drug for CL treatment.
First-trimester screening for fetal growth restriction using Doppler color flow analysis of the uterine artery and serum PAPP-A levels in unselected pregnancies

Abstract Purpose To explore an early diagnostic model for fetal growth restriction (FGR) at 11–13 (+6 days) gestational weeks using Doppler analysis of the uterine artery and measurements of pregnancy-associated plasma protein-A (PAPP-A). Methods This was a prospective study which included 1796 singleton pregnant women, who received routine pregnancy examination at 11–13 (+6 days) gestational weeks in Shanghai Changning Maternity and Infant Health Hospital between 1 June 2017 and 31 July 2018. Uterine artery pulsatility index (PI), uterine resistance index (RI), and notching were recorded using the Doppler ultrasound detector (Voluson E8; GE Healthcare, Kretztechnik, Zipf, Austria). Maternal serum PAPP-A was assayed using time-resolved fluorescence immunoassay (Perkin-Elmer Life Sciences, Waltham, MA, USA) and analyzed using Fetal Medicine Foundation software. Maternal and neonatal outcomes were followed. Results Out of 1796 pregnant women aged 18–42 years, 76 (4.2%) mothers had FGR fetus. In the FGR fetuses, the mean uterine artery PI and RI were higher, the PAPP-A levels were 0.42-fold lower (all p values < .05), and notching was 40% higher (p < .0001) than in non-FGR fetuses. The sensitivity and specificity of early diagnosis of FGR and the area under the curve for the combination of uterine artery PI and PAPP-A were 0.788 (95% CI: 0.735, 0.842), 0.816, and 0.758, respectively. A combination of PAPP-A and Doppler analysis of uterine artery was better than individual measurements for predicting FGR (all p values < .05), and the specificity was significantly improved after including serum PAPP-A. Conclusion The combination of uterine artery PI and PAPP-A measured at 11–13 (+6 days) gestational weeks provides a sensitive and specific predictor for early diagnosis of FGR.
Effects of the recurrence pattern on patient survival following SABR for stage I lung cancer

Abstract Background: Information on the effect of the recurrence pattern on survival for stage I lung cancer following stereotactic ablative radiotherapy (SABR) is limited. Materials and Methods: The recurrence pattern was analyzed for 100 consecutive stage I non-small-cell lung cancer patients treated with SABR using predominantly 12 Gy × 4. Recurrences were classified as local, regional lymph nodes and distant. Distant recurrences included recurrences in the lung and outside the chest. Single lung recurrences were named solitary, if no other location was involved. Kaplan–Meier survival estimates were calculated for different locations of recurrence. Clinical and dosimetrical factors affecting survival were also analyzed. Results: Median follow-up was 32 months (3–123), median age 70 years (49–95). In total, 31 patients had recurrences after a median 21 months (4–60): 5 local; 10 regional; 8 distant outside the chest; 25 non-local lung recurrences, of which 15 were single – 10 of which solitary – and 10 multiple lung nodules. Patients with a solitary lung recurrence had longer survival compared to local or distant recurrences (p = .04 each), and compared to multiple lung nodules (p = .09). 3-year local recurrence-free survival was 92%, disease-free survival 69% and overall survival 59%. On multivariate analysis, disease-free survival was associated with statin use (p = .038) and tumor location (p = .035). Smoking history predicted overall survival (p < .0006). Conclusions: A total of 81% of recurrences involved the lungs. Patients with solitary lung recurrences/second primary lung cancers had the longest overall survival suggesting definitive treatment should be considered. The effects of statin use need to be explored further.
The experiences of Dutch fathers on fathering children with disabilities: 'Hey, that is a father and his daughter, that is it'.

BACKGROUND Due to a predominant focus on mothers, fathers of children with disabilities are greatly overlooked in research. One could argue that there is a lack of research on the multifaceted nature of fatherhood altogether. Therefore, this study aims to gain insight into the perceived experiences of fathers of children with disabilities. METHODS These perceptions were studied by analysing data generated through semi-structured interviews, which were conducted with 12 Dutch fathers of children or young adults with disabilities. RESULTS Categories found during our data analysis were similar to those illustrated in the 'conceptual framework on responsible fathering' by including role identification, commitment, employment characteristics, cultural expectations and social support. CONCLUSIONS Overall, the fathers in this study reported similar experiences, but this study identified new life perspective as an additional category, which might be specific for fathers of children with disabilities. This new life perspective included a positive attitude, living in the moment, appreciation of the little things and transformation of expectations. Some fathers expressed that their child(ren) has enriched their lives, which positively influenced their fathering experience.
Resting-state brain network properties mediate the association between the oxytocin receptor gene and interdependence

ABSTRACT While an increasing number of behavioral findings have provided gene-culture coevolution accounts of human development, whether and how the brain mediates gene-culture associations remain unresolved. Based on the Culture-Behavior-Brain-Loop Model and the recent finding of associations between the oxytocin receptor gene (OXTR, rs53576) and a cultural trait (i.e., interdependence) across populations, we tested the hypothesis that resting-state brain network properties mediate the relationship between OXTR rs53576 and interdependence. G and A allele carriers of OXTR rs53576 were scanned during a resting state using functional magnetic resonance imaging (fMRI) and completed questionnaires to estimate their interdependence cultural values. We identified significant genotype effects on the local network metrics of the right hippocampus and its functional connectivity with the medial prefrontal cortex, dorsal anterior cingulate cortex, amygdala, basal ganglia and thalamus. The local network metrics of the right hippocampus and its functional connectivity with the basal ganglia and thalamus were correlated with interdependence. Moreover, both the degree of the right hippocampus and its functional connectivity with the basal ganglia and thalamus mediated the relationship between OXTR and interdependence. Our results provide brain imaging evidence for a key function of the brain in mediating the relationship between genes and culture.