Miracle-dz/UniFAR-FTUs huggingface dataset:
Integrin α10β1-Selected Mesenchymal Stem Cells Mitigate the Progression of Osteoarthritis in an Equine Talar Impact Model

Background: Early intervention with mesenchymal stem cells (MSCs) after articular trauma has the potential to limit progression of focal lesions and prevent ongoing cartilage degeneration by modulating the joint environment and/or contributing to repair. Integrin α10β1 is the main collagen type II binding receptor on chondrocytes, and MSCs that are selected for high expression of the α10 subunit have improved chondrogenic potential. The ability of α10β1-selected (integrin α10high) MSCs to protect cartilage after injury has not been investigated. Purpose: To investigate integrin α10high MSCs to prevent posttraumatic osteoarthritis in an equine model of impact-induced talar injury. Study Design: Controlled laboratory study. Methods: Focal cartilage injuries were created on the tali of horses (2-5 years, n = 8) by using an impacting device equipped to measure impact stress. Joints were treated with 20 × 106 allogenic adipose-derived α10high MSCs or saline vehicle (control) 4 days after injury. Synovial fluid was collected serially and analyzed for protein content, cell counts, markers of inflammation (prostaglandin E2, tumor necrosis factor α) and collagen homeostasis (procollagen II C-propeptide, collagen type II cleavage product), and glycosaminoglycan content. Second-look arthroscopy was performed at 6 weeks, and horses were euthanized at 6 months. Joints were imaged with radiographs and quantitative 3-T magnetic resonance imaging. Postmortem examinations were performed, and India ink was applied to the talar articular surface to identify areas of cartilage fibrillation. Synovial membrane and osteochondral histology was performed, and immunohistochemistry was used to assess type I and II collagen and lubricin. A mixed effect model with Tukey post hoc and linear contrasts or paired t tests were used, as appropriate. Results: Integrin α10high MSC-treated joints had less subchondral bone sclerosis on radiographs (P = .04) and histology (P = .006) and less cartilage fibrillation (P = .04) as compared with control joints. On gross pathology, less India ink adhered to impact sites in treated joints than in controls, which may be explained by the finding of more prominent lubricin immunostaining in treated joints. Prostaglandin E2 concentration in synovial fluid and mononuclear cell synovial infiltrate were increased in treated joints, suggesting possible immunomodulation by integrin α10high MSCs. Conclusion: Intra-articular administration of integrin α10high MSCs is safe, and evidence suggests that the cells mitigate the effects of joint trauma. Clinical Relevance: This preclinical study indicates that intra-articular therapy with integrin α10high MSCs after joint trauma may be protective against posttraumatic osteoarthritis.
The Limited Role of Glucagon for Ketogenesis During Fasting or in Response to SGLT2 Inhibition

Glucagon is classically described as a counterregulatory hormone that plays an essential role in the protection against hypoglycemia. In addition to its role in the regulation of glucose metabolism, glucagon has been described to promote ketosis in the fasted state. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) are a new class of glucose-lowering drugs that act primarily in the kidney, but some reports have described direct effects of SGLT2i on α-cells to stimulate glucagon secretion. Interestingly, SGLT2 inhibition also results in increased endogenous glucose production and ketone production, features common to glucagon action. Here, we directly test the ketogenic role of glucagon in mice, demonstrating that neither fasting- nor SGLT2i-induced ketosis is altered by interruption of glucagon signaling. Moreover, any effect of glucagon to stimulate ketogenesis is severely limited by its insulinotropic actions. Collectively, our data suggest that fasting-associated ketosis and the ketogenic effects of SGLT2 inhibitors occur almost entirely independent of glucagon.
Predictive Biomarkers for Adjuvant Capecitabine Benefit in Early-Stage Triple-Negative Breast Cancer in the FinXX Clinical Trial

Purpose: Recent studies have demonstrated a benefit of adjuvant capecitabine in early breast cancer, particularly in patients with triple-negative breast cancer (TNBC). However, TNBC is heterogeneous and more precise predictive biomarkers are needed. Experimental Design: Tumor tissues collected from TNBC patients in the FinXX trial, randomized to adjuvant anthracycline–taxane–based chemotherapy with or without capecitabine, were analyzed using a 770-gene panel targeting multiple biological mechanisms and additional 30-custom genes related to capecitabine metabolism. Hypothesis-generating exploratory analyses were performed to assess biomarker expression in relation to treatment effect using the Cox regression model and interaction tests adjusted for multiplicity. Results: One hundred eleven TNBC samples were evaluable (57 without capecitabine and 54 with capecitabine). The median follow-up was 10.2 years. Multivariate analysis showed significant improvement in recurrence-free survival (RFS) favoring capecitabine in four biologically important genes and metagenes, including cytotoxic cells [hazard ratio (HR) = 0.38; 95% confidence intervals (CI), 0.16–0.86, P-interaction = 0.01], endothelial (HR = 0.67; 95% CI, 0.20–2.22, P-interaction = 0.02), mast cells (HR = 0.78; 95% CI, 0.49–1.27, P-interaction = 0.04), and PDL2 (HR = 0.31; 95% CI, 0.12–0.81, P-interaction = 0.03). Furthermore, we identified 38 single genes that were significantly associated with capecitabine benefit, and these were dominated by immune response pathway and enzymes involved in activating capecitabine to fluorouracil, including TYMP. However, these results were not significant when adjusted for multiple testing. Conclusions: Genes and metagenes related to antitumor immunity, immune response, and capecitabine activation could identify TNBC patients who are more likely to benefit from adjuvant capecitabine. Given the reduced power to observe significant findings when correcting for multiplicity, our findings provide the basis for future hypothesis-testing validation studies on larger clinical trials.
Kinematic and kinetic variability associated with the cable put and seated rotation assessments

ABSTRACT When new protocols are developed, there is a requirement to investigate test–retest reliability of measures for valid use and interpretation of data in research and practice. Therefore, the aim of this investigation was to determine the inter-day reliability of the cable put and seated rotation assessment protocols. On three occasions, nine resistance-trained men performed cable puts and cable rotations at different loads between 6 and 42 kg on a commercially available cable cross over machine. Load stack movement was recorded using a PT5A linear position transducer from which all kinematic and kinetic variables were calculated. Reliability was excellent for peak velocity and displacement based on intraclass correlation coefficient (ICC) and coefficient of variation (CV) across the majority of loads and movements (cable put: ICC = 0.92 to 0.99, CV = 3.1% to 8.6%; cable seated rotation: ICC = 0.76 to 0.99, CV = −1.7% to 16.1%). However, kinetic variables demonstrated inadequate reliability across the majority of days, loads and movements (ICC = 0.70, CV >10%). It was concluded that peak velocity is a reliable kinematic measure to assess muscular capability from cable put and seated rotation protocols; however, kinetic measures are too variable to provide reliable outputs across testing occasions.
A potent nuclear export mechanism imposes USP16 cytoplasmic localization during interphase

ABSTRACT USP16 (also known as UBP-M) has emerged as a histone H2AK119 deubiquitylase (DUB) implicated in the regulation of chromatin-associated processes and cell cycle progression. Despite this, available evidence suggests that this DUB is also present in the cytoplasm. How the nucleo-cytoplasmic transport of USP16, and hence its function, is regulated has remained elusive. Here, we show that USP16 is predominantly cytoplasmic in all cell cycle phases. We identified the nuclear export signal (NES) responsible for maintaining USP16 in the cytoplasm. We found that USP16 is only transiently retained in the nucleus following mitosis and then rapidly exported from this compartment. We also defined a non-canonical nuclear localization signal (NLS) sequence that plays a minimal role in directing USP16 into the nucleus. We further established that this DUB does not accumulate in the nucleus following DNA damage. Instead, only enforced nuclear localization of USP16 abolishes DNA double-strand break (DSB) repair, possibly due to unrestrained DUB activity. Thus, in contrast to the prevailing view, our data indicate that USP16 is actively excluded from the nucleus and that this DUB might indirectly regulate DSB repair. This article has an associated First Person interview with the first author of the paper. Summary: USP16 is actively excluded from the nucleus and this DUB might indirectly regulate DSB repair.
African American Nurses Describe Experiences of Mistrust and Trust While in Nursing School

Abstract AIM This qualitative descriptive study is a secondary analysis of previously collected data to describe the consequences of the racial experiences of nursing school for African American students. BACKGROUND African Americans’ health outcomes are negatively influenced by racism and historic oppression. A racially integrated health care workforce can improve health outcomes, yet nursing does not attract or retain an adequate number of African American students. METHOD The sample for this qualitative descriptive study included 14 African American nurses who reflected on their nursing school experiences. RESULTS Two key paradoxical themes across the transcripts were mistrust and trust of European American faculty members. CONCLUSION While working to build trusting relationships with African American students, forge relationships over time, and serve as mentors, faculty members need to understand the impact of societal stereotypes and mistrustful behaviors (e.g., stereotyping, saying one thing and doing another, using a double standard).
Growth rate assays reveal fitness consequences of β-lactamases

Antibiotic resistance is a powerful model for studying evolutionary biology and population genetics. For the purpose of these evolutionary studies, fitness data have been approximated through susceptibility testing methods designed for clinical use in providing appropriate antibiotic therapies. An alternative approach for measuring fitness of microbes has experienced growing popularity: growth rates are a highly sensitive approach for measuring the fitness effects of antibiotics and resistance genes, but they differ from susceptibility testing in that a single concentration of antibiotic is used for the assay. Here we show that despite this key difference, the results of growth rates correlate well with clinical determination of resistance by minimum inhibitory concentration (MIC), while providing the sensitivity required for direct input as fitness values into mathematical models. This means that growth rates at a single sublethal inhibitory concentration can help us understand the fitness effects that result in clinical antibiotic resistance. By measuring the growth rates of sequenced clinical isolates obtained from Dignity Health Mercy Medical Center, we detected the fitness effects of individual resistance genes on bacteria exposed to different antibiotics. In our study, the CTX-M-15 gene conferred the highest fitness in assays with cephalosporins. These results show the strong fitness benefit conferred by CTX-M-15. Non-technical summary Antibiotic resistance is a global human health problem. We partnered with Dignity Health Mercy Medical Center to study antibiotic resistance in clinical isolates. We tested whether growth rates, a sensitive assay used to measure the fitness of bacterial samples, correlate with a clinical test to measure antibiotic resistance. We found a strong correlation between these two methods suggesting that growth rates could be reliably applied to evolutionary studies of clinically relevant problems. Moreover, the sensitivity of the growth rates assay enabled us to identify fitness effects of specific antibiotic resistance genes.
Asiaticoside Alleviates Cerebral Ischemia-Reperfusion Injury via NOD2/Mitogen-Activated Protein Kinase (MAPK)/Nuclear Factor kappa B (NF-κB) Signaling Pathway

Background Cerebral ischemia-reperfusion injury (CIRI) remains a serious health problem. Centella asiatica formulations are used to treat central nervous system disorders. In the present study, asiaticoside, an extract of the plant Centella asiatica, was investigated in CIRI in vivo and vitro. Material/Methods We made a CIRI model in vivo in SD rats treated by middle cerebral artery occlusion, and a cell model of ischemia-reperfusion injury was made in PC12 cells treated by deprivation of oxygen and glucose/restoration. CIRI in vivo was assessed by scores of neurological functions, encephaledema, and cerebral infarction area. Inflammation level and oxidative stress level were detected by the appropriate kits. TUNEL assay was performed for assessment of cell apoptosis and Western blot analysis was performed to assess protein expression levels. CCK8 assay was performed for evaluation of cell survival and flow cytometer was used to detect cell apoptosis in vitro. Results Nervous function injury, brain edema, cell apoptosis, infarct size, apoptosis-related protein expressions, and protein expressions of the NOD2/MAPK/NF-κB signaling pathway in the CIRI model were all reversed by asiaticoside in rats. The cell apoptosis, inflammation level, and oxidative stress level in the model of cerebral ischemia-reperfusion injury were reduced by asiaticoside. The effects of asiaticoside on CIRI were reversed by NOD 2 agonists. Conclusions Asiaticoside showed a protective effect against cerebral ischemia-reperfusion injury via the NOD2/MAPK/NF-κB signaling pathway. These findings are vital for future research on use of asiaticoside in CIRI, providing a new avenue for alleviating CIRI.
A clinicopathological study of oral potentially malignant disorders

Introduction: Oral cancer is the leading cause of cancer in India accounting for approximately 40% of the cancer burden. A significant number of these are preceded by precancerous lesions and conditions, together referred to as potentially malignant disorders (PMDs). It is important to screen patients for these conditions as they allow physicians to intervene early for prevention as well as early diagnosis of oral cancer. Aims: To study the demographic profile, etiology, clinical profile, and histopathology of oral PMDs. Materials and Methods: Patient evaluation was done in the outpatient department of a tertiary referral center, and those who complained of oral mucosal lesions were examined between March 2011 and March 2012. They were evaluated and treated according to their diagnosis and were observed for 1½ years, with minimum of 4 follow-ups. Results: Of the 23,380 patients who attended the outpatient department between March 2011 and March 2012, 70 (0.29% incidence) patients had oral potentially malignant lesions. Age group most commonly affected was 21–30 years (28.57%). Males were affected more than females (m = 50; f = 20). Smokeless tobacco was the most common risk factor (58.57%). Among single site lesions, buccal mucosa was most commonly affected. Based on histopathology, “leukoplakia without atypia” was the most common lesion followed by oral submucous fibrosis. Conclusions: There is a change in the trend of the age distribution of the oral potentially malignant lesions with younger generation and females being involved more and also a definite relation between tobacco-related abuses and oral lesions.
SIRT1 Decreases Emotional Pain Vulnerability with Associated CaMKIIα Deacetylation in Central Amygdala

Emotional disorders are common comorbid conditions that further exacerbate the severity and chronicity of chronic pain. However, individuals show considerable vulnerability to the development of chronic pain under similar pain conditions. Emotional disorders are common comorbid conditions that further exacerbate the severity and chronicity of chronic pain. However, individuals show considerable vulnerability to the development of chronic pain under similar pain conditions. In this study on male rat and mouse models of chronic neuropathic pain, we identify the histone deacetylase Sirtuin 1 (SIRT1) in central amygdala as a key epigenetic regulator that controls the development of comorbid emotional disorders underlying the individual vulnerability to chronic pain. We found that animals that were vulnerable to developing behaviors of anxiety and depression under the pain condition displayed reduced SIRT1 protein levels in central amygdala, but not those animals resistant to the emotional disorders. Viral overexpression of local SIRT1 reversed this vulnerability, but viral knockdown of local SIRT1 mimicked the pain effect, eliciting the pain vulnerability in pain-free animals. The SIRT1 action was associated with CaMKIIα downregulation and deacetylation of histone H3 lysine 9 at the CaMKIIα promoter. These results suggest that, by transcriptional repression of CaMKIIα in central amygdala, SIRT1 functions to guard against the emotional pain vulnerability under chronic pain conditions. This study indicates that SIRT1 may serve as a potential therapeutic molecule for individualized treatment of chronic pain with vulnerable emotional disorders. SIGNIFICANCE STATEMENT Chronic pain is a prevalent neurological disease with no effective treatment at present. Pain patients display considerably variable vulnerability to developing chronic pain, indicating individual-based molecular mechanisms underlying the pain vulnerability, which is hardly addressed in current preclinical research. In this study, we have identified the histone deacetylase Sirtuin 1 (SIRT1) as a key regulator that controls this pain vulnerability. This study reveals that the SIRT1–CaMKIIaα pathway in central amygdala acts as an epigenetic mechanism that guards against the development of comorbid emotional disorders under chronic pain, and that its dysfunction causes increased vulnerability to the development of chronic pain. These findings suggest that SIRT1 activators may be used in a novel therapeutic approach for individual-based treatment of chronic pain.
Mating Attributes Relating to Parasitization and Productivity in Habrobracon hebetor (Hymenoptera: Braconidae) Rearing on Host Indian Meal Moth (Lepidoptera: Pyralidae)

Abstract The mating attributes in relating to parasitism and progeny production capacity of the parasitoid Habrobracon hebetor Say, using Plodia interpunctella (Hübner) as a host, were investigated in laboratory studies. The results indicated that 100% of the host larvae were parasitized by different individuals of H. hebetor females that were mated by the same male. Mating duration did not differ significantly among different successive matings with different females and had no effect on the rate of parasitism. In general, pairs that had their copulation early after emergence exhibited the maximum rate of parasitism as compared to delayed intervals. Moreover, the age of the H. hebetor females had no effect on the percentage of parasitism. The maximum parasitism percentage was recorded for the H. hebetor individuals that had been developed from the age group of the 6-d-old adults. The male: female ratios did not differ significantly among the female age groups. The percentage of parasitism clearly indicated a decrease with the increase of the male: female ratio. Overall, the results of the present work can be further utilized in mass rearing and release of H. hebetor in biological control programs in stored product protection.
Pregnancy outcomes in women with epilepsy using lamotrigine

Objective: The purpose of this study was to investigate pregnancy outcomes in women with epilepsy using lamotrigine (LTG). Methods: We retrospectively reviewed the medical records of all patients who had been diagnosed as epilepsy and gave live singleton births in Yonsei University Health System, Seoul, Korea, between February 1996 and December 2007. Nine patients who were not taking antiepileptic drugs (AEDs) were excluded from this study. We subdivided the enrolled patients into 2 groups; patients exposed to LTG and others exposed to other AEDs. Congenital malformation, spontaneous abortion, small for gestational age, termination of pregnancy, intrauterine fetal death, preterm delivery, and adverse maternal outcomes were documented to evaluate the pregnancy outcomes. The statistical significance was defined as P
Gefitinib and Afatinib Show Potential Efficacy for Fanconi Anemia–Related Head and Neck Cancer

Purpose: Fanconi anemia rare disease is characterized by bone marrow failure and a high predisposition to solid tumors, especially head and neck squamous cell carcinoma (HNSCC). Patients with Fanconi anemia with HNSCC are not eligible for conventional therapies due to high toxicity in healthy cells, predominantly hematotoxicity, and the only treatment currently available is surgical resection. In this work, we searched and validated two already approved drugs as new potential therapies for HNSCC in patients with Fanconi anemia. Experimental Design: We conducted a high-content screening of 3,802 drugs in a FANCA-deficient tumor cell line to identify nongenotoxic drugs with cytotoxic/cytostatic activity. The best candidates were further studied in vitro and in vivo for efficacy and safety. Results: Several FDA/European Medicines Agency (EMA)-approved anticancer drugs showed cancer-specific lethality or cell growth inhibition in Fanconi anemia HNSCC cell lines. The two best candidates, gefitinib and afatinib, EGFR inhibitors approved for non–small cell lung cancer (NSCLC), displayed nontumor/tumor IC50 ratios of approximately 400 and approximately 100 times, respectively. Neither gefitinib nor afatinib activated the Fanconi anemia signaling pathway or induced chromosomal fragility in Fanconi anemia cell lines. Importantly, both drugs inhibited tumor growth in xenograft experiments in immunodeficient mice using two Fanconi anemia patient–derived HNSCCs. Finally, in vivo toxicity studies in Fanca-deficient mice showed that administration of gefitinib or afatinib was well-tolerated, displayed manageable side effects, no toxicity to bone marrow progenitors, and did not alter any hematologic parameters. Conclusions: Our data present a complete preclinical analysis and promising therapeutic line of the first FDA/EMA-approved anticancer drugs exerting cancer-specific toxicity for HNSCC in patients with Fanconi anemia.