Miracle-dz/UniFAR-FTUs huggingface dataset:
Tissue factor pathway inhibitor-2 is specifically expressed in ovarian clear cell carcinoma tissues in the nucleus, cytoplasm and extracellular matrix

Tissue factor pathway inhibitor-2 (TFPI-2) is a promising candidate as a serum biomarker of ovarian clear cell carcinoma (OCCC), a lethal histological subtype of epithelial ovarian cancer (EOC). TFPI-2 is a secreted serine protease inhibitor that suppresses cancer progression through the inhibition of matrix protease activities. Previous studies have also identified TFPI-2 in the nucleus, and a possible function of nuclear TFPI-2 as a transcriptional repressor of matrix metalloproteinase-2 (MMP-2) was recently demonstrated. We are currently establishing TFPI-2 as a serum biomarker for OCCC patients; however, TFPI-2 expression in OCCC tissues has not been previously investigated. In the present study, we examined TFPI-2 expression and its localization in 11 OCCC cell lines by western blotting and enzyme-linked immune assay. Four cell lines expressed TFPI-2 in the nucleus, cytoplasm and culture plate–attached extracellular fraction, while four other cell lines expressed TFPI-2 only in the extracellular fraction. In the remaining three cell lines, TFPI-2 was not identified in any fraction. The amount of secreted soluble TFPI-2 showed similar trends to that of the plate-attached fraction. We next investigated the expression levels and distribution of TFPI-2 in surgically resected EOC tissues by immunohistochemistry. In 52 of the 77 (67.5%) OCCC tumors, TFPI-2 expression was detected in at least one of the nuclear, cytoplasmic and extracellular matrix fractions. In contrast, we did not identify TFPI-2 in the other EOC subtypes (n=65). TFPI-2-positive expression distinguished CCC from the other EOC tissues with a sensitivity of 67.5% and specificity of 100%. Although the inherent tumor suppressor function, statistical analyses failed to demonstrate correlations between TFPI-2 expression and clinical parameters, including 5-year overall survival, except for the patient age. In conclusion, we identified TFPI-2 expression in the nucleus, cytoplasm and extracellular matrix in OCCC tissues. The high specificity of TFPI-2 may support its use for diagnosis of OCCC in combination with existing markers.
Dissection of the Mechanisms of Growth Inhibition Resulting from Loss of the PII Protein in the Cyanobacterium Synechococcus elongatus PCC 7942

Abstract In cyanobacteria, the PII protein (the glnB gene product) regulates a number of proteins involved in nitrogen assimilation including PipX, the coactivator of the global nitrogen regulator protein NtcA. In Synechococcus elongatus PCC 7942, construction of a PII-less mutant retaining the wild-type pipX gene is difficult because of the toxicity of uncontrolled action of PipX and the other defect(s) resulting from the loss of PIIper se, but the nature of the PipX toxicity and the PipX-independent defect(s) remains unclear. Characterization of a PipX-less glnB mutant (PD4) in this study showed that the loss of PII increases the sensitivity of PSII to ammonium. Ammonium was shown to stimulate the formation of reactive oxygen species in the mutant cells. The ammonium-sensitive growth phenotype of PD4 was rescued by the addition of an antioxidant α-tocopherol, confirming that photo-oxidative damage was the major cause of the growth defect. A targeted PII mutant retaining wild-type pipX was successfully constructed from the wild-type S. elongatus strain (SPc) in the presence of α-tocopherol. The resulting mutant (PD1X) showed an unusual chlorophyll fluorescence profile, indicating extremely slow reduction and re-oxidation of QA, which was not observed in mutants defective in both glnB and pipX. These results showed that the aberrant action of uncontrolled PipX resulted in an impairment of the electron transport reactions in both the reducing and oxidizing sides of QA.
Stroke Is Different in Systemic Lupus Erythematosus: Implications for Survival and Functionality

Undoubtedly, individuals with systemic lupus erythematosus (SLE) are at higher risk for developing cerebrovascular disease than counterparts from the general population without SLE. In a metaanalysis of studies from around the world, the likelihood of individuals with SLE developing both ischemic and hemorrhagic stroke (intracerebral and/or subarachnoid hemorrhage) was more than 2 times that of the general population1 Risks for stroke appear to be highest soon after SLE diagnosis, and concomitant antiphospholipid syndrome (APS) in these patients does not markedly exacerbate risks for ischemic stroke2.
Phenotypic Models of CAR T-Cell Activation Elucidate the Pivotal Regulatory Role of CAR Downmodulation

Adoptive cell immunotherapy with chimeric antigen receptor (CAR) showed limited potency in solid tumors, despite durable remissions for hematopoietic malignancies. Therefore, an investigation of ways to enhance the efficacy of CARs' antitumor response has been engaged upon. We previously examined the interplay between the biophysical parameters of CAR binding (i.e., affinity, avidity, and antigen density), as regulators of CAR T-cell activity and detected nonmonotonic behaviors of affinity and antigen density and an interrelation between avidity and antigen density. Here, we built an evolving phenotypic model of CAR T-cell regulation, which suggested that receptor downmodulation is a key determinant of CAR T-cell function. We verified this assumption by measuring and manipulating receptor downmodulation and intracellular signaling processes. CAR downmodulation inhibition, via actin polymerization inhibition, but not inhibition of regulatory inhibitory phosphatases, was able to increase CAR T-cell responses. In addition, we documented trogocytosis in CAR T cells that depends on actin polymerization. In summary, our study modeled the parameters that govern CAR T-cell engagement and revealed an underappreciated mechanism of T-cell regulation. These results have a potential to predict and therefore advance the rational design of CAR T cells for adoptive cell treatments. See related article on p. 872
miR-335 promotes ferroptosis by targeting ferritin heavy chain 1 in in vivo and in vitro models of Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disease characterized by the selective loss of dopaminergic neurons in the substantia nigra (SN). In a previous study, the authors demonstrated that ferritin heavy chain 1 (FTH1) inhibited ferroptosis in a model of 6-hydroxydopamine (6-OHDA)-induced PD. However, whether and how microRNAs (miRNAs/miRs) modulate FTH1 in PD ferroptosis is not yet well understood. In the present study, in vivo and in vitro models of PD induced by 6-OHDA were established. The results in vivo and in vitro revealed that the levels of the ferroptosis marker protein, glutathione peroxidase 4 (GPX4), and the PD marker protein, tyrosine hydroxylase (TH), were decreased in the model group, associated with a decreased FTH1 expression and the upregulation of miR-335. In both the in vivo and in vitro models, miR-335 mimic led to a lower FTH1 expression, exacerbated ferroptosis and an enhanced PD pathology. The luciferase 3′-untranslated region reporter results identified FTH1 as the direct target of miR-335. The silencing of FTH1 in 6-OHDA-stimulated cells enhanced the effects of miR-335 on ferroptosis and promoted PD pathology. Mechanistically, miR-335 enhanced ferroptosis through the degradation of FTH1 to increase iron release, lipid peroxidation and reactive oxygen species (ROS) accumulation, and to decrease mitochondrial membrane potential (MMP). On the whole, the findings of the present study reveal that miR-335 promotes ferroptosis by targeting FTH1 in in vitro and in vivo models of PD, providing a potential therapeutic target for the treatment of PD.
Combining apical torsional load and cyclic fatigue resistance of NiTi instruments: New approach to determine the effective lifespan of rotary instruments.

In the described proof-of-principle experiments, we introduced a novel testing device to investigate how different concurrent torsional loads influence the cyclic fatigue (CF) resistance of a nickel-titanium (NiTi) instrument. The device was designed to test CF resistance of NiTi files with a standardized load on the apical 5 mm; a movable cylinder controlled by a lever provided a uniform real-time load. Thirty-three NiTi instruments 25.04 (F360, Komet, Lemgo, Germany) were rotated until fracture at 30° curvature under three different torsional loads (n = 11 each); Group A: 2.5 Ncm; Group B: 5 Ncm; Group C: 10 Ncm. anova, multiple comparisons Tamhane tests, regression and Kaplan-Meyer analysis were performed to contrast means. Resistance to cyclic fatigue differed significantly among groups (P = 0.0001). Increased torsional loads led to a decrease in time to failure. An inverse correlation (r = -0.721, P = 0.001) was observed between time and torsional load, with higher torsional loads correlated to shorter times to fracture.
Far-infrared phonon modes of selected RNA molecules

Low-frequency phonon modes of DNA and RNA molecules can serve as a signature of their structure, flexibility and, hence, their biological function. To investigate the relationship between RNA structure and far IR absorption spectra, we performed FTIR measurements on RNA molecules with known sequence in the spectral range from 10 cm-1 to 25 cm-1 and calculated their internal vibrations. To understand which phonon modes are determined by a double helical topology of nucleic acids, we compared the spectra of single stranded and double stranded RNA molecules. Homopolymers PolyA, polyU, polyC, and polyG, and double stranded homopolymers PolyA-polyU and polyC-polyG were investigated. Theoretical conformational analysis of the double stranded RNA molecules was performed and utilized to calculate the low-frequency vibrational modes. Conformational energy was minimized in the space of internal coordinates of a molecule using standard A-helical topology as an initial approximation. Normal modes were calculated as eigenfrequencies and eigenvectors of the matrix of energy second derivatives. Oscillator strengths were calculated for all the vibrational modes in order to evaluate their weight in the absorption spectrum of a molecule. The obtained phonon modes were convoluted to derive the far IR spectrum of a molecule. These predicted spectra were compared to those obtained by FTIR spectroscopy. Our results confirm that very far IR absorption spectra of biopolymers reflect specific dynamical properties resulting from their structure and topology and, therefore, can be used as fingerprints for specific molecules.
Research priorities for oral healthcare: agenda setting from the practitioners’ perspective

Abstract Objectives The aim of this study was to develop a research agenda based on the most important information needs concerning the effects and outcomes of oral healthcare provided by oral healthcare professionals (OHPs). Methods A two-stage survey study was used to identify and prioritise topics for future research. The first survey generated topics based on information needs by OHPs. Topics were clustered thematically and overlapping topics were merged in 84 research themes. In the second survey, respondents selected their top 5 from the 84 research themes. Themes were sorted by the rank number based on rank sum. Results In the first survey, 937 topics were suggested. Almost half (n = 430, 46%) were identified as topics related to endodontology, cariology, oral medicine/surgery or tooth restoration. Topics were grouped in 84 research themes, covering 10 research domains. These were prioritised by 235 OHPs. Behaviour change for oral health and oral healthcare for geriatric patients ranked as most important. Conclusions Consultation of OHPs has resulted in a research agenda, which can be used to inform programming future oral health research. The highest prioritised research themes have an interdisciplinary nature, mainly concern oral disease prevention and are under-represented in the current oral healthcare research portfolio.
Metabolic heterogeneity and immunocompetence of infiltrating immune cells in the breast cancer microenvironment

Breast cancer is one of the most common malignancies in women and is characterized by active immunogenicity. Immune cell infiltration plays an important role in the development of breast cancer. The degree of infiltration influences both the response to and effect of treatment. However, immune infiltration is a complex process. Differences in oxygen partial pressure, blood perfusion and nutrients in the tumor microenvironment (TME) suggest that infiltrating immune cells in different sites experience different microenvironments with corresponding changes in the metabolic mode, that is, immune cell metabolism is heterogenous in the TME. Furthermore, the present review found that lipid metabolism can support the immunosuppressive microenvironment in breast cancer based on a review of published literature. Research in this field is still ongoing; however, it is vital to understand the metabolic patterns and effects of different microenvironments for antitumor therapy. Therefore, this review discusses the metabolic responses of various immune cells to different microenvironments in breast cancer and provides potentially meaningful insights for tumor immunotherapy.
Responsiveness of Outcome Measures in Nonsurgical Patients with Lumbar Spinal Stenosis

The authors assessed the responsiveness of the Self-Paced Walking Test (SPWT), Swiss Spinal Stenosis Questionnaire (SSS), and Oswestry Disability Index (ODI) in non-surgical Lumbar Spinal Stenosis (LSS) patients. They found that the SPWT, SSS, and ODI are similarly responsive in non-surgical LSS patients, being useful instruments for clinicians and researchers. Study Design. Secondary analysis from a randomized controlled trial on nonsurgical interventions for patients with lumbar spinal stenosis (LSS). Objective. The aim of this study was to assess the responsiveness of the Self-Paced Walking Test (SPWT), Swiss Spinal Stenosis Questionnaire (SSS), and Oswestry Disability Index (ODI) and determine their minimal clinically important differences (MCID) in nonsurgical LSS patients. Summary of Background Data. Limited information is available about the responsiveness of these tests in nonsurgical LSS population. Methods. A total of 180 participants completed the SPWT, SSS, and ODI at baseline, 2, and 6 months. Responsiveness was assessed by distribution-based method, including effect size and standardized response mean, and anchor-based method, using the patient global index of change (PGIC) as the external anchor to distinguish responders and non-responders. Areas under the curve (AUC) were calculated along with MCIDs for “minimal” and “moderate improvement” subgroups. Results. The following values represent 2- and 6-month analyses of each outcome measure, respectively. Standard effect sizes: 0.48 and 0.50 for SPWT, −0.42 and −0.36 for SSS, and −0.29 and −0.25 for ODI. Spearman correlation coefficients between PGIC and outcomes were: 0.44 and 0.39 for SPWT, −0.53 and −0.55 for SSS, and −0.46 and −0.54 for ODI. MCIDs for the “minimal improvement” subgroup were: 375.9 and 319.3 ms for SPWT, −5.3 and −5.8 points for SSS, and −9.3 and −10.8 points for ODI. AUCs was 0.68 to 0.76. MCIDs for the “moderate improvement” subgroup were: 344.2 and 538.2 m for SPWT, −5.5 and −7.5 points for SSS, and −9.1 and −13.6 points for ODI. AUCs ranged from 0.68 to 0.76. Conclusion. The SPWT, SSS, and ODI are responsive outcome measures to assess nonsurgical patients with LSS. This finding, along with the reported MCIDs, can help clinicians to monitor changes in their patients’ walking and physical function over time and make clinical decisions. They also provide researchers with reference for future studies in LSS. Level of Evidence: 2
Assessing sub-regional-specific strengths of healthcare systems associated with COVID-19 prevalence, deaths and recoveries in Africa

Introduction The coronavirus 2019 (COVID-19) has overwhelmed the health systems of several countries, particularly those within the African region. Notwithstanding, the relationship between health systems and the magnitude of COVID-19 in African countries have not received research attention. In this study, we investigated the relationship between the pervasiveness of the pandemic across African countries and their Global Health Security Index (GHSI) scores. Materials and methods The study included 54 countries in five regions viz Western (16); Eastern (18); Middle (8); Northern (7); and Southern (5) Africa. The outcome variables in this study were the total confirmed COVID-19 cases (per million); total recoveries (per million); and the total deaths (per million). The data were subjected to Spearman’s rank-order (Spearman’s rho) correlation to determine the monotonic relationship between each of the predictor variables and the outcome variables. The predictor variables that showed a monotonic relationship with the outcome were used to predict respective outcome variables using multiple regressions. The statistical analysis was conducted at a significance level of 0.05. Results Our results indicate that total number of COVID-19 cases (per million) has strong correlations (rs >0.5) with the median age; aged 65 older; aged 70 older; GDP per capita; number of hospital beds per thousand; Human Development Index (HDI); recoveries (per million); and the overall risk environment of a country. All these factors including the country’s commitments to improving national capacity were related to the total number of deaths (per million). Also, strong correlations existed between the total recoveries (per million) and the total number of positive cases; total deaths (per million); median age; aged 70 older; GDP per capita; the number of hospital beds (per thousand); and HDI. The fitted regression models showed strong predictive powers (R-squared>99%) of the variances in the total number of COVID-19 cases (per million); total number of deaths (per million); and the total recoveries (per million). Conclusions The findings from this study suggest that patient-level characteristics such as ageing population (i.e., 65+), poverty, underlying co-morbidities–cardiovascular disease (e.g., hypertension), and diabetes through unhealthy behaviours like smoking as well as hospital care (i.e., beds per thousand) can help explain COVID-19 confirmed cases and mortality rates in Africa. Aside from these, other determinants (e.g., population density, the ability of detection, prevention and control) also affect COVID-19 prevalence, deaths and recoveries within African countries and sub-regions.
Mucosal microRNAs relate to age and severity of disease in ulcerative colitis

Despite significant evidence that the expression of several microRNAs (miRNAs) impacts disease activity in patients with ulcerative colitis (UC), it remains unknown if the more severe disease phenotype seen in pediatric onset UC can be explained by an altered miRNA expression. In this study, we assessed the relationship between miRNA expression, age, and disease severity in pediatric and adult patients with UC. Using RT-qPCR, we analyzed the expression of miR-21, miR-31, miR-126, miR-142 and miR-155 in paraffin embedded rectum biopsies from 30 pediatric and 30 adult-onset UC patients. We found that lesions from adult patients had significantly higher expression levels of miR-21 compared to pediatric patients and that the expression levels of miR-31 (all patients) and miR-155 (pediatric patients only) correlated inversely with histological assessed disease severity. Using in situ hybridization followed by image analysis, the expression level estimates of miR-21 and miR-126 correlated with histological assessed disease severity. In conclusion, we found that the expression of miRNAs depends on the age of the patient and/or the severity of the disease, suggesting that miRNAs may contribute to the regulation of inflammation in UC and could be useful biomarkers in the surveillance of disease severity.
The novel cystatin C, lactate, interleukin-6, and N-terminal pro-B-type natriuretic peptide (CLIP)-based mortality risk score in cardiogenic shock after acute myocardial infarction.

BACKGROUND Cardiogenic shock (CS) complicating acute myocardial infarction (AMI) still reaches excessively high mortality rates. This analysis is aimed to develop a new easily applicable biomarker-based risk score. METHODS AND RESULTS A biomarker-based risk score for 30-day mortality was developed from 458 patients with CS complicating AMI included in the randomized CULPRIT-SHOCK trial. The selection of relevant predictors and the coefficient estimation for the prognostic model were performed by a penalized multivariate logistic regression analysis. Validation was performed internally, internally externally as well as externally in 163 patients with CS included in the randomized IABP-SHOCK II trial. Blood samples were obtained at randomization. The two trials are registered with ClinicalTrials.gov (NCT01927549 and NCT00491036), are closed to new participants, and follow-up is completed. Out of 58 candidate variables, the four strongest predictors for 30-day mortality were included in the CLIP score (cystatin C, lactate, interleukin-6, and N-terminal pro-B-type natriuretic peptide). The score was well calibrated and yielded high c-statistics of 0.82 [95% confidence interval (CI) 0.78-0.86] in internal validation, 0.82 (95% CI 0.75-0.89) in internal-external (temporal) validation, and 0.73 (95% CI 0.65-0.81) in external validation. Notably, it outperformed the Simplified Acute Physiology Score II and IABP-SHOCK II risk score in prognostication (0.83 vs 0.62; P < 0.001 and 0.83 vs. 0.76; P = 0.03, respectively). CONCLUSIONS A biomarker-only score for 30-day mortality risk stratification in infarct-related CS was developed, extensively validated and calibrated in a prospective cohort of contemporary patients with CS after AMI. The CLIP score outperformed other clinical scores and may be useful as an early decision tool in CS.
Superiority of Purple Okra (Abelmoschus esculentus) to Green Okra in Insulin Resistance and Pancreatic β Cell Improvement in Diabetic Rats.

INTRODUCTION Antidiabetic medicinal plants are increasingly used in the treatment of diabetes as they are generally assumed to pro-duce minimal side effects. Okra is a quercetin-containing plant which can induce pancreas regeneration and has antidiabetic effect. There has been a lot of research that demonstrate that purple okra contains more quercetin than green okra. AIM To demonstrate the advantages of purple okra over green okra on the diabetic markers improvement in diabetic rats. MATERIALS AND METHODS Fifteen male 2-month-old Wistar rats were injected intraperitoneally with 65 mg streptozotocin and 110 mg niacinamide. Their blood glucose levels were measured three days after the injection. The induction of diabetes was deemed successful if the glucose level of the rats got higher than 250 mg/dL, and then such rats were considered diabetic. The diabetic rats were divided into three groups: an acarbose group, a purple okra powder group, and a green okra powder group. The latter two were given, respectively, purple and green okra powder for 28 days. Blood serum was taken to examine the fasting blood glucose, insulin, HOMA-B and GLUT-4 levels. Pancreas was examined histologically for damage using hematoxylin eosin staining. RESULTS Fasting blood glucose, insulin, HOMA-B, and GLUT-4 levels of diabetic rats that received purple okra powder (p<0.05) were better than those of the rats that received green okra powder. The least damage (p<0.05) to pancreatic beta cells was found in the purple okra powder group. CONCLUSIONS Purple okra is superior to green okra in terms of improving the diabetic markers of rats.