Miracle-dz/UniFAR-FTUs huggingface dataset:
Tissue‐engineered trachea from a 3D‐printed scaffold enhances whole‐segment tracheal repair in a goat model

Traditional treatment therapies for tracheal stenosis often cause severe post‐operative complications. To solve the current difficulties, novel and more suitable long‐term treatments are needed. A whole‐segment tissue‐engineered trachea (TET) representing the native goat trachea was 3D printed using a poly(caprolactone) (PCL) scaffold engineered with autologous auricular cartilage cells. The TET underwent mechanical analysis followed by in vivo implantations in order to evaluate the clinical feasibility and potential. The 3D‐printed scaffolds were successfully cellularized, as observed by scanning electron microscopy. Mechanical force compression studies revealed that both PCL scaffolds and TETs have a more robust compressive strength than does the native trachea. In vivo implantation of TETs in the experimental group resulted in significantly higher mean post‐operative survival times, 65.00 ± 24.01 days (n = 5), when compared with the control group, which received autologous trachea grafts, 17.60 ± 3.51 days (n = 5). Although tracheal narrowing was confirmed by bronchoscopy and computed tomography examination in the experimental group, tissue necrosis was only observed in the control group. Furthermore, an encouraging epithelial‐like tissue formation was observed in the TETs after transplantation. This large animal study provides potential preclinical evidence around the employment of an orthotopic transplantation of a whole 3D‐printed TET.
Nutlin-3-induced Sensitization of Non-Small Cell Lung Cancer Stem Cells to Axitinib-Induced Apoptosis through Repression of Akt1/Wnt Signaling.

To investigate the potential biological activities of nutlin-3 (N-3) in the regulation of growth and proliferation of non-small cell lung cancer (NSCLC)stem cells (CSCs), which may help in sensitizing to axitinib-induced apoptosis. N-3 induction of p53 expression was used to test its role in controlling the cell division pattern and apoptosis of NSCLC cells. A549 cells and H460 cells were pretreated with N-3 and then treated with either an Akt1 activator or shRNA-GSK3β, to investigate the potential role of p53 sensitization in the biological effects of axitinib. We also determined the expression levels of GSK3β and p-Akt1 in patients with NSCLC and determined their potential association with survival data using Kaplan-Meier plots and CBIOTAL. Increased p53 expression stimulated the induction of apoptosis by axitinib and promoted asymmetric cell division (ACD) of NSCLC CSCs. The repression of Akt phosphorylation induced by N-3 promoted the ACD of lung CSCs, decreasing the proportion of the stem cell population. In addition to the induction of apoptosis by axitinib through inhibition of Wnt signaling, N-3 treatment further enhanced axitinib-induced apoptosis by inhibiting Akt1/GSK3β/Wnt signaling. The low expression of GSK3β and increased expression of p-Akt in patients with NSCLC were closely associated with the development of NSCLC. TP53 stimulates the induction of apoptosis in NSCLC by axitinib and the ACD of lung CSCs through its regulatory effects on the p53/Akt/ GSK3β pathways.
Ocular dysfunctions and toxicities induced by antiepileptic medications: Types, pathogenic mechanisms, and treatment strategies

ABSTRACT Introduction: Ocular dysfunctions and toxicities induced by antiepileptic drugs (AEDs) are rarely reviewed and not frequently received attention by treating physicians compared to other adverse effects (e.g. endocrinologic, cognitive and metabolic). However, some are frequent and progressive even in therapeutic concentrations or result in permanent blindness. Although some adverse effects are non-specific, others are related to the specific pharmacodynamics of the drug. Areas covered: This review was written after detailed search in PubMed, EMBASE, ISI web, SciELO, Scopus, and Cochrane Central Register databases (from 1970 to 2019). It summarized the reported ophthalmologic adverse effects of the currently available AEDs; their risks and possible pathogenic mechanisms. They include ocular motility dysfunctions, retinopathy, maculopathy, glaucoma, myopia, optic neuropathy, and impaired retinal vascular autoregulation. In general, ophthalmo-neuro- or retino-toxic adverse effects of AEDs are classified as type A (dose-dependent), type B (host-dependent or idiosyncratic) or type C which is due to the cumulative effect from long-term use. Expert opinion: Ocular adverse effects of AEDs are rarely reviewed although some are frequent or may result in permanent blindness. Increasing knowledge of their incidence and improving understanding of their risks and pathogenic mechanisms are crucial for monitoring, prevention, and management of patients’ at risk.
Push Dose Epinephrine Use in the Management of Hypotension During Critical Care Transport

Abstract Introduction: Hypotension is a critical event during the transport of critically ill patients. Push dose vasopressor use, though widely adopted by anesthesiologists, has only recently found use in the field of emergency medicine and may have utility in the management of out-of-hospital hypotension. This study aimed to characterize the hemodynamic effects and adverse events that occur following push dose epinephrine (PDE) administration by critical care transport (CCT) providers to correct documented hypotension. Methods: We performed a retrospective observational study of patients transported by a regional critical care transport service and who received PDE during transport to correct documented hypotension. Per protocol, 10–20 µg of 1:100,000 epinephrine was given intravenously every 2 min until: (1) the systolic blood pressure (SBP) was at least 90 mmHg, or (2) the mean arterial pressure (MAP) was 65 mmHg or greater. All patients were over 18 years of age and were transported between January 1, 2015 and December 31, 2016. Primary outcomes of interest were the primary diagnoses associated with PDE use, hemodynamic outcomes of the intervention, and adverse events. Results: During the study period 100 doses of push dose epinephrine were given during the transport of 58 patients. Of these, 94 (94.0%) were found to be appropriately dosed and indicated per protocol. The most common diagnoses associated with PDE use were: post-cardiac arrest (n = 24), sepsis (n = 9), altered mental status (n = 7), and cardiogenic shock (n = 3). The median increase in MAP across all doses was 13.0 (5.0–34.0) mmHg, and the heart rate increase was 2.0 (−1.0–9.3) beats per minute. Hypotension was resolved in 55 of 94 instances (58.5%). A single episode of transient extreme hypertension occurred after one PDE dose and did not result in patient harm. Conclusions: Push dose epinephrine may be an effective method of temporarily resolving hypotension during the CCT of critically ill patients. In the cases where PDE was administered, there was close adherence to the established protocol and adverse events were found to be rare directly following PDE administration. Further research is needed to validate these findings, establish optimal dosing, and evaluate use in non-CCT prehospital settings.
Real-time automatic detection system increases colonoscopic polyp and adenoma detection rates: a prospective randomised controlled study

Objective The effect of colonoscopy on colorectal cancer mortality is limited by several factors, among them a certain miss rate, leading to limited adenoma detection rates (ADRs). We investigated the effect of an automatic polyp detection system based on deep learning on polyp detection rate and ADR. Design In an open, non-blinded trial, consecutive patients were prospectively randomised to undergo diagnostic colonoscopy with or without assistance of a real-time automatic polyp detection system providing a simultaneous visual notice and sound alarm on polyp detection. The primary outcome was ADR. Results Of 1058 patients included, 536 were randomised to standard colonoscopy, and 522 were randomised to colonoscopy with computer-aided diagnosis. The artificial intelligence (AI) system significantly increased ADR (29.1%vs20.3%, p<0.001) and the mean number of adenomas per patient (0.53vs0.31, p<0.001). This was due to a higher number of diminutive adenomas found (185vs102; p<0.001), while there was no statistical difference in larger adenomas (77vs58, p=0.075). In addition, the number of hyperplastic polyps was also significantly increased (114vs52, p<0.001). Conclusions In a low prevalent ADR population, an automatic polyp detection system during colonoscopy resulted in a significant increase in the number of diminutive adenomas detected, as well as an increase in the rate of hyperplastic polyps. The cost–benefit ratio of such effects has to be determined further. Trial registration number ChiCTR-DDD-17012221; Results.
Depression and resilience in ulcerative colitis and Crohn's disease patients with ostomy

The purpose of this study is to identify the degree of depression and resilience in ulcerative colitis (UC) and Crohn's disease (CD) patients with ostomy and describe the correlation between depression and resilience in UC and CD patients with ostomy. 24 UC patients and 66 CD patients with ostomy were recruited from Metropolitan Hospital in Seoul, Korea. The total mean scores of depression and resilience in UC patients were 13.42 and 123.75, respectively, and in CD patients with ostomy they were 14.24 and 119.18, respectively. Depression and resilience in UC patients with ostomy were not correlated with general characteristics. Depression in CD patients with ostomy correlated with marital status (t = 2.27, P = 0.027), economic status (F = 3.98, P = 0.012), sleep disorder (t = 4.73, P < 0.001), and sleep time (t = 2.11, P = 0.039). Resilience in UC patients with ostomy correlated with religion (t = 2.47, P = 0.016), marital status (t = −3.61, P = 0.001), economic status (F = 4.06, P = 0.011), and sleep disorder (t = −3.11, P = 0.003). Significant negative correlation was found between depression and resilience in UC (r = −0.668, P < 0.001) and CD patients with ostomy (r = −0.604, P < 0.001). We recommend counselling to wound ostomy continence nurses (WOCNs) about their goal setting, facilitating adaptation of disease and ostomy in clinical setting. And we expect that WOCNs adopt a formalised and tailored long‐term approach or program to follow up for UC and CD patients with ostomy.
High Orotate Phosphoribosyltransferase Gene Expression Predicts Complete Response to Chemoradiotherapy in Patients with Squamous Cell Carcinoma of the Esophagus

Objective: Chemoradiotherapy (CRT) is a possible alternative to surgery for esophageal cancer. As complete response (CR) to CRT is essential for a good prognosis, potential biomarkers predictive of CR were explored. Methods: Endoscopic tumor biopsies were obtained from 41 patients with stage II–III esophageal squamous cell carcinoma before 5-fluorouracil/cisplatin-based definitive CRT. cDNA was derived from RNA isolated from microdissected tumor cells. mRNA expression levels of 10 genes involved in CRT or tumor biology were measured using quantitative real-time RT-PCR. Results: Expression levels of orotate phosphoribosyltransferase (OPRT) and dihydrofolate reductase mRNA were significantly higher in the CR group compared with the non-CR group (p = 0.0206 and 0.0191, respectively). Matrix metalloproteinase 9 mRNA expression was significantly lower in the CR group (p = 0.0436). CR rates were significantly higher in patients with node-negative disease and high expression levels of OPRT and dihydrofolate reductase genes (p = 0.0448, 0.0104 and 0.0104, respectively). No significant difference in CR rates was observed for other variables. Multivariate analysis revealed that high OPRT gene expression was an independent predictive factor of CR (p = 0.0192). It was also significantly associated with good prognosis (p = 0.0450). Conclusion: High OPRT gene expression may be a predictive factor of CR to 5-fluorouracil/cisplatin-based CRT in esophageal cancer.
Cyclooxygenase-2 Selectively Controls Renal Blood Flow Through a Novel PPARβ/δ-Dependent Vasodilator Pathway

Cyclooxygenase-2 (COX-2) is an inducible enzyme expressed in inflammation and cancer targeted by nonsteroidal anti-inflammatory drugs. COX-2 is also expressed constitutively in discreet locations where its inhibition drives gastrointestinal and cardiovascular/renal side effects. Constitutive COX-2 expression in the kidney regulates renal function and blood flow; however, the global relevance of the kidney versus other tissues to COX-2–dependent blood flow regulation is not known. Here, we used a microsphere deposition technique and pharmacological COX-2 inhibition to map the contribution of COX-2 to regional blood flow in mice and compared this to COX-2 expression patterns using luciferase reporter mice. Across all tissues studied, COX-2 inhibition altered blood flow predominantly in the kidney, with some effects also seen in the spleen, adipose, and testes. Of these sites, only the kidney displayed appreciable local COX-2 expression. As the main site where COX-2 regulates blood flow, we next analyzed the pathways involved in kidney vascular responses using a novel technique of video imaging small arteries in living tissue slices. We found that the protective effect of COX-2 on renal vascular function was associated with prostacyclin signaling through PPAR&bgr;/&dgr; (peroxisome proliferator-activated receptor-&bgr;/&dgr;). These data demonstrate the kidney as the principle site in the body where local COX-2 controls blood flow and identifies a previously unreported PPAR&bgr;/&dgr;-mediated renal vasodilator pathway as the mechanism. These findings have direct relevance to the renal and cardiovascular side effects of drugs that inhibit COX-2, as well as the potential of the COX-2/prostacyclin/PPAR&bgr;/&dgr; axis as a therapeutic target in renal disease.
Poly(ADP-ribosyl)ation by PARP1: reaction mechanism and regulatory proteins

Abstract Poly(ADP-ribosyl)ation (PARylation) is posttranslational modification of proteins by linear or branched chains of ADP-ribose units, originating from NAD+. The central enzyme for PAR production in cells and the main target of poly(ADP-ribosyl)ation during DNA damage is poly(ADP-ribose) polymerase 1 (PARP1). PARP1 ability to function as a catalytic and acceptor protein simultaneously made a considerable contribution to accumulation of contradictory data. This topic is directly related to other questions, such as the stoichiometry of PARP1 molecules in auto-modification reaction, direction of the chain growth during PAR elongation and functional coupling of PARP1 with PARylation targets. Besides DNA damage necessary for the folding of catalytically active PARP1, other mechanisms appear to be required for the relevant intensity and specificity of PARylation reaction. Indeed, in recent years, PARP research has been enriched by the discovery of novel PARP1 interaction partners modulating its enzymatic activity. Understanding the details of PARP1 catalytic mechanism and its regulation is especially important in light of PARP-targeted therapy and may significantly aid to PARP inhibitors drug design. In this review we summarize old and up-to-date literature to clarify several points concerning PARylation mechanism and discuss different ways for regulation of PAR synthesis by accessory proteins reported thus far.
A dual pathway inhibition strategy using BKM120 combined with vemurafenib is poorly tolerated in BRAF V600E/K mutant advanced melanoma

Single or dual agent inhibition of the MAPK pathway can induce objective responses in up to 70% of BRAF mutant melanoma patients, but these responses are transient in most patients (e. g. Long et al., 2015). Aberrant signaling in the PI3K pathway has been implicated in both melanoma oncogenesis and in BRAF inhibitor resistance (e. g. Dankort et al., 2009; Goel et al., 2006). PTEN loss, which leads to increased PI3K activity, is common in patients treated with the BRAF inhibitor vemurafenib (McArthur et al., 2011) and decreased PTEN expression has been identified as a predictor of decreased PFS in patients treated with the drug (Nathanson et al., 2013). This article is protected by copyright. All rights reserved.
Prevalence of Dementia and Main Subtypes in Rural Northern China

Background/Aims: The aim of this article was to estimate the prevalence of and to determine the sociodemographic risk factors for dementia, Alzheimer's disease (AD) and vascular dementia (VaD) among individuals residing in rural northern China. Methods: Between 2011 and 2012, residents aged ≥60 years and residing in rural areas of northern China were clinically assessed for symptoms of dementia, AD and VaD. Diagnoses were made using established criteria and standard procedures. Results: Among 5,578 enrolled study participants aged ≥60 years, the prevalence rates of dementia, AD and VaD were 7.7, 5.4 and 1.7%, respectively. Older age (OR = 1.17; 95% CI: 1.14-1.19) and female gender (OR = 2.13; 95% CI: 1.51-3.00) were identified as independent risk factors for AD. In turn, a higher educational level (OR = 0.36; 95% CI: 0.21-0.60) and engagement in social activities (OR = 0.219; 95% CI: 0.163-0.295) were protective factors. Risk factors associated with VaD were older age (OR = 1.11; 95% CI: 1.1-1.12) and hypertension (OR = 1.83; 95% CI: 1.18-2.86), while a higher educational level (OR = 0.53, 95% CI: 0.44-0.65) and engagement in social activities (OR = 0.34; 95% CI: 0.29-0.41) were protective factors. Conclusion: High rates of dementia (7.7%) and AD (5.4%) were found in the rural areas of northern China. Older age and female gender were identified as risk factors for AD, while older age and hypertension were risk factors for VaD. A higher educational level and engagement in social activities were identified as protective factors against both AD and VaD.
Distinctive Reproductive Phenotypes in Peripubertal Girls at Risk for Polycystic Ovary Syndrome.

CONTEXT Increased testosterone (T) levels are a cardinal feature of polycystic ovary syndrome (PCOS). Female relatives of affected women, including premenarchal daughters, have elevated T levels supporting a genetic susceptibility to this phenotype. Girls with obesity (OB-g) also have increased T levels throughout puberty, which may indicate risk for PCOS. OBJECTIVE We tested the hypothesis that premenarchal daughters of women affected with PCOS (PCOS-d) have distinctive phenotypic features compared with OB-g. DESIGN, SETTING, AND PARTICIPANTS Forty-eight PCOS-d, 30 OB-g, and 22 normal weight (NW-g) premenarchal girls were studied. Mothers of OB-g and NW-g had no evidence for PCOS. MAIN OUTCOME MEASURES Reproductive hormones were measured. RESULTS Body mass index differed by design, was highest in OB-g, followed by PCOS-d (P > 0.001). PCOS-d and OB-g had similar increases in free T levels compared with NW-g (PCOS-d vs NW-g, P = 0.01; OB-g vs NW-g, P = 0.0001). Sex hormone binding globulin levels were lowest in OB-g and lower in PCOS-d than in NW-g (PCOS-d vs NW-g, P = 0.005; OB-g vs NW-g, P < 0.0001; PCOS-d vs OB-g, P < 0.0001). Anti-Müllerian hormone (AMH) levels in PCOS-d were significantly increased compared with OB-g, who tended to have lower AMH levels than NW-g (PCOS-d vs OB-g, P < 0.0001; PCOS-d vs NW-g, P = 0.10). CONCLUSIONS Despite similarly elevated free T levels, PCOS-d had increased AMH levels compared with OB-g. This finding suggests that OB-g lack alterations in ovarian folliculogenesis, a key reproductive feature of PCOS. Causal mechanisms may differ in PCOS-d or OB-g, or elevated T in OB-g may not be an early marker for PCOS.
Emerging Therapies for Acute Myelogenus Leukemia Patients Targeting Apoptosis and Mitochondrial Metabolism

Acute Myelogenous Leukemia (AML) is a malignant disease of the hematopoietic cells, characterized by impaired differentiation and uncontrolled clonal expansion of myeloid progenitors/precursors, resulting in bone marrow failure and impaired normal hematopoiesis. AML comprises a heterogeneous group of malignancies, characterized by a combination of different somatic genetic abnormalities, some of which act as events driving leukemic development. Studies carried out in the last years have shown that AML cells invariably have abnormalities in one or more apoptotic pathways and have identified some components of the apoptotic pathway that can be targeted by specific drugs. Clinical results deriving from studies using B-cell lymphoma 2 (BCL-2) inhibitors in combination with standard AML agents, such as azacytidine, decitabine, low-dose cytarabine, provided promising results and strongly support the use of these agents in the treatment of AML patients, particularly of elderly patients. TNF-related apoptosis-inducing ligand (TRAIL) and its receptors are frequently deregulated in AML patients and their targeting may represent a promising strategy for development of new treatments. Altered mitochondrial metabolism is a common feature of AML cells, as supported through the discovery of mutations in the isocitrate dehydrogenase gene and in mitochondrial electron transport chain and of numerous abnormalities of oxidative metabolism existing in AML subgroups. Overall, these observations strongly support the view that the targeting of mitochondrial apoptotic or metabolic machinery is an appealing new therapeutic perspective in AML.
Establishment of a Primary Culture System of Human Periodontal Ligament Cells that Differentiate into Cementum Protein 1-expressing Cementoblast-like Cells

Background/Aim: A better understanding of cementogenesis and cementoblast differentiation would be useful for periodontal therapy. The aim of this study was to establish a cell culture system that reflects cementum formation in periodontal tissue and determine whether or not isolated and cultured primary human periodontal ligament (PDL) cells could be used for the study of the differentiation of cementoblast. Materials and Methods: PDL cells were isolated from the outgrowths of tissue fragments of human PDL. PDL cells were incubated for up to 21 days in differentiation medium containing β-glycerophosphate and ascorbic acid. The changes in the cells were detected by alkaline phosphatase (ALP) and von Kossa staining. Real-time polymerase chain reaction was also performed for cementum protein 1 (CEMP1), which is a specific marker of cementoblasts and their progenitors. Results: On day 5, a small number of PDL cells, which were fibrous, were positive for ALP. On day 7, almost all cells were positive for ALP. On day 14, mineralization nodules appeared, as seen by positive von Kossa staining; the nodules increased in number and size by day 21. The expression of CEMP1 was detected on day 5, and its expression level increased gradually by day 7, reached a peak on day 14, and decreased by day 21. Conclusion: Human PDL cells were used to establish a culture system that reflects cementum formation. Our results suggested that this culture method is convenient and useful for the study of cementogenesis and cementoblast differentiation.
Identifying suicide risk among college students: A systematic review

Abstract Mental health research highlights the need to focus on suicide risk in college students. However, evidence for associated risk and protective factors in this cohort is mixed. This review synthesizes data from 29 independent studies (N = 11,557 participants). Self-reported depression, cumulative stressful life events, sleep difficulties, a disconnection from others, and a sense of hopelessness demonstrated significant associations with heightened suicide risk. Reasons to live and hope provided significant protective effects. The findings highlight key intervention targets, pointing to the importance of cognitive-behavioral interventions to ameliorate suicidal thoughts but also build dispositional hope and goal-directed thinking.