Miracle-dz/UniFAR-FTUs huggingface dataset:
Superoxide Dismutase, Lipid Peroxidation, and Bell-Shaped Dose Response Curves

Cellular metabolism generates the cytotoxic superoxide free radical, O2·−, and a family of enzymes called superoxide dismutases (SOD) protects us from O2·− by catalyzing its conversion to O2 and H2O2. Superoxide production increases in a wide variety of pathological states, especially those involving inflammation or ischemic injury. Most of the literature has described systems wherein added or over expressed SOD produced beneficial effects, yet in some circumstances SOD provided no benefit, or was clearly detrimental, exacerbating cell injury or death. When broad dose-response studies were finally possible in models of reperfusion injury in the isolated heart, hormesis became clear. We propose that the mechanisms underlying the hormesis are related to the paradoxical abilities of the superoxide radical to serve as both an initiator and a terminator of the free radical-mediated chain reaction that results in lipid peroxidation. Lipid peroxidation is a universal feature of oxidative stress, causing loss of cellular structure and function. Under any given conditions, the optimal concentration of SOD is that which decreases chain initiation without elimination of the chain termination properties of the radical, resulting in a minimum of net lipid peroxidation. Mathematical modeling of this hypothesis yields predictions fully consistent with observed laboratory data.
Walk-run training improves the anti-inflammation properties of high-density lipoprotein in patients with metabolic syndrome.

CONTEXT Metabolic syndrome (MetS) is a constellation of cardiovascular risk factors, including central obesity, dysglycemia, hypertension, and dyslipidemia. The anti-inflammatory properties of high density lipoprotein (HDL) can be compromised in MetS. Exercise is recognized as an important factor in the prevention and treatment of MetS. OBJECTIVE This study was designed to investigate whether walk/run training without any specific diet could enhance anti-inflammation capacity of HDL from MetS patients. DESIGN This was a case control study. SETTING The study was conducted in a Zhoudian community, Taian. PATIENTS Thirty nine patients with MetS were recruited and divided into a control group (n = 12) remaining in an untrained state and exercise group (n = 27) performing a 10-week walk/run training program. MAIN OUTCOME MEASURES The anti-inflammation capacities of HDL3 (HDL subfractions) from MetS patients with or without exercise were investigated by co-incubating with TNF- α-injured endothelial cells in vitro. RESULTS The training did not influence serum lipoprotein level in MetS patients and cholesterol efflux capacity of circulating HDL. However, walk/run training increased paraoxonase-1 (PON1) activity and decreased the levels of malondialdehyde in either serum or isolated HDL from MetS patients prominently. More importantly, HDL3 isolated from MetS patients with 10 weeks training protected endothelial cells against tumor necrosis factor-a (TNF-a) -induced injury, decreased monocyte chemotactic protein-1 levels in media and vascular cell adhesion molecule-1 expression markedly. Furthermore, HDL3 isolated from MetS patients with walk/run training inhibited the TNF-á-induced monocyte adhesion to endothelial cells and obviously increased nitric oxide production by activating endothelial nitric oxide synthase. CONCLUSION Walk/run training leads to a significant improvement in HDL anti-inflammation capacity in subjects with MetS without restricted diet, the mechanism underlying which at least partially is due to increased PON1 activity in HDL, NO production, and eNOS expression in endothelial cells.
Expression of p16INK4A and alterations of the 9p21‐23 chromosome region in non‐small‐cell lung carcinomas: Relationship with tumor growth parameters and ploidy status

The 9p21‐23 chromosome region harbors a number of known and putative tumor‐suppressor genes (TSGs). The best characterized gene in this area is p16INK4A (CDKN2A). Alterations of its product have been observed in various malignancies, including non‐small‐cell lung carcinomas (NSCLCs). We earlier investigated the mechanisms underlying p16INK4A inactivation. In the present study, we examined, in a series of 87 NSCLCs, its relationship with the kinetic parameters [proliferation index (PI) and apoptotic index (Al)] and the ploidy status of the tumors. In addition, we extended our previous LOH analysis of the 9p21‐23 region by examining flanking areas of p16INK4A. Aberrant p16 expression was observed in 41.4% of the carcinomas. A significant association was found with increased PI (p = 0.037), but not with apoptosis. Aneuploid tumors were more frequently correlated with abnormal p16 staining (p = 0.05). A high frequency of allelic imbalance (Alm) was noticed at the D9S161 (51.3%) and D9S157 (64.5%) loci, which lie approximately 4cM centromeric and 7cM telomeric, respectively, to CDKN2A. Abnormal p16INK4A expression was strongly correlated with Alm at D9S161 (p = 0.004). Allelic losses at D9S157 occurred more frequently in early stages (p = 0.018) and were significantly associated with deletions at D9S161 (p = 0.035). We conclude that, in a sub‐set of NSCLCs, (i) abnormal p16 expression contributes to tumor growth mainly by increasing the proliferative activity in the initial stages of carcinogenesis; (ii) the association with aneuploidy merely reflects the impact of aberrant p16 on proliferative activity; and (iii) other putative TSGs possibly reside within the 9p21‐23 region that possibly co‐operate in certain cases with CDKN2A in the development of NSCLCs. Int. J. Cancer (Pred. Oncol.) 89:133–141, 2000. © 2000 Wiley‐Liss, Inc.
Analysis of epithelial-mesenchymal interactions in the initial morphogenesis of the mammalian tooth.

Epithelial-mesenchymal interactions govern the development of epidermal organs such as teeth. During the early stages of tooth development, a local ectodermal thickening which expresses several signaling molecules appears. It is believed that these in turn signal to the underlying mesenchyme triggering mesenchymal condensation and tooth development. For example, epithelially expressed Bmp4 induces Msx1 and Lef1 as well as itself in the underlying mesenchyme. In this paper we have investigated the role of four epithelial signaling molecules, Bmp2, Shh, Wnt10a, and Wnt10b, in the early inductive cascades that govern tooth development. We show that all four genes are specifically expressed in the epithelium between E11.0 and E12.0 when tooth morphogenesis is first apparent. Although Shh, Bmp2, and Wnt10b have similar, if not identical, expression patterns, each signal has a distinct molecular action on the jaw mesenchyme. Whereas Shh and Wnt10b can induce general Hedgehog and Wnt targets, Ptc and Gli for Shh and Lef1 for Wnt10b, only Bmp2 is able to induce tooth-specific expression of Msx1. Thus, there are distinct targets for all three pathways. Interestingly, both Bmp and Wnt signaling activate Lef1, making it a candidate for integrating the two distinct signaling pathways.
Relationship between the appearance of preantral follicles in the fetal ovary of Antarctic minke whales (Balaenoptera bonaerensis) and hormone concentrations in the fetal heart, umbilical cord and maternal blood

The present study aimed to determine the relationship among changes in the number of preantral follicles and concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), progesterone (P4), androstenedione (A) and estradiol-17β (E2) in the fetal heart, umbilical cord and maternal blood. Primordial follicles had already appeared in a 20 cm fetus and primary follicles were observed in a 50 cm fetus. In a 70 cm fetus, the number of primordial and primary follicles increased rapidly and secondary follicles were present. The concentrations of LH and FSH did not change between 20 cm and 160 cm in fetal length. When the fetal length became >70 cm, serum levels in the fetus, umbilical cord and mothers, and E2 levels in umbilical cord increased synchronously (p<0.05). These results showed increases in the number of preantral follicles in the Antarctic minke whale fetal ovary along with fetal growth during the early gestation period. These findings suggest that the change in preantral follicles was associated with changes in the concentration of steroids in early gestation periods. The changes in steroid concentrations in the fetal and umbilical cord blood and the increased number of preantral follicles were coincident at around 70 cm in fetal length, whereas the growth and differentiation of primordial and primary follicles appeared to be independent of FSH and LH.
Sclerotic fibroma‐like change in various neoplastic and inflammatory skin lesions: is sclerotic fibroma a distinct entity?

Abstract: Sclerotic fibroma was first described in association with Cowden's disease by Weary et al. in 1972. In 1989, Rapini and Golitz detailed 11 cases of solitary sclerotic fibroma (SFS) in the absence of Cowden's disease, suggesting the term SFS of the skin. Classic histological features include hypocellular, hyalinized bands of collagen sharply demarcated from the surrounding skin. Numerous authors have described sclerotic fibroma‐like changes in other entities including melanocytic nevi, dermatofibromas, lipomas, tendon sheath fibromas, giant cell collagenomas, neurofibromas, angiofibromas, erythema elevatum diutinum, and folliculitis. Dissension has arisen, with some dermatopathologists asserting that sclerotic fibroma is just an evolutionary end‐point of a previous lesion. Others contend that SFS is a distinct lesion and cite recurrent cases and/or proliferation marker studies to corroborate this view. We detail the histopathological findings of lesions consistent with the classic description of SFS and compare these to sclerotic changes observed in an intradermal nevus, blue nevus, erythema elevatum diutinum, neurofollicular hamartoma, angiofibroma, neurofibroma, accessory nipple, and dermatofibromas. Sclerotic fibroma‐like change may be seen in a variety of lesions and may represent a common reaction pattern in the skin.
Safety and Tolerability of Canagliflozin in Patients With Type 2 Diabetes Mellitus: Pooled Analysis of Phase 3 Study Results

Abstract Background: Canagliflozin is a sodium glucose cotransporter 2 inhibitor developed for treating type 2 diabetes mellitus (T2DM). Methods: The safety/tolerability profile of canagliflozin 100 and 300 mg over 26 weeks was assessed using an integrated analysis of data pooled from 4 placebo-controlled, phase 3 studies representing a broad range of patients with T2DM (N = 2313; mean age, 56.0 years; glycated hemoglobin [HbA1c], 8.0%; body mass index, 32.1 kg/m2; estimated glomerular filtration rate, 88.1 mL/min/1.73 m2) on various prespecified background diabetes mellitus treatments. Safety/tolerability evaluations included adverse event (AE) reporting, with additional data collection prespecified for selected AEs, and assessments of renal-related, lipid, and other safety laboratory parameters. Trial Registration: ClinicalTrials.gov, NCT01081834; NCT01106625; NCT01106677; NCT01106690. Results: The overall incidence of AEs was similar with canagliflozin 100 and 300 mg and placebo; incidences of serious AEs and AEs leading to study discontinuation were low across groups. Canagliflozin was associated with higher incidences than placebo of genital mycotic infections and osmotic diuresis–related AEs; these were generally considered by the investigator to be mild to moderate in intensity and infrequently led to discontinuation. Canagliflozin was associated with transient reductions in estimated glomerular filtration rate that trended toward baseline over the assessment period; incidences of renal-related AEs were low across groups. Dose-related increases in the incidence of hypoglycemia episodes were seen with canagliflozin versus placebo in patients on background sulfonylurea; incidences of severe hypoglycemia were low across groups. Hypoglycemia incidence was low overall in patients not on background sulfonylurea, but slightly higher with canagliflozin versus placebo. Relative to placebo, favorable changes in high-density lipoprotein cholesterol and triglycerides were seen with canagliflozin; increases in low-density lipoprotein cholesterol were also seen. Canagliflozin was associated with small changes in other safety laboratory parameters that were not clinically meaningful. Conclusions: Canagliflozin as monotherapy and as combination therapy was generally well tolerated in patients with T2DM inadequately controlled on their current diabetes mellitus treatment.
Characterization of malignant gastrointestinal stromal tumors-a single center experience.

Background The recurrence rate, related to the unpredictable behavior of gastrointestinal stromal tumors (GISTs), continues to be a major topic of investigation, since no actual risk evaluation scales have proven to be exceedingly effective in predicting prognosis. We therefore focus in this study on investigating the predictive variables of disease recurrence. Methods Between September 2004 and January 2011, 34 patients, 18 males and 16 females with a median age of 62 (range, 27-87) years, underwent operations for primary, localized and advanced GISTs. Immunohistochemical profile, KIT and the platelet-derived growth factor receptor-alpha (PDGFR-α) gene mutations, tumor size, tumor site, mitotic index, synchronous tumors, adjuvant therapy, symptoms and gender were considered and analyzed as predictive variables. The receiver operating characteristic (ROC) analysis was used to determine the optimal cut-off value for tumor dimension to predict recurrence. Results The median follow-up (FU) was 20 months (range, 6-86 months). A first-line adjuvant therapy was performed in nine patients. Disease relapse occurred in five cases. The tumor size and the mitotic index were the strongest predictive factors (P<0.001). The optimal maximum value for the tumor size was 7 cm [area under the curve (AUC) =0.955]. Conclusions In light of the most recent evidence, a tumor size of 7 cm should be considered the threshold value for malignancy, and smaller GISTs with low mitotic counts as tumors with a low-grade risk.
Hering-Breuer Reflex in Normal Adults and in Patients with Chronic Obstructive Pulmonary Disease and Interstitial Fibrosis

Background: It has been suggested that the Hering-Breuer reflex (HBR) is unimportant in adults during normal tidal breathing and that it is elicited only if tidal volume is increased above a certain critical threshold. Objective: The aim of this study was (1) to study the occurrence of the HBR in adults with normal pulmonary function and (2) to examine if changes in lung mechanics have any effect on the HBR. Methods: We examined 11 adults with normal pulmonary function, 8 patients with chronic destructive pulmonary disease (COPD) and 3 with interstitial fibrosis (IF). All subjects were lightly sedated with fentanyl, intubated and ventilated with a Servo-900 ventilator. Inspiratory and expiratory flow (and after integration, volume) and mouth pressure were recorded from the endotracheal tube with a pneumotachograph and a pressure transducer. Pressure support ventilation was applied in all patients and functional residual capacity (FRC) was measured with the N2 washout method. Mean (Temean) and maximal expiratory time (Temax) were determined for each individual for 20 breaths. Following several breaths to establish a stable baseline the airway was occluded at end inspiration by a shutter. A positive HBR was interpreted as longer Teocc than Temax (Teocc/Temax, %). Occlusion was maintained until negative airway pressure occurred and the occlusion time (Teocc) was measured. We attempted occlusions after the addition of 5 cm H2O positive end-expiratory pressure (PEEP) and subsequently with 10, 15 and 20 cm H2O PEEP. Teocc was measured of progressively larger lung volumes. To examine the HBR sensitivity in the three groups, we plotted the lung volumes of occlusion against the corresponding Teocc/Temax. Results: The ratio Teocc/Temax increased from 167.5 ± 82.5 at normal FRC to 474 ± 200.2 s (PEEP20). On the contrary, in patients with COPD, Teocc/Temax increased from 125.2 ± 34 to 193.7 ± 74.2 (p < 0.05). Conclusions: The HBR was positive in all subjects. COPD patients were found to be less sensitive to volume changes when compared with normal controls and with IF patients.
Enhancement of Fibroblast Collagenase (Matrix Metalloproteinase-1)Gene Expression by Ceramide Is Mediated by Extracellular Signal-regulated and Stress-activated Protein Kinase Pathways*

Inflammatory cytokines tumor necrosis factor-α and interleukin-1 trigger the ceramide signaling pathway, initiated by neutral sphingomyelinase-elicited hydrolysis of cell membrane phospholipid sphingomyelin to ceramide, a new lipid second messenger. Here, we show that triggering the ceramide pathway by sphingomyelinase or C2- and C6-ceramide enhances collagenase-1 (matrix metalloproteinase-1; MMP-1) gene expression by fibroblasts. C2-ceramide activates three distinct mitogen-activated protein kinases (MAPKs) in dermal fibroblasts, i.e.extracellular signal-regulated kinase 1/2 (ERK1/2), stress-activated protein kinase/Jun N-terminal-kinase (SAPK/JNK), and p38. Stimulation of MMP-1 promoter activity by C2-ceramide is dependent on the presence of a functional AP-1 cis-element and is entirely inhibited by overexpression of MAPK inhibitor, dual specificity phosphatase CL100 (MAPK phosphatase-1). Activation of MMP-1 promoter by C2-ceramide is also effectively inhibited by kinase-deficient forms of ERK1/2 kinase (MEK1/2) activator Raf-1, ERK1 and ERK2, SAPK/JNK activator SEK1, or SAPKβ. In addition, ceramide-dependent induction of MMP-1 expression is potently prevented by PD 98059, a selective inhibitor of MEK1 activation, and by specific p38 inhibitor SB 203580. These results show that triggering the ceramide signaling pathway activates MMP-1 gene expression via three distinct MAPK pathways, i.e. ERK1/2, SAPK/JNK, and p38, and suggest that targeted modulation of the ceramide signaling pathway may offer a novel therapeutic approach for inhibiting collagenolytic activity, e.g. in inflammatory disorders.
Topographical distribution of NADPH‐diaphorase activity in the central nervous system of the frog, Rana perezi

The distribution of NADPH‐diaphorase (ND) activity was histochemically investigated in the brain of the frog Rana perezi. This technique provides a highly selective labeling of neurons and tracts. In the telencephalon, labeled cells are present in the olfactory bulb, pallial regions, septal area, nucleus of the diagonal band, striatum, and amygdala. Positive neurons surround the preoptic and infundibular recesses of the third ventricle. The magnocellular and suprachiasmatic hypothalamic nuclei contain stained cells. Numerous neurons are present in the anterior, lateral anterior, central, and lateral posteroventral thalamic nuclei. Positive terminal fields are organized in the same thalamic areas but most conspicuously in the visual recipient plexus of Bellonci, corpus geniculatum of the thalamus, and the superficial ventral thalamic nucleus. Labeled fibers and cell groups are observed in the pretectal area, the mesencephalic optic tectum, and the torus semicircularis. The nuclei of the mesencephalic tegmentum contain abundant labeled cells and a conspicuous cell population is localized medial and caudal to the isthmic nucleus. Numerous cells in the rhombencephalon are distributed in the octaval area, raphe nucleus, reticular nuclei, sensory trigeminal nuclei, nucleus of the solitary tract, and, at the obex levels, the dorsal column nucleus. Positive fibers are abundant in the superior olivary nucleus, the descending trigeminal, and the solitary tracts. In the spinal cord, a large population of intensely labeled neurons is present in all fields of the gray matter throughout its rostrocaudal extent. Several sensory pathways were heavily stained including part of the olfactory, visual, auditory, and somatosensory pathways. The distribution of ND‐positive cells did not correspond to any single known neurotransmitter or neuroactive molecule system. In particular, abundant codistribution of ND and catecholamines is found in the anuran brain. Double labeling techniques have revealed restricted colocalization in the same neurons and only in the posterior tubercle and locus coeruleus. If ND is in amphibians a selective marker for neurons containing nitric oxide synthase, as generally proposed, with this method the neurons that may synthesize nitric oxide would be identified. This study provides evidence that nitric oxide may be involved in novel tasks, primarily related to forebrain functions, that are already present in amphibians. © 1996 Wiley‐Liss, Inc.
Effects of Life-Event Stress and Hardiness on Peripheral Vision in a Real-Life Stress Situation

Abstract Previous research has only examined perceptual deficits that are hypothesized in a model of stress and injury under laboratory-induced stress conditions. The generalizability of findings from such induced-stress conditions is limited beyond the laboratory. The current research examined the influence of life-event stress and hardiness on peripheral narrowing in a real-life stress situation. Athletes completed life-stress and hardiness questionnaires, along with measures of state anxiety and peripheral vision. The stress condition was obtained by assessing the athletes within 2 hours of a competition. The real-life stress condition had a larger effect on state anxiety and peripheral narrowing than the laboratory-induced situations used in previous research, with effect sizes twice and three times as large as those reported in the literature. All athletes experienced significant reductions in peripheral vision prior to competition, regardless of life-event stress or hardiness levels.
Clinical features, early treatment responses, and outcomes of pediatric acute lymphoblastic leukemia in china with or without specific fusion transcripts: A single institutional study of 1,004 patients

Acute lymphoblastic leukemia (ALL) with distinct fusion transcripts has unique clinical features. In this study, the incidence, clinical characteristics, early treatment response, and outcomes of 1,004 Chinese pediatric ALLs were analyzed. Patients with TEL‐AML1 and E2A‐PBX1 fusion genes or other B cell precursor ALLs (BCP‐ALL) had favorable clinical features, were sensitive to prednisone, had low minimal residual disease (MRD), and an excellent prognosis, with a 5‐year event‐free survival (EFS) of 84–92%. T‐ALL was associated with a high WBC, increased age, more central nervous system involvement, a poor prednisone response, and high MRD, with a 5‐year EFS of 68.4 ± 5.2%. Patients with BCR‐ABL and MLL rearrangements usually had adverse clinical presentations and treatment responses, and a dismal prognosis, with 5‐year EFS of 27.3 and 57.4%, respectively. We also showed that BCR‐ABL and MLL rearrangements, the prednisone response, and MRD were independent prognostic factors. Interestingly, the BCH‐2003 protocol resulted in a better outcome for E2A‐PBX1+ patients than the CCLG‐2008 protocol. Intermediate and late relapses were more common in TEL‐AML1+ patients and other BCP‐ALLs compared with other subgroups (P = 0.018). Therefore, this study suggests that a fusion gene‐specific chemotherapy regimen and/or targeted therapy should be developed to improve further the cure rate of pediatric ALL. Am. J. Hematol. 2012. © 2012 Wiley Periodicals, Inc.