Miracle-dz/UniFAR-FTUs huggingface dataset:
Analysis of failures in patients with stage I ovarian cancer: an Italian multicenter study

Gadducci A, Sartori E, Maggino T, Zola P, Landoni F, Fanucchi A, Stegher C, Alessi C, Buttitta F, Bergamino C. Analysis of failures in patients with stage I ovarian cancer: An Italian multicenter study. Int J GynecolCancer 1997; 7: 445–450. The objective of this retrospective multicenter study was to assess the rates, times, sites, and risk factors for recurrences in 224 patients with surgical stage I ovarian cancer. Postoperative adjuvant treatment was given to 153 of these patients. One hundred and eighty-two (81.3%) patients are currently alive with no clinical evidence of disease after a median time of 84 months (range, 4–191 months) from surgery, whereas 39 (17.4%) developed recurrent disease after a median time of 29 months (range, 5–112 months). The relapse involved the pelvis in 21 (53.8%) cases, abdomen in 19 (48.7%), pelvic and/or para-aortic lymph nodes in 5 (12.8%), and distant sites in 5 (12.8%). The risk of recurrence was significantly related to FIGO substage (P< 0.0001) and tumor grade (P < 0.0001), but not to histological subtype. However, the recurrence rate was lower in mucinous carcinomas (6/52, 11.5%) and higher in clear cell carcinomas (5/14,35.7%). By log-rank test the disease-free survival was significantly related to FIGO substage (P = 0.0006) and grade (P = 0.0001). Cox proportional hazard model showed that grade was the only independent prognostic variable for disease-free survival, with a risk ratio for relapse of 2.831 (95% CI, 1.120–6.624) for grade 2 and 7.725 (95% CI, 3.290–18.140) for grade 3, compared to grade 1. In conclusion, tumor grade is the strongest predictor of recurrence in stage I ovarian cancer.
Neural‐glial interaction in the spinal cord for the development and maintenance of nerve injury‐induced neuropathic pain

Damage to the nervous system often results in neuropathic pain. Current treatment for this disabling state is unsuccessful due to our incomplete understanding of cellular mechanisms causing this pain. Although glial cells were largely ignored in most textbooks of pain, accumulating evidence over the last decade indicates an important role of glial cells in the pathogenesis of pain. Both microglia and astroglia are activated in the spinal cord after peripheral nerve injury. Importantly, activated microglia and astroglia produce multiple inflammatory mediators and neuromodulators, acting on primary afferents or dorsal horn neurons and leading to an enhancement and maintenance of dorsal horn neuron sensitization and subsequent pain sensitization. This neural‐glial interaction after peripheral nerve injury is likely to be triggered by signaling molecules released in the spinal cord from central terminals of damaged sensory neurons, stimulating surrounding glial cells. In addition, there is a microglial‐astroglial interaction; microglia activation occurs before astroglial activation and is known to cause astroglial activation. Glial activation is further enhanced by microglial‐microglial interaction and astroglial‐astroglial interaction. Many signaling molecules (e.g., MAP kinases, ATP receptors, chemokine receptors) are exclusively activated in spinal microglia or astroglia after nerve injury, and an inhibition of these molecules can attenuate neuropathic pain. Since traditional pain‐killers are designed against neuronal targets and are only partially effective to treat neuropathic pain, searching for signaling molecules that are induced in spinal glia in neuropathic pain conditions will identify novel targets for the management of this debilitating chronic pain. Drug Dev. Res. 67:331–338, 2006. © 2006 Wiley‐Liss, Inc.
Avaliação das propriedades mecânicas de quatro cimentos de ionômero de vidro convencionais utilizados na cimentação de bandas ortodônticas

AIM: The aim of this in vitro study was to compare the flexural strength, the compressive strength and the diametral tensile strength of four conventional glass-ionomer cements (Vidrion C/SS White; Meron/Voco; Ketac Cem/3M ESPE; Vivaglass/Ivoclar-Vivadent) used in Orthodontics for band cementation. METHODS: Twelve specimens of each cement were prepared for each test. Specimens were fabricated according to ISO 4049 (flexural strength) and to the ADA specification #66 (compressive strength and diametral tensile strength). Specimens were stored in distilled water at 37oC for 24 hours, and tested using an Instron Universal Testing Machine 4444 with crosshead speeds of 0.75mm/minute (flexural strength) and 1mm/minute (compressive strength and diametral strength). RESULTS: The results (mean ± SD, in MPa) for flexural strength were: 25.85 ± 5.43 (Meron); 21.85 ± 6.96 (Vidrion C); 20.85 ± 4.17 (Vivaglass); 20.50 ± 4.89 (Ketac Cem). Compressive strength (in the same order): 77.72 ± 20.21; 56.49 ± 8.54; 47.84 ± 9.25; 81.93 ± 13.37. The results for diametral tensile strength were (in the same order): 9.59 ± 2.09; 5.25 ± 1.29; 7.69 ± 2.09; 4.08 ± 1.32. CONCLUSIONS: No statistically significant difference was detected in the flexural strength among the different groups. Meron and Ketac Cem yielded greater mean compressive strength values than Vidrion C and Vivaglass. Meron resulted in significantly higher diametral tensile strength mean value than the other cements.
G4 Resolvase 1 Binds Both DNA and RNA Tetramolecular Quadruplex with High Affinity and Is the Major Source of Tetramolecular Quadruplex G4-DNA and G4-RNA Resolving Activity in HeLa Cell Lysates*

Quadruplex structures that result from stacking of guanine quartets in nucleic acids possess such thermodynamic stability that their resolution in vivo is likely to require specific recognition by specialized enzymes. We previously identified the major tetramolecular quadruplex DNA resolving activity in HeLa cell lysates as the gene product of DHX36 (Vaughn, J. P., Creacy, S. D., Routh, E. D., Joyner-Butt, C., Jenkins, G. S., Pauli, S., Nagamine, Y., and Akman, S. A. (2005) J. Biol Chem. 280, 38117–38120), naming the enzyme G4 Resolvase 1 (G4R1). G4R1 is also known as RHAU, an RNA helicase associated with the AU-rich sequence of mRNAs. We now show that G4R1/RHAU binds to and resolves tetramolecular RNA quadruplex as well as tetramolecular DNA quadruplex structures. The apparent Kd values of G4R1/RHAU for tetramolecular RNA quadruplex and tetramolecular DNA quadruplex were exceptionally low: 39 ± 6 and 77 ± 6pm, respectively, as measured by gel mobility shift assay. In competition studies tetramolecular RNA quadruplex structures inhibited tetramolecular DNA quadruplex structure resolution by G4R1/RHAU more efficiently than tetramolecular DNA quadruplex structures inhibited tetramolecular RNA quadruplex structure resolution. Down-regulation of G4R1/RHAU in HeLa T-REx cells by doxycycline-inducible short hairpin RNA caused an 8-fold loss of RNA and DNA tetramolecular quadruplex resolution, consistent with G4R1/RHAU representing the major tetramolecular quadruplex helicase activity for both RNA and DNA structures in HeLa cells. This study demonstrates for the first time the RNA quadruplex resolving enzymatic activity associated with G4R1/RHAU and its exceptional binding affinity, suggesting a potential novel role for G4R1/RHAU in targeting in vivo RNA quadruplex structures.
Pancreatoscopy for Mucus Producing Pancreatic Tumor

Abstract: The mucus producing tumor of the pancreas (MPT) is now drawing attention because of its characteristic clinical features. It is characterized by abundant secretion of mucin into the cystic cavity or the main pancreatic duct and relatively benign biological behavior. In this paper, endoscopic characteristics of MPT and the role of pancreatoscopy in the diagnosis of this entity are discussed. Eight cases of MPT with various histological backgrounds were examined with pancreatoscopy. Six cases underwent peroral pancreatoscopy and intraoperative pancreatoscopy was performed in four cases. The endoscopic findings of MPT are summarized as follows: 1) Granular change of the epithelium of the pancreatic duct. 2) Papillary tumor with dilatation of capillary vessles on its surface. 3) Irregularity or detachment of the epithelium of the pancreatic duct. The findings mentioned above in 1), 2) and 3) were obtained in three cases, two cases, and two cases, respectively. Except in one case, the border of the lesion with the neighboring normal mucosa was well identified.
α-fetoprotein and ultrasonography screening for hepatocellular carcinoma

Although there is no definitive evidence that hepatocellular carcinoma (HCC) screening in high-risk groups improves survival, many physicians screen high-risk populations with various strategies. α-fetoprotein (AFP) and liver ultrasonography (US) are the most widely used tools. AFP sensitivity and specificity depend on the cut-off value chosen. In cirrhotic patients, using a cut-off level of 20 ng/mL, sensitivity is only around 60% and positive predictive value ranges from 9% to 50%, depending on HCC prevalence. Sensitivity and specificity are much higher (94.1% and 99.9%, respectively) in hepatitis B carriers, but positive predictive value is only 5%. The performance of US as a screening tool varies widely depending on the experience of the examiner and the technology used. Recent studies generally indicate a 60% sensitivity or higher, a specificity greater than 90%, and a positive predictive value of 70%. The cost effectiveness of screening strategies using AFP, US, or both have been estimated retrospectively or using decision models. In general, HCC screening using both AFP and US appears to be of borderline cost effectiveness or not cost effective at all. Based on the estimated HCC doubling time, the recommended screening interval is 6 months, although a 1-year interval seems as effective. Currently, HCC screening with AFP only is not recommended except when US is either not available or of poor quality. US seems more efficient as a screening tool. Pathology assessment of liver explants in living-donor transplantation programs will provide more precise and reliable information regarding the value of AFP and US as HCC screening tools.
Membrane Hyperpolarization Drives Cation Influx and Fungicidal Activity of Amiodarone*

Cationic amphipathic drugs, such as amiodarone, interact preferentially with lipid membranes to exert their biological effect. In the yeast Saccharomyces cerevisiae, toxic levels of amiodarone trigger a rapid influx of Ca2+ that can overwhelm cellular homeostasis and lead to cell death. To better understand the mechanistic basis of antifungal activity, we assessed the effect of the drug on membrane potential. We show that low concentrations of amiodarone (0.1–2 μm) elicit an immediate, dose-dependent hyperpolarization of the membrane. At higher doses (>3 μm), hyperpolarization is transient and is followed by depolarization, coincident with influx of Ca2+ and H+ and loss in cell viability. Proton and alkali metal cation transporters play reciprocal roles in membrane polarization, depending on the availability of glucose. Diminishment of membrane potential by glucose removal or addition of salts or in pma1, tok1Δ, ena1-4Δ, or nha1Δ mutants protected against drug toxicity, suggesting that initial hyperpolarization was important in the mechanism of antifungal activity. Furthermore, we show that the link between membrane hyperpolarization and drug toxicity is pH-dependent. We propose the existence of pH- and hyperpolarization-activated Ca2+ channels in yeast, similar to those described in plant root hair and pollen tubes that are critical for cell elongation and growth. Our findings illustrate how membrane-active compounds can be effective microbicidals and may pave the way to developing membrane-selective agents.
Prolonged-release melatonin for the treatment of insomnia in patients over 55 years

Background: Clinical data show that poor quality, rather than quantity, of sleep corresponds negatively to measures of health, well-being and satisfaction with life. However, until now treatment of insomnia has primarily targeted quantity of sleep. PR (prolonged release)-melatonin offers a new treatment option in insomnia. Objectives: To provide an overview of PR-melatonin, the first melatonin receptor agonist to be granted marketing authorisation in Europe as monotherapy for the treatment of primary insomnia in patients aged > 55 years. Methods: Review data published in peer review journals and the EMEA (European Medicines Agency) website. Results/conclusion: PR-melatonin significantly improves morning alertness and quality of sleep compared with placebo. There are no safety concerns.
Rho-kinase Contributes to Sustained RhoA Activation through Phosphorylation of p190A RhoGAP*

RhoA is transiently activated by specific extracellular signals such as endothelin-1 (ET-1) in vascular smooth muscle cells. RhoGAP negatively regulates RhoA activity: thus, RhoA becomes the GDP-bound inactive form afterward. Sustained activation of RhoA is induced with high doses of the extracellular signals and is implicated in certain diseases such as vasospasms. However, it remains largely unknown how prolonged activation of RhoA is induced. Here we show that Rho-kinase, an effector of RhoA, phosphorylated p190A RhoGAP at Ser1150 and attenuated p190A RhoGAP activity in COS7 cells. Binding of Rnd to p190A RhoGAP is thought to enhance its activation. Phosphorylation of p190A RhoGAP by Rho-kinase impaired Rnd binding. Stimulation of vascular smooth muscle cells with a high dose of ET-1 provoked sustained RhoA activation and p190A RhoGAP phosphorylation, both of which were prohibited by a Rho-kinase inhibitor. The phosphomimic mutation of p190A RhoGAP weakened Rnd binding and RhoGAP activities. Taken together, these results suggest that ET-1 induces Rho-kinase activation and subsequent phosphorylation of p190A RhoGAP, leading to prolonged RhoA activation.
Timing of caloric intake during weight loss differentially affects striatal dopamine transporter and thalamic serotonin transporter binding

Recent studies have shown that meal timing throughout the day contributes to maintaining or regaining weight after hypocaloric diets. Although brain serotonin and dopamine are well known to be involved in regulating feeding, it is unknown whether meal timing during energy restriction affects these neurotransmitter systems. We studied the effect of a 4 wk hypocaloric diet with either 50% of daily calories consumed at breakfast (BF group) or at dinner (D group) on hypothalamic and thalamic serotonin transporter (SERT) binding and on striatal dopamine transporter (DAT) binding. The BF and D groups lost a similar amount of weight. Striatal DAT and thalamic SERT binding increased in the BF group, while decreasing in the D group after the diet (ΔDAT 0.37 ± 0.63 vs. −0.53 ± 0.77, respectively; P = 0.005; ΔSERT 0.12 ± 0.25 vs. −0.13 ± 0.26 respectively, P = 0.032). Additional voxel‐based analysis showed an increase in DAT binding in the ventral striatum in the BF group and a decrease in the dorsal striatum in the D group. During weight loss, striatal DAT and thalamic SERT binding increased weight independently when 50% of daily calories were consumed at breakfast, whereas it decreased when caloric intake was highest at dinner. These findings may contribute to the earlier reported favorable effect of meal timing on weight maintenance after hypocaloric diets. —Versteeg, R. I. , Schrantee, A. , Adriaanse, S. M. , Unmehopa, U. A. , Booij, J., Reneman, L. , Fliers, E. , la Fleur, S. E. , Serlie, M. J. Timing of caloric intake during weight loss differentially affects striatal dopamine transporter and thalamic serotonin transporter binding. FASEB J. 31, 4545–4554 (2017). www.fasebj. org
Parkin Regulates Eg5 Expression by Hsp70 Ubiquitination-dependent Inactivation of c-Jun NH2-terminal Kinase*

Eg5 is a motor protein of the kinesin family that is critical for spindle assembly during mitosis and has recently been implicated in tumorigenesis. It is largely unknown how Eg5 expression is regulated in cells. In this study, we present the first evidence that the cellular Eg5 level is down-regulated by Parkin, an E3 ubiquitin ligase well known for its role in the development of Parkinson disease. Our data show that Parkin does not trigger Eg5 protein degradation through the ubiquitin-proteasome pathway. Instead, Parkin represses Eg5 gene transcription by blocking c-Jun binding to the activator protein 1 site present in the Eg5 promoter. Our data further show that Parkin inactivates c-Jun NH2-terminal kinase (JNK), resulting in decreased phosphorylation of c-Jun. The inactivation of JNK is further mediated by multiple monoubiquitination of Hsp70. Importantly, both the ubiquitination of Hsp70 and the subsequent inactivation of the JNK-c-Jun pathway are crucial for Parkin to down-regulate Eg5 expression. These results thus uncover a novel function for Parkin in modulating the expression of Eg5 through the Hsp70-JNK-c-Jun signaling pathway.
A terapia celular no tratamento da isquemia crítica dos membros inferiores

The authors review the history of the researches on embryonic and umbilical cord vein stem cells, their advantages and disadvantages. They proceed with comments on adult stem cells, their concept, history, sources and role on tissue regenerative processes, mainly on the endothelium. They stress the importance of factors that mobilize the adult stem cells from the bone marrow: cytokines, angyopoietine and other growth factors. The adult stem cells are mobilized as endothelial progenitor cells, which have a common origin with the endothelial cells from the hemangioblasts. The mobilizing factors are activated under hypoxia and promote the homing of the endothelial progenitor cells on the ischemic sites in order to generate the neovasculogenesis, which is accomplished through three possible mechanisms: angiogenesis (new capillaries from sprouts of the existing ones), arteriogenesis (related to collateral circulation) and vasculogenesis (actual new vessels). An appraisal of the literature is made with regard to animal and clinical sets Finally, they stress that adult stem cells, although bearing an enormous potential, still demand a considerable amount of work to become a current therapeutic method.
Nitration of Solvent-exposed Tyrosine 74 on Cytochrome c Triggers Heme Iron-Methionine 80 Bond Disruption

Cytochrome c, a mitochondrial electron transfer protein containing a hexacoordinated heme, is involved in other physiologically relevant events, such as the triggering of apoptosis, and the activation of a peroxidatic activity. The latter occurs secondary to interactions with cardiolipin and/or post-translational modifications, including tyrosine nitration by peroxynitrite and other nitric oxide-derived oxidants. The gain of peroxidatic activity in nitrated cytochrome c has been related to a heme site transition in the physiological pH region, which normally occurs at alkaline pH in the native protein. Herein, we report a spectroscopic characterization of two nitrated variants of horse heart cytochrome c by using optical spectroscopy studies and NMR. Highly pure nitrated cytochrome c species modified at solvent-exposed Tyr-74 or Tyr-97 were generated after treatment with a flux of peroxynitrite, separated, purified by preparative high pressure liquid chromatography, and characterized by mass spectrometry-based peptide mapping. It is shown that nitration of Tyr-74 elicits an early alkaline transition with a pKa = 7.2, resulting in the displacement of the sixth and axial iron ligand Met-80 and replacement by a weaker Lys ligand to yield an alternative low spin conformation. Based on the study of site-specific Tyr to Phe mutants in the four conserved Tyr residues, we also show that this transition is not due to deprotonation of nitro-Tyr-74, but instead we propose a destabilizing steric effect of the nitro group in the mobile Ω-loop of cytochrome c, which is transmitted to the iron center via the nearby Tyr-67. The key role of Tyr-67 in promoting the transition through interactions with Met-80 was further substantiated in the Y67F mutant. These results therefore provide new insights into how a remote post-translational modification in cytochrome c such as tyrosine nitration triggers profound structural changes in the heme ligation and microenvironment and impacts in protein function.
Leukocyte diversity in resolving and nonresolving mechanisms of cardiac remodeling

In response to myocardial infarction (MI), time‐dependent leukocyte infiltration is critical to program the acute inflammatory response. Post‐MI leukocyte density, residence time in the infarcted area, and exit from the infarcted injury predict resolving or nonresolving inflammation. Overactive or unresolved inflammation is the primary determinant in heart failure pathology post‐MI. Here, our review describes supporting evidence that the acute inflammatory response also guides the generation of healing and regenerative mediators after cardiac damage. Time‐dependent leukocyte density and diversity and the magnitude of myocardial injury is responsible for the resolving and nonresolving pathway in myocardial healing. Post MI, the diversity of leukocytes, such as neutrophils, macrophages, and lymphocytes, has been explored that regulate the clearance of deceased cardiomyocytes by using the classic and reparative pathways. Among the innovative factors and intermediates that have been recognized as essential in acute the self‐healing and clearance mechanism, we highlight specialized proresolving mediators as the emerging factor for post‐MI reparative mechanisms—translational leukocyte modifiers, such as aging, the source of leukocytes, and the milieu around the leukocytes. In the clinical setting, it is possible that leukocyte diversity is more prominent as a result of risk factors, such as obesity, diabetes, and hypertension. Pharmacologic agents are critical modifiers of leukocyte diversity in healing mechanisms that may impair or stimulate the clearance mechanism. Future research is needed, with a focused approach to understand the molecular targets, cellular effectors, and receptors. A clear understanding of resolving and nonresolving inflammation in myocardial healing will help to develop novel targets with major emphasis on the resolution of inflammation in heart failure pathology. —Tourki, B. , Halade, G. Leukocyte diversity in resolving and nonresolving mechanisms of cardiac remodeling. FASEB J. 31, 4226–4239 (2017). www.fasebj. org
Haemonchus contortus calreticulin binds to C‐reactive protein of its host, a novel survival strategy of the parasite

Calreticulin (CalR), a Ca2+ binding multifunctional protein, is secreted by the parasitic nematode Haemonchus contortus. We have earlier observed binding of this protein to a 24‐kDa polypeptide (p24) present in an enriched preparation of prothrombin. In the present study, the identity of p24 was established as a C‐reactive protein (CRP) by several criteria. CalR binding to CRP is an elegant strategy devised by the parasite to survive in the host. The secreted CalR may achieve this either by limiting the free concentration of CRP, which has antiparasite activity or inhibit the activation of the classical complement pathway triggered on binding of CRP to C1q protein. CalR binding to CRP would also ensure a check on the procoagulant activity of the CRP enabling parasite to feed on the host blood. Thus, targeting CalR could be a novel strategy to tackle this parasite, which has developed resistance to many anthelmintics.