Miracle-dz/UniFAR-FTUs huggingface dataset:
Long-term drug survival and predictor analysis of the whole psoriatic patient population on biological therapy in Hungary

Abstract Persistence is an important component of therapeutic success, which depends on a variety of factors. Persistence measured under optimal conditions during clinical trials does not necessarily coincide with persistence observed in the real-world settings. The aim of the present study was to compare persistence rate of TNF-alpha inhibitors and interleukin 12/23 inhibitor in all psoriasis patients in Hungary, as well as to analyze the predictors of persistence. Data collected from 1263 patients over a period of 46 months were subjected to a retrospective analysis. Drug survival rate has been calculated according to Kaplan–Meier analysis and Cox regression was used to study the predictors. The overall persistence rate for the four biologicals exceeded 60% after 3 years. The persistence rate of ustekinumab at 3 years was 67.83%, which was superior compared to that of the TNF-alpha inhibitors, where the mean persistence rate was shown to be 50.76% (p < .05). Male patients showed significantly higher persistence than females (HR = .76, p < .05 CI: 0.63, 0.92). Age, therapy-naïve status and use of concomitant MTX did not have significant effect on drug survival. Persistence rate of ustekinumab was significantly higher than that of TNF-alpha inhibitors, and among predictors, only male gender influenced persistence significantly.
Clinical correlates and prognostic value of different metastatic sites in patients with malignant melanoma of the skin: a SEER database analysis

Abstract Background: Population-based data on the clinical correlates and prognostic value of the pattern of metastases among patients with cutaneous melanoma are needed. Methods: Surveillance, Epidemiology and End Results (SEER) database (2010–2013) has been explored through SEER*Stat program. For each of six distant metastatic sites (bone, brain, liver, lung, distant lymph nodes, and skin/subcutaneous), relevant correlation with baseline characteristics were reported. Survival analysis has been conducted through Kaplan–Meier analysis, and multivariate analysis has been conducted through a Cox proportional hazard model. Results: A total of 2691 patients with metastatic cutaneous melanoma were identified in the period from 2010 to 2013. Patients with isolated skin/subcutaneous metastases have the best overall and melanoma-specific survival (MSS) followed by patients with isolated distant lymph node metastases followed by patients with isolated lung metastases. Patients with isolated liver, bone, or brain metastases have the worst overall and MSS (p < .0001 for both end points). Multivariate analysis revealed that age more than 70 at diagnosis (p = .012); multiple sites of metastases (p <.0001), no surgery to the primary tumor (p <.0001), and no surgery to the metastatic disease (p < .0001) were associated with worse overall survival (OS). For MSS, nodal positivity (p = .038), multiple sites of metastases (p < .0001), no surgery to the primary tumor (p < .0001), and no surgery to the metastatic disease (p < .0001) were associated with worse survival. Conclusions: The prognosis of metastatic cutaneous melanoma patients differs considerably according to the site of distant metastases. Further prospective studies are required to evaluate the role of local treatment in the management of metastatic disease.
Towards the use of non‐psychoactive cannabinoids for prostate cancer

The palliative effects of Cannabis sativa (marijuana), and its putative main active ingredient, Δ9‐tetrahydrocannabinol (THC), which include appetite stimulation, attenuation of nausea and emesis associated with chemo‐ or radiotherapy, pain relief, mood elevation, and relief from insomnia in cancer patients, are well‐known. Because of the adverse psychoactive effects of THC, numerous recent preclinical studies have been focused on investigating other non‐psychoactive constituents of C. sativa, such as cannabidiol, for potential therapeutic use. In this issue of the British Journal of Pharmacology, De Petrocellis and colleagues present comprehensive evidence that plant‐derived cannabinoids, especially cannabidiol, are potent inhibitors of prostate carcinoma viability in vitro. They also showed that the extract was active in vivo, either alone or when administered with drugs commonly used to treat prostate cancer (the anti‐mitotic chemotherapeutic drug docetaxel (Taxotere) or the anti‐androgen bicalutamide (Casodex)) and explored the potential mechanisms behind these antineoplastic effects.
Effectiveness of etanercept in children with plaque psoriasis in real practice: a one-year multicenter retrospective study

Abstract Background: Etanercept is licensed for the treatment of moderate-to-severe plaque psoriasis in children. Objectives: The aim of this analysis was to investigate effectiveness, tolerability, and reasons for discontinuation of etanercept in a real-life cohort of children and adolescents with moderate to severe plaque psoriasis. Methods: Data collected from a number of centers belonging to the ‘Pediatric Dermatology Group’ of the Italian Society of Dermatology (SIDeMaST) were examined in patients (age ≤17 years) who started treatment with etanercept from 2011 to 2015. A group of 23 patients were identified. Efficacy assessment was defined as the proportion of patients with a ≥50% and ≥75% improvement in Psoriasis Area Severity Index (PASI) at weeks 12, 24, and 52. Safety was evaluated on adverse event reporting. Reasons for discontinuation were classified as ineffectiveness, adverse events, remission, or other reasons. Results: At week 12, 56.5% of patients achieved PASI 75, 86.9% achieved PASI 50. Efficacy was sustained through week 52. In 15 patients etanercept was still ongoing at the time of data collection. In three patients the therapy was suspended due to inefficacy. The medication was overall well tolerated. Conclusions: Etanercept was an effective and well-tolerated treatment in this real-life cohort of patients.
Carbamazepine directly inhibits adipocyte differentiation through activation of the ERK 1/2 pathway

Carbamazepine (CBZ), known for its anti‐epileptic, analgesic and mood‐stabilizing properties, is also known to induce weight gain but the pathophysiology of this adverse effect is still largely unknown. We tested the hypothesis that CBZ could have a direct effect on adipocyte development and metabolism.
MT1‐Selective Melatonin Receptor Ligands: Synthesis, Pharmacological Evaluation, and Molecular Dynamics Investigation of N‐{[(3‐O‐Substituted)anilino]alkyl}amides

The design of compounds selective for the MT1 melatonin receptor is still a challenging task owing to the limited knowledge of the structural features conferring selectivity for the MT1 subtype, and only few selective compounds have been reported so far. N‐(Anilinoalkyl)amides are a versatile class of melatonin receptor ligands that include nonselective MT1/MT2 agonists and MT2‐selective antagonists. We synthesized a new series of N‐(anilinoalkyl)amides bearing 3‐arylalkyloxy or 3‐alkyloxy substituents at the aniline ring, looking for new potent and MT1‐selective ligands. To evaluate the effect of substituent size and shape on binding affinity and intrinsic activity, both flexible and conformationally constrained derivatives were prepared. The phenylbutyloxy substituent gave the best result, providing the partial agonist 4 a, which was endowed with high MT1 binding affinity (pKi=8.93) and 78‐fold selectivity for the MT1 receptor. To investigate the molecular basis for agonist recognition, and to explain the role of the 3‐arylalkyloxy substituent, we built a homology model of the MT1 receptor based on the β2 adrenergic receptor crystal structure in its activated state. A binding mode for MT1 agonists is proposed, as well as a hypothesis regarding the receptor structural features responsible for MT1 selectivity of compounds with lipophilic arylalkyloxy substituents.
Padronização de condições para detecção de DNA de Leishmania spp. em flebotomíneos (Diptera, Psychodidae) pela reação em cadeia da polimerase

The correct identification of etiological agents in vector insects is crucial for epidemiological studies. Identification of flagellates in such vectors, usually by dissection of the digestive tract and microscopic observation of the contents as well as attempts at parasite isolation from insects in culture media, have proven operationally inadequate and with poor diagnostic specificity, since female sand flies are also hosts for other flagellates like Trypanosoma and Endotrypanum. Due to the efficiency and specificity of DNA target sequence amplification by polymerase chain reaction (PCR), the latter could be used to investigate the presence of Leishmania in sand flies, although the insects need to be properly stored and the Leishmania DNA extracted using appropriate methodology. This paper describes methodologies to standardize sand fly storage and Leishmania DNA extraction in such specimens as a more practical method in field studies.
The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL‐4 and IL‐10

Anti‐complement therapies have not been advanced for treating the inflammatory bowel diseases (IBDs) despite a growing body of evidence that blocking C5a protects against induced colitis in rodents. The purpose of this study was to further build on this evidence by examining the efficacy, mechanism and specificity of a potent, non‐competitive and orally active C5a receptor (CD88) antagonist, PMX205, in the dextran sulphate sodium (DSS) model of murine innate colitis.
Differential effects of cathinone compounds and MDMA on body temperature in the rat, and pharmacological characterization of mephedrone‐induced hypothermia

Recreational users report that mephedrone has similar psychoactive effects to 3,4‐methylenedioxymethamphetamine (MDMA). MDMA induces well‐characterized changes in body temperature due to complex monoaminergic effects on central thermoregulation, peripheral blood flow and thermogenesis, but there are little preclinical data on the acute effects of mephedrone or other synthetic cathinones.
Effect of neutron capture therapy on the cell cycle of human squamous cell carcinoma cells

Purpose: The effects of boronophenylalanine (BPA)-mediated boron neutron capture therapy (BNCT) on the growth potential and cell cycle of human oral squamous cell carcinoma (SCC) cells were examined. Materials and methods: SAS cells expressing a functional wild-type p53 were exposed to neutron beams in the presence of BPA and growth potential was measured by colony formation assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The cell cycle and cell cycle-related proteins were examined by flow cytometry and immunoblot analysis. Results: BNCT affected the colony-forming ability and viability of SAS cells. In the flow-cytometric analysis of BNCT-treated cells, the cell cycle was arrested at the G1 and G2 checkpoints, and sub-G1 cells appeared. Apoptotic cells were detected by nuclear DNA staining. Immunoblot analysis revealed the phosphorylation of p53, up-regulation of p21, and down-regulation of retinoblastoma (Rb) gene protein at 6 h after BNCT. Twelve hours after BNCT, the up-regulation of Wee1, phosphorylation of cdc2, and up-regulation of cyclin B1 were observed. Cleavage of poly (ADP-ribose) polymerase (PARP) occurred from 6 h after BNCT. Conclusion: These results indicate that the early inhibitory effect of BNCT on the growth of human oral SCC cells can be ascribed to arrest at the G1 and G2 checkpoints and apoptosis associated with G1 arrest.
Status of Antepartum Depression and Its Influencing Factors in Pregnant Women

The purpose of this study was to identify the rate and influencing factors on antepartum depression in pregnant women. A self-administered questionnaire-based study was performed in 160 pregnant women who visited outpatient clinics or attended special lectures of the general hospital in D metropolitan city. All participants were interviewed using the Korean version of Edinburgh Postnatal Depression Scale(EPDS). The data were analyzed using descriptive statistics, t-test, ANOVA, Pearson's correlation coefficients, and stepwise multiple regression. On the results, the mean score of antepartum depression was 7.80±4.86 scores(0-30 scores). The percentage of all participants for EPDS scale were 56.3% with normal level, 20.6% with a boundary line and 23.1% with serious level. Influencing factors on antepartum depression were accounted for 36.7% of the total variance which consisted of perceived health status, pregnancy stress and self esteem. The results indicate that these variables should be considered in preventing depression of pregnant women.
PARS PLANA VITRECTOMY FOR DIABETIC MACULAR EDEMA: A Systematic Review, Meta-Analysis, and Synthesis of Safety Literature

Purpose: To assess the risk and benefit of pars plana vitrectomy for diabetic macular edema. Methods: The authors conducted a systematic literature review using PubMed, EMBASE, Web of Science, and Cochrane Central Database of Controlled Trials until September 2014. The population was patients with diabetic macular edema, intervention vitrectomy, comparator macular laser or observation, and efficacy outcome visual acuity and central retinal thickness. Safety outcomes were intraoperative and postoperative surgical complications. The efficacy meta-analysis included only randomized controlled trials. The safety analysis included prospective, retrospective, controlled, and uncontrolled studies. Results: Five studies were eligible for the efficacy meta-analysis (n = 127 eyes) and 40 for the safety analysis (n = 1,562 eyes). Combining follow-up intervals from 6 to 12 months, the meta-analysis found a nonsignificant 2 letter visual acuity difference favoring vitrectomy, and a significant 102 &mgr;m greater reduction in central retinal thickness favoring vitrectomy, but a post hoc subgroup analysis found that a 6-month central retinal thickness benefit reversed by 12 months. The most frequent complications were retinal break (7.1%), elevated intraocular pressure (5.2%), epiretinal membrane (3.3%), and vitreous hemorrhage (2.4%). Cataract developed in 68.6% of 121 phakic eyes. Conclusion: Vitrectomy produces structural and functional improvements in select eyes with diabetic macular edema, but the visual gains are not significantly better than with laser or observation. No major safety concerns were identified.
CHOROIDAL AND RETINAL ATROPHY OF BIETTI CRYSTALLINE DYSTROPHY PATIENTS WITH CYP4V2 MUTATIONS COMPARED TO RETINITIS PIGMENTOSA PATIENTS WITH EYS MUTATIONS

Purpose: To compare atrophy of the choroid and retina between Bietti crystalline dystrophy (BCD) patients and EYS-related retinitis pigmentosa (RP) patients with a similar degree of central visual field defects, age, and axial length (AL). Methods: Nine eyes of nine BCD patients with CYP4V2 mutations (BCD group) were examined. Moreover, we selected 10 eyes of 10 RP patients with EYS mutations matched for age, axial length, and mean deviation (measured with the 10-2 SITA standard program; EYS-RP group), and 10 eyes of 10 normal volunteers matched for age and axial length (control group). Macular thicknesses of the choroid and retina were measured via swept-source optical coherence tomography. Results: The macular choroid was significantly thinner in the BCD group than in the EYS-RP and control groups, although the thickness did not significantly differ between the EYS-RP and control groups. The macular retina was significantly thinner in the BCD and EYS-RP groups than in the control group, although the thickness did not significantly differ between the BCD and EYS-RP groups at most sites. Conclusion: Bietti crystalline dystrophy patients with CYP4V2 mutations showed more severe macular choroid atrophy as compared to EYS-related RP patients. These different damage patterns suggest differences in choroidal expression between CYP4V2 and EYS.
Distal Chevron Osteotomy for Correction of Hallux Valgus Deformity

Distal chevron osteotomy has been used successfully for correction of mild to moderate hallux valgus deformity as an alternative to modified McBride bunionectomy for many years. Patients who have experienced a successful outcome typically have less than 35° of hallux valgus deformity and intermetatarsal angles of less than 15°. Pitfalls of distal chevron osteotomy include shortening of the first metatarsal shaft, nonunion and malunion of the osteotomy, transfer metatarsalgia, avascular necrosis of the first metatarsal head, and subsequent joint stiffness. The distal chevron osteotomy can be augmented with a release of the lateral joint capsule and adductor hallucis tendon through the medial joint space. This release often provides better sesamoid correction and has not been associated with avascular necrosis if performed properly.
Computer‐Aided Design, Synthesis and Validation of 2‐Phenylquinazolinone Fragments as CDK9 Inhibitors with Anti‐HIV‐1 Tat‐Mediated Transcription Activity

The activity of the cyclin‐dependent kinase 9 (CDK9) is critical for HIV‐1 Tat‐mediated transcription and represents a promising target for antiviral therapy. Here we present computational studies that, along with preliminary synthetic efforts, allowed us to identify and characterize a new class of nontoxic anti‐CDK9 chemotypes based on the 2‐phenylquinazolinone scaffold. Inhibition of CDK9 translated into the ability to interfere selectively with Tat‐mediated transactivation of the viral promoter and in the inhibition of HIV‐1 reactivation from latently infected cells, with the most potent derivative 37 (2‐(4‐aminophenyl)‐7‐chloroquinazolin‐4(3H)‐one) showing an IC50 value of 4.0 μM. Because the herein reported 2‐phenylquinazolinones are merely fragments, they are largely optimizable, paving the way to derivatives with improved potency.
Results of randomized phase II trial combining Iressa® (gefitinib) and arimidex in women with advanced breast cancer (ABC). EORTC protocol 10021.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #6133 Background: Preclinical data suggest that EGFR inhibitors could overcome endocrine resistance in breast cancer. This European multicenter, double-blind, placebo-controlled trial was designed to test the hypothesis that Gefitinib (G), as inhibitor of the EGFR pathway, can delay the onset of endocrine resistance in ABC. Methods: Postmenopausal patients (pts) previously treated for ABC (including locally recurrent or metastatic or elderly with locally ABC or bone metastases only) were randomly assigned in a 1:1 ratio to G 250 mg/day plus anastrozole (A, 1 mg/day) or to placebo plus A. Prior treatment with an aromatase inhibitor in metastatic setting or trastuzumab or anti EGF or anti VEGF was not allowed. Treatment was given until progression of the disease, unacceptable toxicity or patient refusal and the progression free rate was assessed at one year with disease evaluations according to RECIST performed every 8 weeks. Results: The trial was prematurely closed in August 2007 due to slow recruitment. Seventy one out of a planned 108 pts were entered with a median age of 64 (range 42-84). 26 pts had prior chemotherapy and 43 prior endocrine therapy (adjuvant tamoxifen 60% and metastatic 16%). Median PS was 0 and 41 pts had visceral disease. To date, 326 months of treatment have been fully documented, for a median duration of 6 months. For 36 pts end of treatment has been reported: 26 due to progression and 6 due to toxicity (including one SAE: diarrhea gr 3 and spastic dyspnea gr 2). The most common adverse events were fatigue (49%), arthralgia/myalgia (39%), nausea (37%), diarrhea (35%), rash (35%), bone pain (29%), and hot flushes (26%). To date, the estimated progression free rate at one year is 42%. Conclusion: All patients will reach one year of follow up in August 2008. The database has not been unblinded yet. By the time of the conference unblinded final results will be available. A late breaking abstract will be sent in September. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6133.
AIR TAMPONADE COMBINED WITH NONSUPINE POSITIONING IN MACULAR HOLE SURGERY FOR PSEUDOPHAKIC EYES

Purpose: To investigate the closure rate of primary full-thickness macular hole, following intraocular air tamponade combined with a nonsupine positioning regimen. Methods: A prospective study of patients with full-thickness macular hole, who underwent pars plana vitrectomy with internal limiting membrane peeling and intraocular air tamponade followed by 3 days of nonsupine positioning. Outcome measures were primary full-thickness macular hole closure and improvement in best-corrected visual acuity after 6 months. Results: A total of 34 eyes were included. In the group of full-thickness macular hole ⩽400 &mgr;m, primary closure occurred in 95% (19/20), whereas only 57% (8/14) of those >400 &mgr;m closed (P = 0.01). The mean gain in best-corrected visual acuity was 3.5 ETDRS (Early Treatment Diabetic Retinopathy Study) lines (SD = 1.5) (P < 0.01). The air bubble meniscus height at the first postoperative day was estimated to a mean of 59% (range, 50–70%), at the second postoperative day it was 46% (range, 40–55%), and the third day it was 39% (range, 30–45%). Mean intraocular air bubble duration was 10 days (range, 8–13 days). Conclusion: The combination of air tamponade and nonsupine positioning regimen leads to high closure rates for small/medium macular holes (⩽400 &mgr;m), but not for large macular holes (>400 &mgr;m).
Mitochondrial KATP channels and cardioprotection

Since its identification in 1983, the myocardial ATP‐sensitive potassium channel (KATP channel) has been recognized as an important ion channel that couples the cellular energy status to electrical activity in ischemic or hypoxic myocytes, and early studies with selective potassium channel openers suggested that opening this channel may result in cellular protection. This concept was strengthened in 1992, when it was shown that this channel was an integral part of ischemic preconditioning (IPC), a phenomenon in which one or several short periods of coronary artery occlusion were shown to protect the heart from a more prolonged coronary artery occlusion. Endpoints of injury, which have been used as indices to demonstrate the efficacy of IPC, include a reduction in myocardial infarct size, a reduction in contractile dysfunction after brief periods of ischemia (myocardial stunning), and a decrease in the incidence of cardiac arrhythmias during coronary artery occlusion and/or reperfusion. Since the seminal observation of a myocrdial KATP channel, two KATP channels have been identified: one in the sarcolemmal membrane (sarc KATP) and one in the inner mitochondrial membrane (mito KATP). There is evidence to support a role for both channels in mediating cardioprotection; however, the majority of recent evidence suggests that the mito KATP channel is the major channel responsible for cardioprotection after IPC or the administration of KATP opener drugs. This review will summarize the evidence supporting a role for the mito KATP channel in both acute and delayed preconditioning produced by ischemia. The review will also summarize, from a pharmacological viewpoint, the potential mechanisms responsible for the cardioprotection observed and the potential clinical implications of developing drugs that are selective mito KATP channel openers. Drug Dev. Res. 55:17–21, 2002. © 2002 Wiley‐Liss, Inc.