Miracle-dz/UniFAR-FTUs huggingface dataset:
Differential mechanisms of CDKN2A (p16) alteration in oral tongue squamous cell carcinomas and correlation with patient outcome

CDKN2A (p16) disruption is reported as a frequent event in head and neck squamous cell carcinomas that confers poor prognosis. We investigated the frequency of different potential mechanisms of CDKN2A inactivation in oral tongue squamous cell carcinomas (OTSCC) and their impact on patient outcome. From a cohort of 153 OTSCC patients, 131 formalin fixed paraffin embedded blocks of pre‐treatment primary tumours were suitable for further molecular analysis. We assessed CDKN2A (p16) levels by immunohistochemistry (IHC), promoter methylation status by methylation‐sensitive high resolution melting, mutation status by Sanger sequencing, gene copy number variation by fluorescence in situ hybridisation, and correlated these with patient outcome. We found that the majority of OTSCC did not overexpress p16 (110/116, 95%), assessed by IHC. The frequency of CDKN2A mutations was 20% (21/103), homozygous loss was 7% (7/97), hemizygous loss 31% (30/97), and promoter methylation was 18% (20/113). We found no evidence of these mechanisms in 24/106 (23%) p16 IHC negative tumours. No significant correlation was identified between any potential mechanism of CDKN2A inactivation and clinical features, including smoking status and age. There was a non‐significant trend for worse overall survival for p16 IHC negative patients versus positive patients (HR = 1.81, 95% CI = 0.44–7.47, p = 0.40). No relationship was found between mechanisms of CDKN2A disruption and patient outcome. In conclusion, we demonstrate that CDKN2A alteration is a frequent event in OTSCC tumourigenesis. However, no correlation was identified between different potential mechanisms of CDKN2A disruption and clinical characteristics or patient outcome.
Educators’ Adherence to Learning Theories and Their Perceptions on the Advantages and Disadvantages of e-Learning

Information and Communication Technologies (ICTs) are pervasive nowadays, including in education where they are expected to improve the performance of learners. However, the hope placed in ICTs to find viable solutions to the problem of poor academic performance in schools in the developing world has not yet yielded the expected benefits. This problem serves as a motivation to this study whose aim is to examine the perceptions of educators on the advantages and disadvantages of e-learning. This aim will be subdivided into two types of research objectives. Objectives on the identification and design of theories and models will be achieved using content analysis and literature review. However, the objective on the empirical testing of such theories and models will be achieved through the survey of educators from different schools in the Pinetown District of the South African Kwazulu-Natal province. SPSS is used to quantitatively analyse the data collected by the questionnaire of this survey using descriptive statistics and Pearson correlations after assessing the validity and the reliability of the data. The main hypothesis driving this study is that there is a relationship between the demographics of educators’ and their adherence to learning theories on one side, and their perceptions on the advantages and disadvantages of e-learning on the other side, as argued by existing research; but this research views these learning theories under three perspectives: educators’ adherence to self-regulated learning, to constructivism, and to progressivism. This hypothesis was fully confirmed by the empirical study except for the demographic factor where teachers’ level of education was found to be the only demographic factor affecting the perceptions of educators on the advantages and disadvantages of e-learning. Keywords—Academic performance, e-learning, Learning theories, Teaching and Learning.
Comparative evaluation of two flowcytometric analysers as diagnostic tools for the automated detection of malaria.

GOALS Automated flowcytometric analysers are used to analyse complete blood count (CBC) in most patients. They differentiate WBC depending on their size, internal granularity, and nuclear content by producing various scattergrams. In malaria, haemozoin pigment-containing cells (parasitized RBC and phagocytic cells) are able to depolarize the laser beam and therefore exhibit abnormal scattergram. PROCEDURE A study was conducted to evaluate the diagnostic utility and to determine the sensitivity and specificity of flowcytometric haematology analysers [Sysmex XE-2100 (System 1) and Cell-Dyn 3700 (System 2)] in comparison with the conventional microscopy (QBC, AO, Giemsa) and ICT (Immunochromatographic test) for detection of the malaria parasite. RESULTS Fifty-eight of 320 samples were found to be positive for malaria by conventional methods. Considering atypical scattergram, System 1 showed the sensitivity and specificity of 68.9% and 90.6%, respectively; whereas System 2 showed a sensitivity of 100% and specificity of 98.8%. CONCLUSION System 2 (Cell-Dyn 3700) was found to be a highly sensitive and specific tool compared to System 1 and conventional methods. Hence, it may be preferred for automated detection of malaria in the blood samples of patients with a differential diagnosis of malaria and those who are subjected to CBC analysis.
Evaluation of Biomarker Modulation by Fenretinide in Prostate Cancer Patients

An NCI-sponsored, phase II trial of N-(4-hydroxyphenyl)- retinamide (4-HPR) in patients with organ-confined prostate cancer in the period prior to radical prostatectomy was carried out. Thirty-seven men with the histologic diagnosis of prostate cancer planning to have radical prostatectomy entered the study after informed consent and were given 4-HPR (or matching placebo) as a single daily dose (two 100-mg capsules of 4-HPR or two capsules of placebo daily) for 3 weeks prior to surgery. Four men dropped out for unrelated reasons. Thirty-three men completed the study. At the time of surgery, repeat biopsies of the prostate were performed to study the effects of the drug on potential surrogate endpoint biomarkers (SEBs) of malignancy within the tissue. The panel of potential SEBs of malignancy include p53, cytomorphometric indices, ploidy, PNCA, erbB-2, erbB-3, EGF receptor, TGF-α tumor-associated glycoprotein-72, fatty acid synthetase and Lewis Y antigen. Twenty-three patients had matching pre- and posttherapy lesions and were considered informative. Results from the patients indicate significant differential expression of biomarkers in pretreatment specimens of uninvolved prostatic tissue (normal-appearing epithelia) prostatic intraepithelial neoplasia (PIN) and prostate cancer. The mean erbB-2 expression was 0.58 in uninvolved vs. 1.04 in PIN (p = 0.002); while the mean erbB-2 expression was 1.35 in prostate cancer (p = 0.0007, uninvolved vs. prostate cancer). A similar pattern of increased biomarker expression between uninvolved and PIN or prostate cancer tissues can be observed for EGF receptor (mean = 1.21, 1.87 and 1.76 for uninvolved, PIN and prostate cancer, respectively) and erbB-3 (mean = 0.81, 1.59 and 1.30 for uninvolved, PIN and prostate cancer, respectively). There were no statistically significant differences in biomarkers observed in the 4-HPR-treated patients when compared with placebo-treated control patients. There was a posttreatment up-regulation of biomarkers observed in both groups of patients. This observation is most likely explained by an effect due to the diagnostic sextant biopsy equally affecting both groups of patients. Results from this study do not demonstrate a chemoprevention effect of 4-HPR on tissue-based SEBs at the dose given.
Identification of a Novel Protein with Guanylyl Cyclase Activity in Arabidopsis thaliana *

Guanylyl cyclases (GCs) catalyze the formation of the second messenger guanosine 3′,5′-cyclic monophosphate (cGMP) from guanosine 5′-triphosphate (GTP). While many cGMP-mediated processes in plants have been reported, no plant molecule with GC activity has been identified. When the Arabidopsis thalianagenome is queried with GC sequences from cyanobacteria, lower and higher eukaryotes no unassigned proteins with significant similarity are found. However, a motif search of the A. thalianagenome based on conserved and functionally assigned amino acids in the catalytic center of annotated GCs returns one candidate that also contains the adjacent glycine-rich domain typical for GCs. In this molecule, termed AtGC1, the catalytic domain is in the N-terminal part. AtGC1 contains the arginine or lysine that participates in hydrogen bonding with guanine and the cysteine that confers substrate specificity for GTP. When AtGC1 is expressed in Escherichia coli, cell extracts yield >2.5 times more cGMP than control extracts and this increase is not nitric oxide dependent. Furthermore, purified recombinant AtGC1 has Mg2+-dependent GC activity in vitro and >3 times less adenylyl cyclase activity when assayed with ATP as substrate in the absence of GTP. Catalytic activity in vitro proves that AtGC1 can function either as a monomer or homo-oligomer. AtGC1 is thus not only the first functional plant GC but also, due to its unusual domain organization, a member of a new class of GCs.
Randomized trial comparing six versus three cycles of epirubicin-based adjuvant chemotherapy in premenopausal, node-positive breast cancer patients: 10-year follow-up results of the French Adjuvant Study Group 01 trial.

PURPOSE To evaluate the duration and dose intensity of epirubicin-based regimens in premenopausal patients with lymph node-positive breast cancer. PATIENTS AND METHODS Between 1986 and 1990, 621 patients with operable breast cancer were randomly assigned to receive fluorouracil (Roche SA, Basel, Switzerland) 500 mg/m2, epirubicin (Pharmacia SA, Milan, Italy) 50 mg/m2, and cyclophosphamide (Asta Medica AG, Frankfurt, Germany) 500 mg/m2 every 21 days (FEC 50) for six cycles (6 FEC 50); FEC 50 for three cycles (3 FEC 50); or the same regimen with epirubicin 75 mg/m2 (FEC 75) for three cycles (3 FEC 75). All patients in the three arms received chest wall irradiation at the end of the third cycle. RESULTS After a 131-month median follow-up, the 10-year disease-free survival (DFS) was 53.4%, 42.5%, and 43.6% (P =.05) in the three arms, respectively. Pairwise comparisons demonstrate that 6 FEC 50 was superior both to 3 FEC 50 (P =.02) and to 3 FEC 75 (P =.05). The 10-year overall survival (OS) for the 6 FEC 50 arm was 64.3%, for the 3 FEC 50 arm it was 56.6%, and for the 3 FEC 75 arm, it was 59.7% (P =.25), respectively. Pairwise comparisons demonstrate that 6 FEC 50 was more effective than 3 FEC 50 (P =.10). Cox regression analysis demonstrates that OS was significantly better in the 6 FEC 50 than in the 3 FEC 50 arm (P =.046). No severe infections (grade 3 to 4), acute cardiac toxicity, or deaths from toxicity have been observed. Only five patients developed delayed cardiac dysfunctions, and three patients developed acute myeloblastic leukemia. CONCLUSION After a long-term follow-up in an adjuvant setting, the benefit of six cycles of FEC 50 compared with three cycles, whatever the dose, is highly significant in terms of DFS. As regards OS, the group receiving six cycles of FEC 50 has significantly better results than the group receiving three cycles of FEC 50.
Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection.

BACKGROUND Effective treatment for hepatitis C virus (HCV) genotype 1 infection in patients who have not had a sustained virologic response to prior interferon-based therapy represents an unmet medical need. METHODS We conducted a phase 3, randomized, open-label study involving patients infected with HCV genotype 1 who had not had a sustained virologic response after treatment with peginterferon and ribavirin, with or without a protease inhibitor. Patients were randomly assigned to receive the NS5A inhibitor ledipasvir and the nucleotide polymerase inhibitor sofosbuvir in a once-daily, fixed-dose combination tablet for 12 weeks, ledipasvir-sofosbuvir plus ribavirin for 12 weeks, ledipasvir-sofosbuvir for 24 weeks, or ledipasvir-sofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS Among the 440 patients who underwent randomization and were treated, 20% had cirrhosis and 79% had HCV genotype 1a infection. The rates of sustained virologic response were high in all treatment groups: 94% (95% confidence interval [CI], 87 to 97) in the group that received 12 weeks of ledipasvir-sofosbuvir; 96% (95% CI, 91 to 99) in the group that received 12 weeks of ledipasvir-sofosbuvir and ribavirin; 99% (95% CI, 95 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir; and 99% (95% CI, 95 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir and ribavirin. No patient discontinued treatment owing to an adverse event. The most common adverse events were fatigue, headache, and nausea. CONCLUSIONS Treatment with a once-daily, single-tablet regimen of ledipasvir and sofosbuvir resulted in high rates of sustained virologic response among patients with HCV genotype 1 infection who had not had a sustained virologic response to prior interferon-based treatment. (Funded by Gilead Sciences; ION-2 ClinicalTrials.gov number, NCT01768286.).
Disrupted RabGAP Function of the p85 Subunit of Phosphatidylinositol 3-Kinase Results in Cell Transformation*

Rab proteins regulate vesicle fusion events during the endocytosis, recycling, and degradation of activated receptor tyrosine kinases. The p85α subunit of phosphatidylinositol 3-kinase has GTPase-activating protein activity toward Rab5 and Rab4, an activity severely reduced by a single point mutation (p85-R274A). Expression of p85-R274A resulted in increased platelet-derived growth factor receptor (PDGFR) activation and downstream signaling (Akt and MAPK) and in decreased PDGFR degradation. We now report that the biological consequences of p85-R274A expression cause cellular transformation as determined by the following: aberrant morphological phenotype, loss of contact inhibition, growth in soft agar, and tumor formation in nude mice. Immunohistochemistry shows that the tumors contain activated PDGFR and high levels of activated Akt. Coexpression of a dominant negative Rab5-S34N mutant attenuated these transformed properties. Our results demonstrate that disruption of the RabGAP function of p85α due to a single point mutation (R274A) is sufficient to cause cellular transformation via a phosphatidylinositol 3-kinase-independent mechanism partially reversed by Rab5-S34N expression. This critical new role for p85 in the regulation of Rab function suggests a novel role for p85 in controlling receptor signaling and trafficking through its effects on Rab GTPases.
The outcome of bladder neck closure in children with severe urinary incontinence.

PURPOSE We evaluated the outcome of children who underwent bladder neck closure for the management of severe urinary incontinence. MATERIALS AND METHODS Bladder neck closure was performed in 12 patients with bladder exstrophy, 4 with myelomeningocele and 4 with urogenital sinus anomalies for severe urinary incontinence that persisted after multiple failed bladder outlet procedures. The effectiveness of bladder neck closure and the need for subsequent surgeries were ascertained. RESULTS Mean followup was 5.4 years (range 1 to 12). At 3 months after surgery 40% of the patients were completely dry, 20% had leakage via the stoma and 40% had a urethral fistula. After additional surgeries 85% of the patients were completely continent 2 years following bladder neck closure (15% declined further surgeries or had an ileal conduit). Of the 15 patients with followup longer than 3 years only 40% remained completely dry, and leakage via the stoma developed in 47% after being dry for 1 year. Repeat urodynamic studies did not show any adverse changes in bladder dynamics in the incontinent patients. Stomal stenosis occurred in 30% of the patients and bladder stones developed in 40%. None of the patients had hydronephrosis or bladder perforation. The early complication of fistula formation and the late development of leakage via the stoma appear to be related in part to compliance with intermittent catheterization. CONCLUSIONS Bladder neck closure is an effective method of achieving urinary continence in children in whom other bladder outlet surgery has failed. However, its success is dependent in part upon compliance with intermittent catheterization. Finally children who have undergone bladder neck closure are at an increased risk for stomal stenosis and bladder stones.
Immunohistochemical expression of endothelin protein in oral squamous cell carcinoma.

CONTEXT Endothelin-1 (ET-1) plays a significant role in cancer biology and is considered as a potential target for molecular therapy. Alteration of ET-1 was detected in oral squamous cell carcinoma (OSCC). AIM To evaluate the immunohistochemical expression and distribution of ET-1 in OSCC and to correlate its expression with the degree of histopathologic differentiation as well as the regional metastatic status of OSCC. MATERIALS AND METHODS The immunohistochemical expression and distribution of ET-1 was evaluated in total number of 30 cases of OSCC. The specimens were retrieved as formalin-fixed, paraffin-embedded blocks from the archival files. Detection of ET-1 expression in different grades of metastatic and non-metastatic OSCC was quantified using an image analyzer computer system. STATISTICAL ANALYSIS USED Statistical software package SPSS v. 19. RESULTS ET-1 immunoreactivity was observed in all studied specimens. On comparing optical density values for ET-1 expression in different grades of OSCC, poorly differentiated OSCC showed a significantly greater expression than moderately differentiated OSCC, which was also significantly greater than well-differentiated OSCC ( P = 0.001). Moreover, ET-1 expression was higher in metastatic OSCC than that in non-metastatic OSCC ( P = 0.018). CONCLUSIONS Increased ET-1 expression could enhance the aggressive behavior of poorly differentiated OSCC, especially metastasis. Accordingly, ET-1 could be a therapeutic target in OSCC.
Reducing antipsychotic medication in people with a learning disability

Background The use of antipsychotic drugs in people with learning disabilities is currently receiving intensified scrutiny and attempts are being made to reduce it. Aims A randomised controlled trial was designed to investigate factors influencing antipsychotic drug reduction among people with learning disabilities prescribed such medication for behavioural problems. Method Thirty-six participants randomly allocated to the experimental group underwent four, monthly 25% drug reduction stages. There were no planned drug changes for the control group (n = 20). Results Twelve participants (33%) completed full withdrawal; afurther seven (19%) achieved and maintained at least a 50% reduction. Drug reduction was associated with increased dyskinesia and higher activity engagement but not increased maladaptive behaviour. Some setting characteristics were associated with drug reinstatement. Conclusions A substantial proportion of people with learning disability prescribed antipsychotic medications for behavioural purposes rather than for treating psychotic illness can have their drugs reduced or withdrawn.
Oral appliances for managing sleep bruxism in adults: a systematic review from 2007 to 2017

The review focuses on the last decade of research regarding the use of various oral appliances (OAs) in the management of sleep bruxism (SB) in adults. Sixteen (n = 16) papers of 641 identified citations involving 398 participants were included in the review. Of them, seven were randomised controlled trials (RCTs), seven were uncontrolled before-after studies and two were crossover trials. Analysis of the included articles revealed a high variability of study designs and findings. Generally, the risk of bias was low-to-unclear for RCTs and high for crossover studies, whilst the before-after studies exhibited several structural limitations. Nine studies used polysomnography/polygraphy/electromyography for SB diagnosis, whilst others were based on history taking and clinical examination. Most of them featured small samples and were short term. Of the studies using objective SB evaluations, eight showed positive results for almost every type of OA in reducing SB activity, with a higher decrease for devices that are designed to provide a certain extent of mandibular advancement. Among the studies using a subjective SB evaluation, one demonstrated a significant reduction in SB activity, and additional two showed a myorelaxant effect of OA in SB patients. Although many positive studies support the efficiency of OA treatment for SB, accepted evidence is insufficient to support its role in the long-term reduction of SB activity. Further studies with larger samples and sufficient treatment periods are needed to obtain more acknowledgements for clinical application.
Effect of diabetes on enzymes involved in rat hepatic corticosterone production

Background: Numerous studies have explored the etiologic or permissive role of 11β‐hydroxysteroid dehydrogenase (11β‐HSD1) in obesity and Type 2 diabetes, biochemical conditions often with concurrent hyperinsulinism. In contrast, there are limited data on the effect of insulin deficiency (i.e. Type 1 diabetes) on 11β‐HSD1 or endoplasmic reticulum enzymes that generate the reduced pyridine cofactor NADPH. Thus, the aim of the present study was to examine the effect of insulin‐deficient, streptozotozin diabetes on key microsomal enzymes involved in rat hepatic corticosterone production.
Effect of low-dose French maritime pine bark extract on climacteric syndrome in 170 perimenopausal women: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE To evaluate the efficacy of a relatively low daily dosage of Pycnogenol French maritime pine bark extract for improvement of climacteric symptoms. STUDY DESIGN In a double-blind, placebo-controlled study 170 perimenopausal women were enrolled and treated with 30 mg Pycnogenol or placebo twice daily over a period of 3 months. Climacteric symptoms were evaluated by the Women's Health Questionnaire (WHQ) and by the Kupperman index, accompanied by an investigation of sex hormones and routine blood chemistry. RESULTS Seven women dropped out of each group due to noncompliance or personal reasons, but not as a result of treatment. A significant placebo effect was apparent in this study, suggesting an improvement of a majority of the WHQ categories. Compared to baseline, Pycnogenol significantly (p < 0.05) improved all symptoms with the exception of formication sensation and abnormal perceptions. Pycnogenol was found to be especially effective for improving vasomotor and insomnia/sleep problem symptoms, which were significantly better after 4 and 12 weeks than with placebo (p < 0.05). Total Kupperman's index for perimenopausal symptom severity score decreased significantly by 56% as compared to placebo (-39%) after 12 weeks of treatment (p < 0.05). Symptom score was also significantly better already after 4 weeks of treatment with Pycnogenol as compared to placebo. CONCLUSION This study, applying a relatively low daily dose, allows identification of those climacteric symptoms which respond particularly well to supplementation with Pycnogenol.