Miracle-dz/UniFAR-FTUs huggingface dataset:
BRAF/NRAS mutation frequencies among primary tumors and metastases in patients with melanoma.

PURPOSE The prevalence of BRAF, NRAS, and p16CDKN2A mutations during melanoma progression remains inconclusive. We investigated the prevalence and distribution of mutations in these genes in different melanoma tissues. PATIENTS AND METHODS In all, 291 tumor tissues from 132 patients with melanoma were screened. Paired samples of primary melanomas (n = 102) and synchronous or asynchronous metastases from the same patients (n = 165) were included. Tissue samples underwent mutation analysis (automated DNA sequencing). Secondary lesions included lymph nodes (n = 84), and skin (n = 36), visceral (n = 25), and brain (n = 44) sites. RESULTS BRAF/NRAS mutations were identified in 58% of primary melanomas (43% BRAF; 15% NRAS); 62% in lymph nodes, 61% subcutaneous, 56% visceral, and 70% in brain sites. Mutations were observed in 63% of metastases (48% BRAF; 15% NRAS), a nonsignificant increase in mutation frequency after progression from primary melanoma. Of the paired samples, lymph nodes (93% consistency) and visceral metastases (96% consistency) presented a highly similar distribution of BRAF/NRAS mutations versus primary melanomas, with a significantly less consistent pattern in brain (80%) and skin metastases (75%). This suggests that independent subclones are generated in some patients. p16CDKN2A mutations were identified in 7% and 14% of primary melanomas and metastases, with a low consistency (31%) between secondary and primary tumor samples. CONCLUSION In the era of targeted therapies, assessment of the spectrum and distribution of alterations in molecular targets among patients with melanoma is needed. Our findings about the prevalence of BRAF/NRAS/p16CDKN2A mutations in paired tumor lesions from patients with melanoma may be useful in the management of this disease.
Theory, Design, and Operation of Large-Orbit High-Harmonic Gyroklystron Amplifiers

The high-harmonic gyroklystron is a compact RF amplifier which relies on the synchronous interaction between large-orbit axis-encircling electrons and high-order azimuthal cylindrical cavity TEn11 modes. Because of this unique structure, it offers the promise of moderate- to high-millimeter-wave output power. Experimental results for a fifth-harmonic two-cavity device are compared to both small-signal analytic theory and large-signal numerical calculations which assess gain, bandwidth, sensitivity to longitudinal velocity spread, self-oscillation, and saturation characteristics. Principal theoretical results include the transition to infinite gain as the start-oscillation current threshold is reached as well as the demonstration of the insensitivity of the small-signal gain to parallel velocity spread. The required high-energy rotating electron beam is provided through gyroresonant RF acceleration. To date, over 20 dB of small-signal gain has been achieved at 11.3 GHz in a 1.3-kG magnetic field. The design of a four-cavity configuration is also presented along with simulation of its gain, bandwidth, amplitude modulation (AM) and phase modulation (PM) sensitivity, dependence upon guiding-center spread, and large-signal saturation characteristics. This device has been constructed and initial tests have yielded a gain of 30 dB. Gain in excess of 50 dB is predicted.
Regularity of free boundaries a heuristic retro

This survey concerns regularity theory of a few free boundary problems that have been developed in the past half a century. Our intention is to bring up different ideas and techniques that constitute the fundamentals of the theory. We shall discuss four different problems, where approaches are somewhat different in each case. Nevertheless, these problems can be divided into two groups: (i) obstacle and thin obstacle problem; (ii) minimal surfaces, and cavitation flow of a perfect fluid. In each case, we shall only discuss the methodology and approaches, giving basic ideas and tools that have been specifically designed and tailored for that particular problem. The survey is kept at a heuristic level with mainly geometric interpretation of the techniques and situations in hand.
miR‐16 inhibits the proliferation and angiogenesis‐regulating potential of mesenchymal stem cells in severe pre‐eclampsia

Pre‐eclampsia is thought to be a systemic disease of maternal endothelial cell dysfunctions. miRNAs regulate various basic biological functions in cells, including stem cells. Mesenchymal stem cells exist in almost all tissues and are the key cellular source for tissue repair and regeneration. Our aims are to investigate whether miRNAs regulate MSCs in fetal–maternal interfaces to influence the pathogenesis of pre‐eclampsia. The differential expression of miRNAs in decidua‐derived mesenchymal stem cells of all patients with severe pre‐eclampsia (n = 20) and normal groups (n = 20) was first screened by microarray analysis and validated by quantitative real‐time PCR analysis. The integrated bioinformatics analysis showed that miR‐16 showed the highest number of connections in the miRNA GO network and the miRNA gene network. Moreover, over‐expressed miR‐16 inhibited the proliferation and migration of decidua‐derived mesenchymal stem cells and induced cell‐cycle arrest by targeting cyclin E1. Interestingly, over‐expression of miR‐16 by decidua‐derived mesenchymal stem cells reduced the ability of human umbilical vein endothelial cells to form blood vessels and reduced the migration of trophoblast cells. Furthermore, decidua‐derived mesenchymal stem cell‐expressed endothelial growth factor VEGF‐A was involved in migration of trophoblast cells and human umbilical vein endothelial cells as well as tube and network formation. Importantly, the levels of cyclin E1 and VEGF‐A were negatively correlated with the level of miR‐16 expression in decidua‐derived mesenchymal stem cells from the patients with severe pre‐eclampsia. Together, these data suggest that the alteration of miR‐16 expression in decidua‐derived mesenchymal stem cells may be involved in the development of pre‐eclampsia.
Age and organ damage correlate with poor survival in myeloma patients: meta-analysis of 1435 individual patient data from 4 randomized trials

Thalidomide and bortezomib are extensively used to treat elderly myeloma patients. In these patients, treatment-related side effects are frequent and full drug doses difficult to tolerate. We retrospectively analyzed data from 1435 elderly patients enrolled in 4 European phase III trials including thalidomide and/or bortezomib. After a median follow up of 33 months (95%CI: 10–56 months), 513 of 1435 patients (36%) died; median overall survival was 50 months (95%CI: 46–60 months). The risk of death was increased in patients aged 75 years or over (HR 1.44, 95%CI: 1.20–1.72; P<0.001), in patients with renal failure (HR 2.02, 95%CI: 1.51–2.70; P<0.001), in those who experienced grade 3–4 infections, cardiac or gastrointestinal adverse events during treatment (HR 2.53, 95%CI: 1.75–3.64; P<0.001) and in those who required drug discontinuation due to adverse events (HR 1.67, 95%CI; 1.12–2.51; P=0.01). This increased risk was restricted to the first six months after occurrence of adverse events or drug discontinuation and declined over time. More intensive approaches, such as the combination of bortezomib-thalidomide, negatively affected outcome. Bortezomib-based combinations may overcome the negative impact of renal failure. Age 75 years or over or renal failure at presentation, occurrence of infections, cardiac or gastrointestinal adverse events negatively affected survival. A detailed geriatric assessment, organ evaluation and less intense individualized approaches are suggested in elderly unfit subjects.
Inhibition of microRNA-17 improves lung and heart function in experimental pulmonary hypertension.

RATIONALE MicroRNAs (miRs) control various cellular processes in tissue homeostasis and disease by regulating gene expression on the posttranscriptional level. Recently, it was demonstrated that the expression of miR-21 and members of the miR-17-92 cluster was significantly altered in experimental pulmonary hypertension (PH). OBJECTIVES To evaluate the therapeutic efficacy and antiremodeling potential of miR inhibitors in the pathogenesis of PH. METHODS We first tested the effects of miR inhibitors (antagomirs), which were specifically designed to block miR-17 (A-17), miR-21 (A-21), and miR-92a (A-92a) in chronic hypoxia-induced PH in mice and A-17 in monocrotaline-induced PH in rats. Moreover, biological function of miR-17 was analyzed in cultured pulmonary artery smooth muscle cells. MEASUREMENTS AND MAIN RESULTS In the PH mouse model, A-17 and A-21 reduced right ventricular systolic pressure, and all antagomirs decreased pulmonary arterial muscularization. However, only A-17 reduced hypoxia-induced right ventricular hypertrophy and improved pulmonary artery acceleration time. In the monocrotaline-induced PH rat model, A-17 treatment significantly decreased right ventricular systolic pressure and total pulmonary vascular resistance index, increased pulmonary artery acceleration time, normalized cardiac output, and decreased pulmonary vascular remodeling. Among the tested miR-17 targets, the cyclin-dependent kinase inhibitor 1A (p21) was up-regulated in lungs undergoing A-17 treatment. Likewise, in human pulmonary artery smooth muscle cells, A-17 increased p21. Overexpression of miR-17 significantly reduced p21 expression and increased proliferation of smooth muscle cells. CONCLUSIONS Our data demonstrate that A-17 improves heart and lung function in experimental PH by interfering with lung vascular and right ventricular remodeling. The beneficial effects may be related to the up-regulation of p21. Thus, inhibition of miR-17 may represent a novel therapeutic concept to ameliorate disease state in PH.
Frequency of respiratory virus infections and next-generation analysis of influenza A/H1N1pdm09 dynamics in the lower respiratory tract of patients admitted to the ICU

Recent molecular diagnostic methods have significantly improved the diagnosis of viral pneumonia in intensive care units (ICUs). It has been observed that 222G/N changes in the HA gene of H1N1pdm09 are associated with increased lower respiratory tract (LRT) replication and worse clinical outcome. In the present study, the frequency of respiratory viruses was assessed in respiratory samples from 88 patients admitted to 16 ICUs during the 2014–2015 winter-spring season in Lombardy. Sixty-nine out of 88 (78.4%) patients were positive for a respiratory viral infection at admission. Of these, 57/69 (82.6%) were positive for influenza A (41 A/H1N1pdm09 and 15 A/H3N2), 8/69 (11.6%) for HRV, 2/69 (2.9%) for RSV and 2/69 (2.9%) for influenza B. Phylogenetic analysis of influenza A/H1N1pdm09 strains from 28/41 ICU-patients and 21 patients with mild respiratory syndrome not requiring hospitalization, showed the clear predominance of subgroup 6B strains. The median influenza A load in LRT samples of ICU patients was higher than that observed in the upper respiratory tract (URT) (p<0.05). Overall, a greater number of H1N1pdm09 virus variants were observed using next generation sequencing on partial HA sequences (codons 180–286) in clinical samples from the LRT as compared to URT. In addition, 222G/N/A mutations were observed in 30% of LRT samples from ICU patients. Finally, intra-host evolution analysis showed the presence of different dynamics of viral population in LRT of patients hospitalized in ICU with a severe influenza infection.
Specificity, Promiscuity and Localization of ARF Protein Interactions with NCS‐1 and Phosphatidylinositol‐4 Kinase‐IIIβ

ADP‐ribosylation factor (ARF) proteins are involved in multiple intracellular vesicular transport pathways. Most studies have focused on the functions of ARF1 or ARF6 and little is known about the remaining ARF isoforms. Although the mammalian ARF proteins share a high degree of sequence identity, recent evidence has indicated that they may control distinct trafficking steps within cells. A unanswered issue is the degree of specificity of ARF family members for different interacting proteins. To investigate potential functional differences between the human ARF proteins, we have examined the localization of all human ARF isoforms and their interactions with two ARF1 binding proteins, neuronal calcium sensor‐1 (NCS‐1) and phosphatidylinositol‐4 kinase‐IIIβ (PI4Kβ). Use of a fluorescent protein fragment complementation method showed direct interactions between ARFs 1, 3, 5 and 6 with NCS‐1 but at different intracellular locations in live HeLa cells. Photobleaching experiments indicated that complementation did not detect dynamic changes in protein interactions over short‐time scales. A more specific interaction between ARFs 1/3 and PI4Kβ was observed. Consistent with these latter findings ARF1 but not ARF5 or 6 enhanced the stimulatory effect of PI4Kβ on regulated exocytosis, suggesting a specific role for class‐I ARFs in the regulation of PI4Kβ.
Exposure characteristics and cutaneous problems in operating room staff

Health care personnel have exposure to a variety of cutaneous irritants and allergens and a high prevalence of cutaneous problems. The objectives of this exploratory study were to characterize the exposures and determine the prevalence of cutaneous symptoms and findings in operating room personnel, and to examine relationships between exposure characteristics and cutaneous outcomes. A questionnaire and standardized hand examination were used to assess the exposures and cutaneous status of operating room personnel. 184 operating room staff (90% of the eligible population) were assessed. Current skin problems were reported by 26%. Hand examination revealed that 9% had findings consistent with eczema and 10% changes of moderate dryness. A variety of preventive practices were being used by those with symptoms or findings. Cutaneous problems are common in operating room personnel. The use of preventive strategies (changing the type of gloves worn or the type of soap used for scrubbing, the use of glove liners and emollients) varied between different groups. These workers might benefit from more education regarding cutaneous hazards, preventive stategies and the importance of appropriate investigation of these problems.
Treatment of acne vulgaris with a pulsed dye laser: a randomized controlled trial.

CONTEXT The high prevalence of acne vulgaris and its significant morbidity underscore the need for convenient, low-risk, and efficacious therapy. Treatment with various lasers has been reported to improve acne. OBJECTIVE To evaluate the clinical efficacy of pulsed dye laser therapy in the treatment of acne. DESIGN, SETTING, AND PATIENTS Randomized, single-blind, controlled, split-face clinical trial of a volunteer sample of 40 patients aged 13 years or older with facial acne conducted at an academic referral center from August 2002 to September 2003. INTERVENTION One or 2 nonpurpuric pulsed dye laser treatments to half of the face (fluence of 3 J/cm2), serial blinded clinical assessments (lesion counts), and grading of acne severity using standardized bilateral serial photographs. MAIN OUTCOME MEASURES Comparison of the changes in lesion counts from baseline to 12 weeks between treated and untreated sides of the face and changes in photographic evidence of acne severity as graded by a panel of dermatologists blinded to treatment assignment. RESULTS After 12 weeks, using intent-to-treat analysis with last observation carried forward, there were no significant differences between laser-treated and untreated skin for changes in mean papule counts (-4.2 vs -2.2; P =.08), mean pustule counts (0 vs -1.0; P =.12), or mean comedone counts (2.9 vs 1.6; P =.63). Grading of serial photographs confirmed the clinical assessments, showing no significant mean (SE) differences in Leeds scores (range, 1-12) for treated skin (3.98 [0.32] at baseline and 3.94 [0.27] at week 12) compared with untreated skin (3.83 [0.32] at baseline and 3.79 [0.28] at week 12) (P>.99). CONCLUSIONS In this study, the nonpurpuric pulsed dye laser therapy did not result in significant improvement of facial acne. More research is needed before this laser therapy may be recommended as an acne treatment.
Anxiety and depression among AL amyloidosis patients: the role of cardiac symptoms

Light-chain (AL) amyloidosis has the worst prognosis out of the different forms of cardiac amyloidosis, However, data are not available about the incidence of the disease-related psychological impact of AL amyloidosis in this population. In particular, no data are available about the impact of diagnosis communication or about the impact of cardiac symptom onset and severity on anxiety and depression levels among AL patients. Aim: To evaluate the role of time that has passed since the diagnosis was communicated, time that has passed since the onset of cardiac symptoms, and actual cardiac symptom severity have on level of anxiety, depression and psychological stress among cardiology patients with AL. Thirty-two AL patients with cardiac-related symptoms were administered General Health Questionnaire, State-Trait Anxiety Inventory and Centre for Epidemiological Study–Depression Scale. Clinical variables such as months gone by since diagnosis, months gone by since the onset of cardiac symptoms, and cardiac symptom severity (New York Heart Association (NYHA) class) were measured. Troponin, NT-pro BNP levels, Mayo Stage and echocardiographic characteristics were also collected. Results: According to questionnaire normative values, AL patients presented severe psychological distress, severe anxiety and clinical depression. Moreover, anxiety levels were determined by psychological distress (p < 0.001) and months gone by since the onset of cardiac symptoms (p < 0.01) while depression levels were influenced by NYHA class (p < 0.001). Conclusions: Our results suggest that there is a need to plan psychological support for these patients with consideration for the onset of cardiac symptoms and symptom severity.
Stability of Neurocognitive Impairment in Different Subtypes of Mild Cognitive Impairment

There has been increasing interest in delineating different cognitive subtypes of mild cognitive impairment (MCI). It remains unclear, however, the extent to which neuropsychological impairment associated with amnestic, nonamnestic, and amnestic+ subtypes of MCI remains stable over time. In this study, 70 persons meeting the criteria for MCI and 38 cognitively normal elderly subjects received a baseline neuropsychological evaluation and were reevaluated 1 year later. Our results indicated that 84.6% of the persons initially classified as amnestic, 75% of those classified as nonamnestic, and 80% of the persons classified as MCI+ evidenced stable or more pronounced neuropsychological impairment across the follow-up period. Less than 7% of the amnestic and amnestic+ cases had nonimpaired neuropsychological profiles at their reevaluation at 12 months, and 16.7% of the nonamnestic cases had nonimpaired neuropsychological test profiles at follow-up. Approximately 87% of the cognitively normal subjects at baseline continued to have unimpaired neuropsychological performance at follow-up. These results indicate that the presence of neuropsychological impairment is relatively stable over a 12-month follow-up period among different cognitive subtypes of MCI, although 15–25% of the cases did not exhibit the specific cognitive deficits that characterized their performance at baseline.
Minimally Invasive Aortic Valve Surgery - New Solutions to Old Problems

Aortic stenosis is the most frequent valvulopathy in the western world and basically affects people over 60 years old. It is currently the most common cause of valve replacement in Europe and North America (Schmitto et al., 2011) and its incidence increases with age. (Lung et al., 2003) 25% of people over 65 suffer sclerosis of the aortic valve which can be detected in image tests such as echocardiography and 3% of those over 75 develop aortic stenosis (Lindroos et al., 1993; Stewart et al., 1997). Approximately 16% of patients with aortic valve sclerosis develop stenosis within the space of 7 years. (Cosmi et al., 2002) This rate of progression is variable and has been related with factors common to those for arterial sclerosis. The average reduction in the valve area has been stated as being around 0.1 cm2 per year. (Otto et al., 1997) and the annual increase in gradient as about 10 mmHg. Rheumatic etiology is not common in the more developed countries and its origin is usually degenerative. In approximately half of the cases there usually exists a bicuspid aortic valve basis. Bicuspid aortic valve valvulopathy affects 2% of the population (Kurtz & Otto, 2010) and constitutes the most frequent congenital anomaly. Aortic valve stenosis is more prevalent in men than women (Chambers et al., 2009). This disease normally remains asymptomatic for a long time and represents a low sudden death risk of less than 1%. When stenosis becomes symptomatic, however, the prognosis is much worse. The symptoms usually appear at the end of the disease with three of them being typical and each one of them determining a state which is both evolutionary and prognostic: dyspnea (due to heart faillure), angina and syncope. In aortic stenosis there coexist three physiological phenomena: cardiac ischemia, elevated pressure in the left ventricle and diminished cardiac output. Diminished tolerance to exercise is generally the first symptom of aortic stenosis and could be the result of the three previously mentioned phenomena. A careful medical history investigation is necessary in order to obtain this information as the earliest clinical signs may be insidious and may not be accompanied by dyspnea as such, and may be consciously or unconsciously disguised by the patient in the progressive restriction of their day-to-day activity as the disease develops.
Adverse Drug Reaction and Medication Error Reporting by Pharmacy Students

BACKGROUND: The reporting of adverse drug reactions (ADRs) and medication errors is the responsibility of all who are involved, particularly pharmacists. Since pharmacists are often privy to information surrounding ADRs and medication errors, it is of utmost importance that they are educated regarding the procedures of reporting. OBJECTIVE: To determine pharmacy students' knowledge of and ability to report ADRs and medication errors. METHODS: A total of 1322 students from 9 colleges of pharmacy were surveyed. RESULTS: The largest group of respondents was fifth-year pharmacy students (38%) followed by third-, fourth-, and sixth-year students (28%, 26%, and 8%, respectively). The majority of students reported learning about ADR and medication error reporting programs via didactic experiences. In comparison, fewer students cited alternative mechanisms of learning, including experiential rotations and work experience. Overall, respondents demonstrated the most experience with MedWatch and the least experience with the Vaccine Adverse Event Reporting System (VAERS). As students progressed through pharmacy curricula, there was a positive trend in the ability to locate and complete MedWatch forms. For VAERS and Medication Error Reporting (MER) program forms, however, this positive trend was broken at year 4. For all programs, significantly fewer students demonstrated appropriate use of the forms compared with those indicating familiarity with the programs. CONCLUSIONS: This study demonstrated that students are becoming familiar with ADR and MER programs via the college curriculum; however, there is opportunity for greater exposure and understanding. Colleges of pharmacy should continually seek methods to strengthen the education provided to pharmacy students regarding these programs.