Miracle-dz/UniFAR-FTUs huggingface dataset:
Pathological activation of KIT in metastatic tumors of acral and mucosal melanomas

Recent studies showed KIT gene aberrations in a substantial number of melanomas on acral skin and mucosa, suggesting the therapeutic benefit of tyrosine kinase inhibitors, such as imatinib. We therefore examined the expression and mutations of KIT in 4 primary and 24 metastatic acral and mucosal melanomas. Immunohistochemistry revealed moderate or strong KIT protein expression in 13 (48%) tumors. Sequence analysis revealed K642E and D820Y mutations in two metastases. Amplification of KIT was identified by real‐time PCR in 4 tumors, including one that had K642E. Western blot analysis showed phosphorylation of the KIT receptor in 8 (62%) of 13 cryopreserved samples, indicating the frequent pathological activation of the receptor in vivo. Phosphorylation of KIT protein was detected in 2 tumors harboring KIT mutations, as well as in one tumor with KIT gene amplification. Furthermore, 5 tumors without detectable KIT gene aberrations showed phosphorylation of the KIT receptor. Expression of stem cell factor (SCF) in melanoma cells as well as stromal cells suggests SCF/KIT autocrine and paracrine activation in these tumors. Finally, we found significant growth suppressive effects of sunitinib in two acral melanoma cell lines; one harboring the D820Y mutation and one showing SCF‐dependent KIT activation. These results show pathological activation of KIT in a substantial number of metastatic tumors of acral and mucosal melanomas, and suggest a potential therapeutic benefit of sunitinib for these melanomas. © 2008 Wiley‐Liss, Inc.
Decreased expression of angiogenesis antagonist EFEMP1 in sporadic breast cancer is caused by aberrant promoter methylation and points to an impact of EFEMP1 as molecular biomarker

EGF‐containing fibulin‐like extracellular matrix protein 1 (EFEMP1) was recently described as an antagonist of angiogenesis. Motivated by a strong dependence of tumor growth and metastasis on angiogenesis, we investigated the role of EFEMP1 in human breast cancer. We applied RNA microarray expression analysis and quantitative real‐time PCR (QRT) in a total of 45 sporadic breast cancer tissues and found EFEMP1 down‐regulation in 59% and 61% of the analyzed tissues, respectively. This down‐regulation was confirmed on protein level. Immunohistochemistry in 211 breast cancer tissues resulted in reduced or even abolished EFEMP1 expression in 57–62.5% of the tumors. Bisulphite genomic sequencing in breast cancer cell lines and primary breast cancer tissues revealed promoter methylation as the major cause of this down‐regulation. Furthermore, analysis of 203 clinically well characterized primary breast cancers displayed a significant correlation of reduced EFEMP1 protein expression with poor disease‐free (p = 0.037) and overall survival (p = 0.032), particularly in those node‐positive patients who received adjuvant anthracycline‐based chemotherapy, but not in those treated by either cyclophosphamide‐methotrexate‐5‐fluorouracil (CMF) or Tamoxifen. In summary, the presented data demonstrate for the first time the reduced EFEMP1 expression on RNA and protein level in a substantial number of sporadic breast carcinomas and its correlation with epigenetic alterations. Furthermore, these data point towards a possible predictive impact of EFEMP1 expression in primary breast cancer. © 2008 Wiley‐Liss, Inc.
From goals to muscles: motor familiarity shapes the representation of action-related sounds in the human motor system

ABSTRACT Numerous studies corroborated the idea that the sound of familiar motor acts triggers a muscle-specific replica of the perceived actions in the listener’s brain. We recently contradicted this conclusion by demonstrating that the representation of newly-learned action-related sounds is not somatotopically organised but rather it corresponds to the goal a particular action aims to achieve. In the present study, we aimed at reconciling these results. We measured MEPs to TMS as an index of the functional correspondence between the sensory stimulation and the activity in the listener’s motor cortex. Participants heard two tones of different pitch, void of previous motor meaning, before and after an acquisition phase in which they generated them by performing 400 free-choice button presses. We then disentangled the representation of the action goal (button–tone association) from the somatotopic (muscle–tone) association by reversing the muscle–button contingencies. Our result supports the hypothesis that the neuronal representations of action-related sounds depends on motor familiarity: perceptuomotor representations of newly-learned actions are muscle–independent and correspond to the button–tone contingencies, whilst longer-term practice results in representations that rely on lower-level intrinsic parameters associated with the kinematics of specific movements.
The Karyopherin proteins, Crm1 and Karyopherin β1, are overexpressed in cervical cancer and are critical for cancer cell survival and proliferation

The Karyopherin proteins are involved in nucleo‐cytoplasmic trafficking and are critical for protein and RNA subcellular localization. Recent studies suggest they are important in nuclear envelope component assembly, mitosis and replication. Since these are all critical cellular functions, alterations in the expression of the Karyopherins may have an impact on the biology of cancer cells. In this study, we examined the expression of the Karyopherins, Crm1, Karyopherin β1 (Kpnβ1) and Karyopherin α2 (Kpnα2), in cervical tissue and cell lines. The functional significance of these proteins to cancer cells was investigated using individual siRNAs to inhibit their expression. Microarrays, quantitative RT‐PCR and immunofluorescence revealed significantly higher expression of Crm1, Kpnβ1 and Kpnα2 in cervical cancer compared to normal tissue. Expression levels were similarly elevated in cervical cancer cell lines compared to normal cells, and in transformed epithelial and fibroblast cells. Inhibition of Crm1 and Kpnβ1 in cancer cells significantly reduced cell proliferation, while Kpnα2 inhibition had no effect. Noncancer cells were unaffected by the inhibition of Crm1 and Kpnβ1. The reduction in proliferation of cancer cells was associated with an increase in a subG1 population by cell cycle analysis and Caspase‐3/7 assays revealed increased apoptosis. Crm1 and Kpnβ1 siRNA‐induced apoptosis was accompanied by an increase in the levels of growth inhibitory proteins, p53, p27, p21 and p18. Our results demonstrate that Crm1, Kpnβ1 and Kpnα2 are overexpressed in cervical cancer and that inhibiting the expression of Crm1 and Kpnβ1, not Kpnα2, induces cancer cell death, making Crm1 and Kpnβ1 promising candidates as both biomarkers and potential anticancer therapeutic targets. © 2008 Wiley‐Liss, Inc.
Caffeic acid phenethyl ester decreases cholangiocarcinoma growth by inhibition of NF‐κB and induction of apoptosis

Caffeic acid phenethyl ester (CAPE) inhibits the growth of tumor cells and is a known inhibitor of nuclear factor kappa beta (NF‐κB), which is constitutively active in cholangiocarcinoma (CCH) cells. We evaluated the effects of CAPE on CCH growth both in vitro and in vivo. Inhibition of NF‐κB DNA‐binding activity was confirmed in nuclear extracts treated with CAPE at 50, 40 and 20 μM. CAPE decreases the expression of NF‐κB1 (p50) and RelA (p65). CAPE decreased the growth of a number of CCH cells but not normal cholangiocytes. Cell cycle decrease was seen by a decrease in PCNA protein expression and the number of BrdU‐positive cells treated with CAPE at 20 μM compared to vehicle. Inhibition of growth and increased cell cycle arrest of Mz‐ChA‐1 cells by CAPE were coupled with increased apoptosis. Bax expression was increased, whereas Bcl‐2 was decreased in cells treated with CAPE compared to vehicle. In vivo studies were performed in BALB/c nude (nu/nu) mice implanted subcutaneously with Mz‐ChA‐1 cells and treated with daily IP injections of DMSO or CAPE (10 mg/kg body weight in DMSO) for 77 days. Tumor growth was decreased and tumor latency was increased 2‐fold in CAPE compared to vehicle‐treated nude mice. In tumor samples, decreased CCH growth by CAPE was coupled with increased apoptosis. CAPE both in vivo and in vitro decreases the growth of CCH cells by increasing apoptosis. These results demonstrate that CAPE might be an important therapeutic tool in the treatment of CCH. © 2009 UICC
Barrier dysfunction and bacterial uptake in the follicle‐associated epithelium of ileal Crohn's disease

The ability to control uptake across the mucosa and protect from harmful substances in the gut lumen is defined as intestinal barrier function. The etiology of Crohn's disease is unknown, but genetic, environmental, and immunological factors all contribute. The frontline between these factors lies in the intestinal barrier. The most important inflammation‐driving environmental factor in Crohn's disease is the microbiota, where Esherichia coli strains have been assigned a key role. The first observable signs of Crohn's disease are small aphtoid ulcers over Peyer's patches and lymphoid follicles. The overlaying follicle‐associated epithelium (FAE) is specialized for luminal sampling and is an entry site for antigens and bacteria. We have demonstrated increased E. coli uptake across the FAE in Crohn's disease, which may initiate inflammation. This short review will discuss barrier dysfunction and bacteria in the context of ileal Crohn's disease, and how the FAE might be the site of initial inflammation.
Ribosome‐inactivating proteins isolated from dietary bitter melon induce apoptosis and inhibit histone deacetylase‐1 selectively in premalignant and malignant prostate cancer cells

Epidemiologic evidence suggests that a diet rich in fruits and vegetables is associated with a reduced risk of prostate cancer (PCa) development. Although several dietary compounds have been tested in preclinical PCa prevention models, no agents have been identified that either prevent the progression of premalignant lesions or treat advanced disease. Momordica charantia, known as bitter melon in English, is a plant that grows in tropical areas worldwide and is both eaten as a vegetable and used for medicinal purposes. We have isolated a protein, designated as MCP30, from bitter melon seeds. The purified fraction was verified by SDS‐PAGE and mass spectrometry to contain only 2 highly related single chain Type I ribosome‐inactivating proteins (RIPs), α‐momorcharin and β‐momorcharin. MCP30 induces apoptosis in PIN and PCa cell lines in vitro and suppresses PC‐3 growth in vivo with no effect on normal prostate cells. Mechanistically, MCP30 inhibits histone deacetylase‐1 (HDAC‐1) activity and promotes histone‐3 and ‐4 protein acetylation. Treatment with MCP30 induces PTEN expression in a prostatic intraepithelial neoplasia (PIN) and PCa cell lines resulting in inhibition of Akt phosphorylation. In addition, MCP30 inhibits Wnt signaling activity through reduction of nuclear accumulation of β‐catenin and decreased levels of c‐Myc and Cyclin‐D1. Our data indicate that MCP30 selectively induces PIN and PCa apoptosis and inhibits HDAC‐1 activity. These results suggest that Type I RIPs derived from plants are HDAC inhibitors that can be utilized in the prevention and treatment of prostate cancer. © 2009 UICC
Psychiatric Implications of Adolescent Methamphetamine Exposures

Objectives Methamphetamine abuse has reached epidemic proportions during the last decade. Abuse among adolescents is linked to increased rates of depression and suicidal ideation. Sources suggest that there is an increase rate of suicide attempts in the methamphetamine-abusing adolescent patient population. Our study seeks to examine adolescent methamphetamine exposures reported to the California Poison Control System during the past decade of suicidal ideation and suicide attempts in comparison to rates reported by population-based surveys. Methods The records of the California Poison Control System were searched for methamphetamine exposures from 2000 to 2009. All charts of patients identified between the ages of 11 and 18 years were reviewed and abstracted. Results The records of 293 youth between the ages of 11 and 18 years were identified and assigned levels of severity according to parameters set by the National Poison Data System Medical Outcome Criteria of the American Association of Poison Control Centers. Charts were categorized as follows: 11 as major, 52 as moderate, and 75 as minor. The remainder of the charts were not evaluated because of no effect (n = 13) or unable to follow (n = 142). In this cohort, more females were reported than males (57%). The most common presenting symptom in this patient population was agitation (39%). The most common events were suicidal ideation (31%) and suicide attempts (21%). Conclusions In this data set, adolescent methamphetamine exposures were associated with increased rates of suicidal ideation and suicide attempts that are disproportionate to population-based surveys during the same period.
Impact of an Emergency Department Pharmacy on Medication Omission and Delay

Objectives The objective of the study was to evaluate the impact of adding a clinical pharmacist within a pediatric emergency department (ED) on medication omissions and delays, as well as medication errors on patients with prolonged ED stays of 8 hours or greater. Methods This is a retrospective review of medication omissions and delays on all patients admitted to a large, tertiary-care children’s hospital through the ED during a month before the addition of a clinical pharmacist (April 2007), during a month immediately after the addition of a clinical pharmacist (April 2009), and 6 months after the addition of a clinical pharmacist (October 2009). The medication omissions and delays were separated for urgent and nonurgent medications. A subgroup was further analyzed to evaluate the rate of medication omissions and delays for admitted patients boarded within the ED for 8 hours or greater. Results Medication omissions and delays decreased immediately after the addition of a clinical pharmacist for urgent medications (P = 0.007) and nonurgent medications (P < 0.0001). This decrease persisted 6 months after the addition of a clinical pharmacist approaching significance for urgent medications (P = 0.06) and statistically significant for nonurgent medications (P < 0.0001). For the patients who were boarded within the ED for 8 hours or greater, 52.8% experienced a medication omission or delay before the addition of a clinical pharmacist, compared with 28.6% and 36.2% experiencing an omission or delay in medications administration immediately after or 6 months after the addition of a clinical pharmacist, respectively. Conclusions Medication omissions and delays are common within the ED. Admitted patients boarded within the ED for 8 hours or greater are at an increased risk for medications omissions and delays. The addition of a clinical pharmacist within an ED may reduce the number of medication omissions and delays occurring.
Changes in DNA methylation of tandem DNA repeats are different from interspersed repeats in cancer

Hypomethylation of DNA repetitive elements is a common finding in cancer, but very little is known about the DNA methylation changes of different types of DNA repetitive elements, such as interspersed repeats (LINE1 and Alu Yb8) and tandem repeats (Sat‐α, NBL‐2 and D4Z4). We used bisulfite‐PCR Pyrosequencing to quantitatively measure the DNA methylation of five different DNA repetitive elements in normal tissue and cancer. In all we studied 10 different tissues from four individuals undergoing autopsy, 34 paired normal and tumor tissues from patients with bladder cancer, 58 patients with chronic myelogenous leukemia and 23 patients with acute promyelocytic leukemia. We found that the DNA methylation of interspersed repeats (LINE1 and Alu Yb8) was very consistent from person to person and tissue to tissue while tandem DNA repeats appeared more variable in normal tissues. In bladder cancer we found clear hypomethylation of LINE1, Alu Yb8, Sat‐α and NBL‐2. Conversely, we found an increase in the DNA methylation levels of D4Z4 from normal to cancer. In contrast leukemia showed no significant changes in the DNA methylation of LINE1 and Alu Yb8, but DNA methylation increases in NBL‐2 and D4Z4 tandem repeats. Our findings show that the changes in DNA methylation levels of individual DNA repetitive elements are unique for each repetitive element, which may reflect distinct epigenetic factors and may have important implications in the use of DNA methylation of repetitive elements as global DNA methylation biomarkers. © 2009 UICC.
Serum Procalcitonin Concentration in the Evaluation of Febrile Infants 2 to 60 Days of Age

Objective Febrile infants younger than 60 days are at risk for serious bacterial infections (SBIs) and often undergo extensive laboratory investigation and hospitalization. We aim to determine the diagnostic value of serum procalcitonin (PCT) concentration for identification of febrile infants at low risk for SBI in comparison to the Rochester Criteria (RC). Methods Infants 2 to 60 days of age with rectal temperature 38°C were enrolled between May 2004 and March 2007. Blood was obtained from each, and PCT was assessed using BRAHMS PCT LIA method. Information for identification of low-risk infants using RC was obtained. Negative predictive value, sensitivity, specificity, and likelihood ratio of PCT were compared with the RC. In univariate analysis, the components of RC and PCT were considered. Variables holding a significant association with the absence of SBI were included in a backward stepwise logistic regression model with SBI as the dependent variable, creating new low risk criteria. Results One hundred fifty-five patients were enrolled. Thirteen (8.4%) had an SBI. Procalcitonin concentration at a cutoff value of 0.26 ng/mL is similar in sensitivity (92%) and better in specificity (64%) than RC. A combination of urine white blood cell and PCT was the best model in the regression analysis. Conclusions Procalcitonin concentration is a serological marker for identification of or exclusion of SBI in infants aged 2 to 60 days. The predictive value of PCT in combination with urinary white blood cell count may be clinically useful. A validation study is indicated.
IL‐8 induces exocytosis of arginase 1 by neutrophil polymorphonuclears in nonsmall cell lung cancer

Arginase 1 (ARG1) inhibits T‐cell proliferation by degrading extracellular arginine, which results in decreased responsiveness of T cells to CD3/TCR stimulation. In humans, ARG1 is stored in inactive form within granules of polymorphonuclear neutrophils (PMNs) and gets activated on release. We studied the role of PMNs‐related ARG1 activity in nonsmall cell lung cancer (NSLC), in which tumor‐infiltrating lymphocytes showed reduced proliferation in response to CD3/TCR triggering. Patients with NSCLC had increased ARG1 plasma levels as compared to healthy controls. Furthermore, immunohistochemistry showed that tumor‐infiltrating PMNs display reduced intracellular ARG1, in comparison to intravascular or peritumoral PMNs, suggesting a role of tumor microenvironment in ARG1 release. Indeed, supernatants of NSCLC cell lines induced exocytosis of ARG1 from PMNs. All (4/4) NSCLC cell lines and all (7/7) CD14− cell samples from NSCLC expressed interleukin (IL)‐8 mRNA, whereas TNFα mRNA was expressed by 1 cell line and by 2 tumor specimens. Furthermore, all NSCLC cell lines secreted immunoreactive IL‐8, albeit at different levels. IL‐8 was as effective as TNFα in triggering ARG1 release and the 2 cytokines acted synergistically. Secreted ARG1 was biologically active and catabolized extracellular arginine. The supernatant of IL‐8 gene‐silenced NSCLC cells did not mediate ARG1 release by PMNs. Altogether these findings demonstrate a role of IL‐8 in ARG1 exocytosis by PMNs and indicate that, due at least in part to IL‐8 secreted by NSCLC cells, PMNs infiltrating NSCLC release ARG1. This phenomenon could contribute to local immune suppression. © 2009 UICC
False negative fecal occult blood tests due to delayed sample return in colorectal cancer screening

Delayed return of immunochemical fecal occult blood test (iFOBT) samples to a laboratory might cause false negatives because of hemoglobin degradation. Quantitative iFOBT's became increasingly more accepted in colorectal cancer screening. Therefore, we studied the effects of delay between sampling and laboratory delivery on iFOBT performance. IFOBT positivity (≥50 ng/ml hemoglobin) in colorectal cancer screening participants without delay between sampling and laboratory delivery (<5 days), was compared with positivity in participants with ≥5 and ≥7 days delay. Additionally, positive tests were stored at room temperature and retested 5 times within 10–14 days. The sampling date was reported by 61% (n = 3,767) of the participants: in 19% delay was ≥5 days and in 5% ≥7 days. Compared with no‐delay, the adenoma detection rate was already significantly decreased after ≥5 days delay (OR 0.6; 95%CI 0.4–0.9). We retested iFOBT samples of 170 positives of which 139 (82%) had a colonoscopy: 45 (32%) had advanced adenomas (not colorectal cancer) and 8 (6%) had colorectal cancer. Mean daily fecal hemoglobin decrease was 29 ng/ml (S.D. 38 and median 11 ng/ml). In patients with advanced adenomas, hemoglobin in the sample was <50 ng/ml in 5 (11%) 2–3 days after the initial test and in 16 (36%) after 10–14 days. Seven days after the initial test, 2 (25%) colorectal cancer patients became false negative. Both had stage I colorectal cancer and initial values below 100 ng/ml, where the average for stage I is 532 ng/ml. Delay in sample return increased false negative immunochemical FOBT's. Mainly precursor lesions, but also colorectal cancer, will be missed due to delayed sample return. © 2009 UICC
A Secure Network Coding-based Data Gathering Model and Its Protocol in Wireless Sensor Networks

Abstract To provide security for data gathering based on network coding in wireless sensor networks (WSNs), a secure network coding-based data gathering model is proposed, and a data-privacy preserving and pollution preventing (DPP&PP) protocol using network coding is designed. DPP&PP makes use of a new proposed pollution symbol selection and pollution (PSSP) scheme based on a new obfuscation idea to pollute existing symbols. Analyses of DPP&PP show that it not only requires low overhead on computation and communication, but also provides high security on resisting brute-force attacks.
Multifocal pulmonary aspergillomas: case series and review

Multifocal lung parenchymal cavities containing multiple aspergillomas are not well‐recognized features of chronic pulmonary aspergillosis (CPA). We identified five patients with multiple cavities containing fungal balls from our accumulated cohort of ∼300 patients with CPA. Corticosteroid exposure and radiological and serological characteristics were assessed. The patients, aged 19–55 years, developed 3–11 cavities (or nodules in one case) with thin walls, usually within the lung parenchyma, with very limited pleural involvement. Four had asthma (severe in three) and one had cystic fibrosis; three had allergic bronchopulmonary aspergillosis. All patients had received corticosteroids orally or by inhalation. Four patients had elevated Aspergillus IgG antibodies; one had elevated Aspergillus‐specific IgE. Three patients developed azole resistance on antifungal therapy, after benefit, one of whom underwent a successful bilateral lung transplant, later complicated by a fatal mycotic cerebral aneurysm. Multiple aspergillomas is a new distinct manifestation of CPA. The lack of inflammatory response and the distribution of the cavities in the lungs are remarkable. Aspergillus nodules could evolve into cavities with aspergillomas. The management and development of azole resistance in these patients is problematic.