tbuckley/cabot-search huggingface dataset:
Abstract 74: Naturally Occurring Human α1a-Adrenergic Receptor Genetic Variant Induces Transformation of Cardiomyoblasts to Fibroblast-Like Phenotype
Authors: Maren Kleine-Brueggeney, Irina Gradinaru, Ekaterina Babaeva, Debra A Schwinn, Anush Oganesian
Journal: Circulation Research (2012)

Hypertensive heart disease is a progressive condition leading to myocardial remodeling, alterations in cardiomyocytes and fibrosis. Three α1 adrenergic receptor (AR) subtypes are expressed in human heart (α1a, α1b, α1d). Recently, we reported that human α1aAR with the naturally occurring G247R SNP (247R), originally identified in a hypertensive patient, constitutively couples to EGFR-transactivation pathway in fibroblasts and leads to hyperproliferation. We hypothesized that expression of 247R in cardiomyoblasts plays an important role in their remodeling. We demonstrate that constitutive expression of 247R in H9C2 cardiomyoblasts changes the morphology of myoblasts to fibroblast-like cells (transformed, tr247R); higher 247R expression results in earlier onset of transformation. Expression of α1aAR-WT does not affect cell morphology. Tr247R cells exhibit 2-3 fold increased constitutive proliferation compared to control or WT cells as determined by cell counts and thymidine incorporation assays; pERK is upregulated in tr247R cells as determined by Western blot analyses. Treatment with AraC, a DNA replication inhibitor, eliminates the 247R cells but not the H9C2 myoblasts. Expression of cell-specific markers is being evaluated in tr247R and control cells. RT-PCR and zymograms revealed increased MMP2 mRNA and protein levels in tr247R cells compared to control or WT cells and are comparable to MMP2 levels in fibroblasts. Increased proliferation of tr247R cells is reduced by EGFR specific inhibitor AG1478 but not general MMP inhibitor GM6001. Agonist stimulation of tr247R results in hypertrophy as determined by leucine incorporation. Interestingly, hypertrophy but not cell proliferation is inhibited by prazosin, an α1aAR inverse agonist, suggesting that increased proliferation and hypertrophy observed in transformed cells are two independent pathways triggered by 247R. Our data demonstrate that expression of α1aAR genetic variant triggers alterations in cardiomyoblasts via distinct signaling pathways leading to hyperproliferation, transformation of the cells to fibroblast-like phenotype and hypertrophy. Consequently, these changes may lead to fibrosis in human heart, extracellular matrix remodeling and heart failure.
Correlation of shedding cryptic epitope (HU177) levels and treatment response in sera of melanoma patients
Authors: P. A. Ott, A. C. Pavlick, A. Zoloretev, B. Ng, M. T. Buckley, P. P. Brooks, L. Liebes
Journal: Journal of Clinical Oncology (2008)

20018 Background: We have previously shown that shedding of the recently identified cryptic epitope HU177 can be measured in melanoma patients’ sera and correlates with invasiveness of primary melanomas. Here we prospectively measured HU177 collagen epitope (HCE) titers in sera of stage IV melanoma patients (pts) enrolled in two clinical trials conducted at our institution. Methods: Serum samples from 37 pts (11-M1a, 10-M1bM, 16-M1c) who received Sorafenib on an NCI phase II trial (6617) (study A) and from 18 stage IV pts who were treated 2nd line with Carboplatin, Paclitaxel, and PABA on a phase I trial (study B), were analyzed for HCE by a dual sandwich ELISA during each of up to 12 cycles. Serum was aliquoted into 200 μl volumes and stored at - 20°C until assayed. Correlation of HCE levels with treatment response as measured by PET/CT or CT imaging was examined. Results: In 2 of 3 radiographically responding pts in study A correlation with HCE was seen. In one pt, HCE levels dropped from 74.4 ng/ml to undetectable by cycle 2. Another pt who had a response that lasted >200 days, HCE titers progressively decreased from 55.1 to 15.8 ng/ml over the first 3 cycles (71.5% drop) and subsequently remained in the range from 0 - 9.7 ng/ml from cycle 4 to cycle 7 (mean decrease (± SD) from baseline of 89.6±6.1% below pre-treatment levels). During this time, the mean standard uptake values (SUV) measured in PET/CT scans decreased from 11.3 (pre-treatment) to 4.3 and 2.3, respectively. In study B, 4 of 6 responders demonstrated a drop in HCE titers that correlated with treatment response. For example, one patient had HCE levels decrease from 54.0 ng/ml to 30.2 ng/ml by cycle 1 and remained in the range from 20.6 ng/ml to 41.1 ng/ml from cycle 2 to cycle 9 (mean 38.6±12.0 % below pre-treatment levels) while serial CT imaging demonstrated continued treatment response lasting > 200 days. Conclusions: Our data demonstrate, in two separate trials, the utility of serial HCE measurements for the monitoring of therapeutic responses in metastatic melanoma pts. Since the assay is not tumor-type specific, it may not only prove useful in future melanoma studies, but other cancer trials as well. No significant financial relationships to disclose.
Germline BRCA1/2 Mutations and p27<sup>Kip1</sup> Protein Levels Independently Predict Outcome After Breast Cancer
Authors: Pierre O. Chappuis, Linda Kapusta, Louis R. Bégin, Nora Wong, Jean-Sébastien Brunet, Steven A. Narod, Joyce Slingerland, William D. Foulkes
Journal: Journal of Clinical Oncology (2000)

PURPOSE: Decreased levels of the cyclin-dependent kinase inhibitor p27 Kip1 in breast cancer are associated with a poor outcome. The prognostic significance of BRCA1/2 mutations is less clear, and the relationship between BRCA1/2 mutation status, p27 Kip1 protein levels, and outcome has not been studied. PATIENTS AND METHODS: Pathology blocks from 202 consecutive Ashkenazi Jewish women with primary invasive breast cancer were studied. Tumor DNA was tested for the three common BRCA1/2 founder mutations present in Ashkenazi Jews, and p27 Kip1 expression was evaluated by immunohistochemistry. The median follow-up was 6.4 years. RESULTS: Thirty-two tumors (16%) were positive for a BRCA1/2 mutation. Low p27 Kip1 expression was seen in 110 tumors (63%) and was significantly associated with BRCA1/2 mutations (odds ratio, 4.0; 95% confidence interval [CI], 1.4 to 11.1; P = .009). BRCA1/2 mutation carriers had a significantly worse 5-year distant disease-free survival (DDFS) compared with women without BRCA1/2 mutations (58% v 82%; P = .003). Similar results were seen for women whose tumors expressed low levels of p27 Kip1 , compared with those with high levels (5-year DDFS, 68% v 93%; P &lt; .0001). In a multivariate analysis, both BRCA1/2 mutation and low p27 Kip1 expression were associated with a shorter DDFS (relative risk [RR], 2.1; 95% CI, 1.0 to 4.3; P = .05; and RR, 3.9; 95% CI, 1.4 to 11.1; P = .01, respectively). CONCLUSION: In this study, we showed that BRCA1/2 mutations were associated with low levels of p27 Kip1 in breast cancer. Both BRCA1/2 and p27 Kip1 status were identified as independent prognostic factors.
Rate of tumor regression as a prognostic factor following neoadjuvant chemoradiotherapy in locally advanced rectal cancer.
Authors: P. D. Dickinson, A. M. Zaitoun, E. M. Bessell, A. S. Dhadda
Journal: Journal of Clinical Oncology (2010)

e14030 Background: Our previous work (Dhadda AS, et al. Clinical Oncology. 2009;21:23-31) has shown that the median tumour volume-halving time (TVH), for locally advanced rectal cancers, to neoadjuvant chemoradiotherapy is 14 days. The rate of tumour regression has been shown to be a prognostic factor in cervical cancer but has never been investigated in rectal cancer. Methods: The study involved 94 patients with locally advanced rectal cancer treated with preoperative chemo/radiotherapy at Nottingham University Hospital between April 2001 and December 2005. Patients were treated with CT planned radiotherapy to a dose of 50 Gy in 25 fractions over 5 weeks with or without concurrent capecitabine chemotherapy at a dose of 1,650 mg/m2/day. Surgery was performed after an interval of 6-10 weeks. The tumour volumes were measured on CT images by two independent observers and compared to pathological volumes assessed by a single pathologist. The median TVH times were calculated using the equation for exponential regression. Results: The median tumour volume in our series was 54 cm3. A tumour of this size would need a TVH of less than 7 days to regress completely prior to surgery. Patients were deemed fast (TVH < 7 days) or slow (TVH > 7 days) responders and were assessed for long term disease free (DFS) and overall survival (OS). The median follow-up was 40 months (range 3–90 months). 14 patients (15%) were deemed fast responders and 80 (85%) slow responders. The rate of response was clearly linked to both DFS (p = 0.016) and OS (p= 0.036). Conclusions: The rate of tumour regression is a prognostic factor following preoperative chemoradiotherapy for locally advanced rectal cancer. No significant financial relationships to disclose.
만성 B형 간염 환자에서 lamivudine 12주 치료의 효과와 안전성
Authors: 서동진(Dong Jin Suh), 정영화(Young Hwa Chung), 이영상(Yung Sang Lee), 이민호(Min Ho Lee), 한광협(Kwang Hyub Han)
Journal: Clinical and Molecular Hepatology (1999)

Background/Aims: Lamivudine, an oral nucleoside analogue, effectively inhibits hepatitis B virus replication and reduces hepatic necroinflammation in patients with chronic hepatitis B. This study investigated the effect and safety of 12 week lamivudine therapy in Korean patients with chronic hepatitis B (CHB). Methods: In an open clinical trial, 113 patients with CHB were enrolled. They received 100 mg of lamivudine orally once daily for 12 weeks, and they were followed until 2 weeks after cessation of lamivudine. HBV DNA (by bDNA assay), liver enzymes, creatine phosphokinase, creatinine and CBC were checked at 0, 2, 4, 8, 12 and 14 weeks. Compliance and side effects were evaluated at the same time. Results: After receiving lamivudine 100 mg, serum HBV DNA levels fell rapidly, remaining in 94.3% below baseline values at 2 weeks and 99.8% below baseline values at 12 weeks. Serum HBV DNA was cleared in 75.2% and alanine aminotransferase level (ALT) was normalized in 64.8% at 12 weeks. Cumulative percentage of HBeAg clearance (defined by clearance of serum HBV DNA and HBeAg) was 14.4%. Clearance of HBV DNA was more frequent in patients with lower pretreatment serum HBV DNA and higher ALT. During the treatment periods, adverse effects were negligible and transient. Two weeks after cessation of lamivudine, serum HBV DNA reappeared in 70.6% of responders. Conclusion: It is suggested that lamivudine is effective and safe in the treatment of CHB in Korean patients, but further study for adequate duration of treatment is needed because of high recurrence after 12 weeks therapy. (Korean J Hepatol 1999;5:89－96)
Changing Relationship between the Public and the Medical Profession
Authors: G L W Bonney
Journal: Journal of the Royal Society of Medicine (2001)

Sir Donald Irvine got a number of things wrong in his Lloyd Roberts Lecture (April 2001, JRSM pp. 162-169). He was, I think, most wrong and most dangerously so in his understanding of Mrs (now Baroness) Thatcher's ‘reforms’ of the late 1980s: ‘Mrs Thatcher...signalled that patients...had to come first’. The prospectus for the ‘reforms’ was indeed titled ‘Working for patients’, but practically all doctors and nurses knew well that for the past forty years that is what they and their predecessors had been doing or trying to do. The prospectus was so named in order to disguise the intent of the changes—namely, by privatization to relieve the State of much of the burden of maintaining a health service. Not all doctors perceived this at the time: some were persuaded by the prospect of advancement to give their enthusiastic support; others were glad of the opportunity to make money offered by the encouragement of private practice; others were so much terrified by the power of management that they abandoned their role as patients' advocates; many others had by then had enough, and just gave up the struggle.

Meanwhile, the advance of Thatcherism persuaded many in this country that there was indeed ‘no such thing as society’, and many others that the highest good was to be found in the accumulation of money. In the National Health Service, these changes, together with the subordination of the clinical to the managerial ethos, seriously damaged the standard of service offered to patients. Prospects for managers and for ‘chief executives’ in particular have, in contrast, greatly been improved.

Sir Donald and his colleagues must, I think, recognize that improvement in the quality of the service offered to patients will not be achieved by further regulation or by the creation of a new regulatory body every time something goes wrong. It will be achieved only when the primacy of the clinical ethos is restored, when doctors learn again to regulate the conduct of their affairs, when undergraduate teaching and graduate training are reformed, and when management is restored to its proper role of facilitating clinical objectives. It may well be impossible to achieve all this within the Health Service as at present constituted, just as it is now plainly impossible to restore the efficient operation of the railways without radical reform of their administrative structure.
18F-FDG PET/CT Reveals Disease Remission in a Patient With Ipilimumab-Refractory Advanced Melanoma Treated With Pembrolizumab
Authors: Christos Sachpekidis, Jessica C. Hassel, Antonia Dimitrakopoulou-Strauss
Journal: Clinical Nuclear Medicine (2015)

Pembrolizumab is an anti-programmed cell death receptor 1 (anti-PD-1) antibody, recently approved for the treatment of ipilimumab-refractory metastatic melanoma. We report on a 49-year-old patient with unresectable metastatic melanoma initially treated with 4 cycles of ipilimumab. Because of demonstration of progressive disease on PET/CT, the patient was enrolled into a clinical trial of pembrolizumab. After completion of 4 cycles of pembrolizumab, the follow-up PET/CT scans performed early after and 7 months after the end of treatment exhibited complete disease remission, reflecting the potential role of the modality in treatment response evaluation of melanoma patients receiving anti-PD-1 therapy.
Distribution of Copper Among Components of Human Serum&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: P L Wirth, M C Linder
Journal: JNCI Journal of the National Cancer Institute (1985)

We examined the distribution of copper among four components of human serum separated by chromatography on Sephadex G-150 and Affi-gel blue. Analysis of copper by furnace atomic absorption indicated that normal adults have copper at an average of 600 ng/ml associated with ceruloplasmin; at 120 ng/ml with transcuprein, a new copper transport protein; at 150 ng/ml with albumin; and at 90 ng/ml with one to three components of low molecular weight (less than 30,000). Cancer patients had more total copper but similar proportions in the four serum fractions. In both groups, some individuals had very high levels of copper in transcuprein, albumin, and/or one or more components of the low-molecular-weight fraction. The results showed that, contrary to earlier conclusions, ceruloplasmin copper only comprised about 60% of the total in human serum; and not just ceruloplasmin but also other forms of serum copper may be elevated in cancer patients.
Abstract 13632: Antidiabetic Monotherapy by Linagliptin Provides Multiple Antiatherosclerotic Effects Independent of Diabetic Improvement for Type-2 Diabetics With Coronary Artery Disease
Authors: Tatsuaki Murakami, Hiromasa Kokado
Journal: Circulation (2013)

Background: Diabetes mellitus is thought to be highly involved in complex atherothrombogenic processes, but the antiatherosclerotic therapies in patients with type-2 diabetes mellitus have not been...
Abstract 11572: Use of Sirolimus in Pediatric Heart Transplant Patients: A Multi-Institutional Study From the Pediatric Heart Transplant Study Group
Authors: Joseph W Rossano, John L Jefferies, Elfriede Pahl, David C Naftel, Elizabeth Pruitt, Kathy Lupton, William J Dreyer, Richard Chinnock, Gerard J Boyle, William T Mahle
Journal: Circulation (2013)

Introduction:  Proliferation signal inhibitors such as sirolimus are increasingly utilized in solid-organ transplantation and are associated with improved outcomes in adults in some studies. Only small single center studies, however, exist on the use and outcomes of sirolimus treated pediatric patients.   Hypothesis:  The use of sirolimus has increased over time, is more common in patients with renal dysfunction, and is associated with improved outcomes.   Methods:  A retrospective review and propensity matched analysis of the Pediatric Heart Transplant Registry was performed on primary heart transplant patients in two cohorts, patients with the opportunity for 1-year follow-up (Cohort 1) and for 5-year follow-up (Cohort 2).   Results:  There were 2,085 patients who underwent transplant between 2004 and 2010 and 1,117 had a one year-follow completed (Cohort 1), mean age at transplant was 6.5 years ± 6.1, 43% congenital heart disease, 67% status IA. Overall 18% of patients were on sirolimus at some point, 8% at 30 days post-transplant, 10% at 1-year, and 16% at 5 years. The use of sirolimus has increased over time, 13% in 2005 and 17% in 2011 (p=0.02). Among patients on sirolimus at 1-year post-transplant, tacrolimus was used in 71%, mycophenolate mofetil in 34%, steroids in 23%, and sirolimus monotherapy in 13%. Factors associated with sirolimus use at 1-year included use of sirolimus at discharge, later year of listing, history of renal insufficiency, longer donor ischemic time, and history of rejection during the first year post transplant (p   Conclusions:  The use of sirolimus is increasing in pediatric heart transplant patients and is more common among patients with a history of renal insufficiency and rejection. While the overall outcomes were similar in sirolimus treated and non-treated patients, early use of sirolimus may be associated with an increased risk of rejection and infections.
Transfer factor, lung volumes, resistance and ventilation distribution in healthy adults
Authors: Sylvia Verbanck, Alain Van Muylem, Daniel Schuermans, Ivan Bautmans, Bruce Thompson, Walter Vincken
Journal: European Respiratory Journal (2015)

Monitoring of chronic lung disease requires reference values of lung function indices, including putative markers of small airway function, spanning a wide age range.We measured spirometry, transfer factor of the lung for carbon monoxide (TLCO), static lung volume, resistance and ventilation distribution in a healthy population, studying at least 20 subjects per sex and per decade between the ages of 20 and 80 years.With respect to the Global Lung Function Initiative reference data, our subjects had average z-scores for forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC of -0.12, 0.04 and -0.32, respectively. Reference equations were obtained which could account for a potential dependence of index variability on age and height. This was done for (but not limited to) indices that are pertinent to asthma and chronic obstructive pulmonary disease studies: forced expired volume in 6 s, forced expiratory flow, TLCO, specific airway conductance, residual volume (RV)/total lung capacity (TLC), and ventilation heterogeneity in acinar and conductive lung zones.Deterioration in acinar ventilation heterogeneity and lung clearance index with age were more marked beyond 60 years, and conductive ventilation heterogeneity showed the greatest increase in variability with age. The most clinically relevant deviation from published reference values concerned RV/TLC values, which were considerably smaller than American Thoracic Society/European Respiratory Society-endorsed reference values.
Undetectable PSA level following prostate brachytherapy
Authors: W. L. Barrett
Journal: Journal of Clinical Oncology (2006)

14609 Background: Following radical prostatectomy for adenocarcinoma of the prostate, a long term undetectable PSA level is associated with cure. Patients with persistent long term detectable but low PSA levels after prostate radiation are frequently thought to be cured with the assumption that residual benign prostate tissue may produce low levels of PSA in the absence of cancer. There is not an established PSA nadir following radiation therapy that is universally associated with cure. In our institutional experience PSA nadirs of less than or equal to (≤) 0.2 and ≤ .5 have been associated with disease control by the ASTRO consensus statement in 95% and 89% of patients respectively. None of our patients who have obtained an undetectable PSA following prostate brachytherapy have subsequently gone on to have a rising PSA. The purpose of this study is to determine the frequency of undetectable PSA following prostate brachytherapy. Methods: 209 consecutive patients were treated with radioactive Iodine 125 seed implantation alone as definitive treatment between 1/96 and 1/03. No patients received external radiation therapy or hormone therapy. Post treatment PSA levels were reviewed to ascertain the number of patients achieving undetectable PSA levels, PSA of ≤ 0.2, PSA ≤ 0.5, and PSA failure based on the ASTRO consensus statement definition. Results: At a median follow up of 80 months (range 36 to 120), 75 patients (36%) have achieved and maintained an undetectable PSA level. 27 patients (13%) have experienced biochemical failure by the ASTRO definition. 72% and 78% have achieved and maintained PSA nadirs of ≤ 0.2 and ≤ 0.5 respectively. Conclusions: There has been difficulty in comparing treatment results in patients treated with radical prostatectomy compared to radiation therapy for cancer of the prostate due to the different PSA patterns following the different treatments and the varying definitions of success or failure. Undetectable PSA level after prostate brachytherapy appears in our experience to be consistently associated with disease free status based on the most stringent definition of disease free status following prostatectomy. No significant financial relationships to disclose.
The 2016 International League of Dermatological Societies' revised glossary for the description of cutaneous lesions
Authors: A. Nast, C.E.M. Griffiths, R. Hay, W. Sterry, J.L. Bolognia
Journal: British Journal of Dermatology (2016)

In order to facilitate effective communication in dermatology, a clearly defined glossary with precise descriptions is essential. The International League of Dermatological Societies' (ILDS) 'Glossary of basic dermatology lesions' was first published in 1987. A quarter of a century later, the ILDS made the decision to revise and expand this nomenclature.Revision and expansion of an international nomenclature for the description of cutaneous lesions.The ILDS nominated a committee on nomenclature. Based on a review of the literature and major textbooks, the committee assembled a list of terms and definitions. National member societies of the ILDS were then invited to participate in a Delphi voting exercise (two rounds for basic descriptive terms, one round for additional terms). The committee reviewed and consolidated comments and consented the final version.The revised and expanded version of the ILDS nomenclature includes 13 basic terms and over 100 additional descriptive terms. Forty-six and then 34 national member societies participated in the first and second voting rounds, respectively.A unifying nomenclature is crucial for effective communication among dermatologists and those who care for skin diseases. The next step will be a roll-out programme to national member societies of the ILDS that will include translations into languages other than English and adaptations reflecting local circumstances.