tbuckley/cabot-search huggingface dataset:
Efficacy of Novel Topical Liposomal Formulation of Cyclosporine in Mild to Moderate Stable Plaque Psoriasis
Authors: Rajiv Kumar, Sunil Dogra, Basant Amarji, Bhupinder Singh, Suresh Kumar, None Sharma, Keshavamurthy Vinay, Rahul Mahajan, O. P. Katare
Journal: JAMA Dermatology (2016)

<h3>Importance</h3> Attempts to use topical cyclosporine in treatment of psoriasis have failed because of unfavorable physicochemical properties and inappropriate formulation design of the conventional dosage forms. <h3>Objective</h3> To evaluate the efficacy of topical cyclosporine using liposomal nanocarriers (lipogel) in limited chronic plaque psoriasis. <h3>Design, Setting, and, Participants</h3> A single-center randomized clinical trial was conducted using a 3-arm parallel group, double-blind, vehicle and active comparator design and included 38 patients with chronic plaque psoriasis measuring less than or equal to 100 cm<sup>2</sup>performed in a tertiary care hospital. <h3>Interventions</h3> In the first arm, a total of 24 patients were randomized to receive either cyclosporine lipogel, 2.0% weight by weight (w/w), or placebo lipogel. In the second arm, 7 patients were randomized to receive cyclosporine lipogel, 2.0%, or conventional cyclosporine cream, 2.0% w/w. The third arm comprised 7 patients randomized with cyclosporine lipogel, 2.0% or standard clobetasol propionate cream, 0.05% w/w. Patients were examined twice weekly for 14 weeks, or until total lesional clearance was observed, whichever was earlier. <h3>Main Outcomes and Measures</h3> The primary outcome measure was the dermatological sum score (DSS) assessing erythema, scaling, and plaque elevation on a 4-point scale (0, absent; 1, minimal; 2, moderate; 3, severe). <h3>Results</h3> In 38 patients (23 men and 15 women with a mean [SD] age range from 35 [8] to 40 [13] years), a 19% decrease in DSS score from a mean (SD) of 8.45 (0.67) to 6.82 (0.77) compared with baseline was observed after 2 weeks of treatment with cyclosporine lipogel, 2.0% w/w (<i>P</i> &lt; .001; 95% CI, 13.77-24.51) in 59% of psoriasis lesional sites. At the end of the eighth week, a significant reduction (approximately 83%) in DSS was seen in all sites treated with cyclosporine lipogel, (<i>P</i> &lt; .001; 95% CI, 77.48-88.22). At the end of the study period, complete clearance (ie, DSS = 0) was observed in 16 (41%) psoriasis lesional sites treated with cyclosporine lipogel, 85.7% of sites treated with clobetasol propionate cream, and none of the sites treated with conventional cyclosporine cream or placebo gel. <h3>Conclusions and Relevance</h3> Topical liposomal formulation of cyclosporine, 2.0% w/w, is effective in treatment of limited chronic plaque psoriasis with a satisfactory safety profile. Future clinical trials should assess liposomal cyclosporine in larger study populations. <h3>Trial Registration</h3> Clinical Trials Registry-India Identifier:CTRI/2011/12/002307
Abstract P3-05-10: Non-coding RNAs derived from near the <i>ESR1</i> gene acts as a transcriptional regulator during estrogen deprivation adaptation of ER positive breast cancer cells
Authors: S Fujiwara, N Saitoh, S Tomita, MO Abdalla, H Iwase, M Nakao
Journal: Cancer Research (2016)

Abstract Endocrine therapies that blocks estrogen production are effective for estrogen receptor (ER)-positive breast cancer. However, endocrine therapy treated patients eventually experience relapse after a long period of estrogen deprivation. The mechanism underlying acquisition of estrogen independent growth by ER positive breast cancer cells remains unclear. To understand such molecular mechanism, we used a cell model LTED (long term estrogen deprivation) which MCF7 cells were cultured under estrogen deprivation for 4-10 months. In LTED cells, we found that ER encoded gene ESR1 was up-regulated and ER overproduction was essential for estrogen-independent cell growth. We also revealed that RNA transcriptions of the ESR1 and several neighbor genes were co-induced from both coding and non-coding regions in LTED cells, using RNA-sequence. These highly transcribed regions were corresponded to active histone modifications and transcription factor bindings according to publically available genome-wide analyses data. Fluorescence in situ hybridization (FISH) analyses indicated that RNA from the chromatin domain region nearby ESR1 were co-localized and made foci in nucleus. We found non-coding regions that are particularly highly transcribed. FISH analyses indicated that RNAs from these regions might interact with the parental ESR1 gene locus. Recent studies have shown that non-coding RNAs are involved in transcriptional regulation and chromatin regulation. To understand the role of the non-coding RNA, we have generated MCF7 cells lines that lack the non-coding site, using CRISPR/CAS9 system. We found that mRNA transcription of multiple genes including ESR1 were impaired by the deletion. These findings suggested that these non-coding RNAs may be involved in chromatin regulation of the chromatin domain nearby ESR1. In this study, we found non-coding RNAs that control transcription of chromatin domain genes in ER positive breast cancer cells. Such non-coding RNA mediated transcriptional regulation might be critical for endocrine therapy resistance adaptation. Citation Format: Fujiwara S, Saitoh N, Tomita S, Abdalla MO, Iwase H, Nakao M. Non-coding RNAs derived from near the ESR1 gene acts as a transcriptional regulator during estrogen deprivation adaptation of ER positive breast cancer cells. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-05-10.
Failure of Guanidine Therapy in Botulism a
Authors: Gerald A. Faich, Robert W. Graebner, Susumu Sato
Journal: New England Journal of Medicine (1971)

Botulism, Type A, developed in four members of a family who ingested contaminated bottled meatballs. All four patients survived, but required prolonged hospitalization, tracheostomy and mechanical respiratory support. Antitoxin therapy was administered within 12 hours of the onset of symptoms, and within 36 hours guanidine hydrochloride therapy was begun. No clinical benefit resulted from the use of guanidine, and its role as an adjunctive measure in human botulism remains to be more clearly defined.
Cognitive and behavioral effects of the coadministration of dextroamphetamine and haloperidol in schizophrenia
Authors: T E Goldberg, L B Bigelow, D R Weinberger, D G Daniel, J E Kleinman
Journal: American Journal of Psychiatry (1991)

The authors sought to determine if an acute dose of dextroamphetamine might have positive effects on affect and cognition in schizophrenic patients maintained on a regimen of haloperidol and, if so, what variables might predict such improvements.Twenty-one patients with chronic schizophrenia who were hospitalized on a research ward received a single oral dose of dextroamphetamine (0.25 mg/kg) in a double-blind, placebo-controlled, crossover study. All patients were receiving 0.4 mg/kg per day of haloperidol. Cognitive tests, motor tests, global ratings, mood ratings, and videotape ratings were used to determine the effect of the coadministration of these drugs. Ventricle-brain ratios derived from CT scans were used to predict response to the coadministration of these drugs.Amphetamine improved performance on a measure of concept formation on the Wisconsin Card Sorting Test but did not result in changes in performance on tests of memory or attention. As a group, the patients were more active and performed psychomotor tests more quickly while receiving amphetamine. Six patients were judged by clinical raters to have improved in terms of affect, cooperation, and engagement with the environment. Improvement was associated with enlarged cerebral ventricles and increases in blink rate from the placebo to the active drug condition. No patient unequivocally worsened.These results may be consistent with the theory that coadministration of amphetamine and haloperidol produces relatively selective enhancement of cortical dopaminergic activity. However, because of the acute nature of the trial and the specialized research environment in which it was conducted, the authors do not advocate amphetamine as a routine clinical treatment of schizophrenia.
Case 14-2005
Authors: Sekar Kathiresan, Peter B. Kelsey, Allen C. Steere, C. Stephen Foster, Marcio S. Curvelo, James R. Stone
Journal: New England Journal of Medicine (2005)

A 38-year-old man with a history of ulcerative colitis had fever, arthralgias, leg pain, purpuric skin lesions, and blurred vision within two weeks after excision of a pilonidal cyst followed by treatment with antibiotics. Examination disclosed palpable purpura of the lower leg and retinal hemorrhages and exudates. During his hospitalization, abdominal and testicular pain and hematochezia developed. Diagnostic procedures were performed.
Pemetrexed overcomes primary and secondary resistance to erlotinib in human non-small cell lung cancer (NSCLC) cell lines
Authors: T. Li, Y. Ling, R. Perez-Soler
Journal: Journal of Clinical Oncology (2006)

17040 Background: Erlotinib (E) and pemetrexed (P) have proven single agent activity in advanced NSCLC after first-line chemotherapy. The presence of K-Ras or EGFR T790M mutations in NSCLC tumors has been associated with primary or secondary resistance to erlotinib. We have previously reported that sequential administration of P followed by E results in synergistic cytotoxicity in NSCLC cells that contain the wild-type EGFR gene. In this study, we evaluate the cytotoxic effects of E and P in E-resistant human NSCLC cell lines that have either EGFR or K-Ras mutations and validate predictive biomarkers for drug sensitivity. Methods: E-resistant NSCLC cell lines [H1650 (EGFR del E746-A750 ), H1975 (EGFR L858R/T790M ), and A549 (K-Ras G12S )] were exposed to E and P continuously for 72 hrs. Combinations of E and P were compared with E or P alone. Cellular effects assayed include cell survival by cell count and MTT assay, cell cycle distribution and apoptosis by flow cytometry after propidium iodide staining, and expression of different elements of the EGFR axis by immunoblots. The degree of cytotoxic synergism was expressed by the combination index (C.I.). Results: P and E have significant cytotoxic synergism (C.I. &lt;1) in these E-resistant NSCLC cell lines. The cytotoxic synergism is, at least in part, mediated by the inhibitory effect of E on the P-induced activation of EGFR-mediated proliferation and/or survival responses (mainly via the PI3K/AKT pathway). Sensitivity of NSCLC cells to P and E might be predicted by the ratio of (p-EGFR:EGFR) to (p-AKT:AKT), reflecting tumor dependency on the EGFR axis for growth and survival. Conclusions: Together with our previous data, we have demonstrated that the combination of P and E is synergistic in E-resistant NSCLC cell lines that have either a wild-type or mutant EGFR gene, or a mutant K-Ras gene. This combination deserves further evaluation in a clinical trial for the treatment of advanced NSCLC. No significant financial relationships to disclose.
P11 Pirfenidone treatment is only available in the UK for a minority of patients with usual interstitial pneumonitis
Authors: G Burge, D Petkova, S Ghani, J Reynolds, M Djearman, E Hoey, S Hussain, PS Burge
Journal: Thorax (2015)

<h3>Introduction</h3> Usual Interstitial Pneumonitis (UIP) may be caused by asbestos exposure (asbestosis), collagen vascular diseases (CVD) or agents causing hypersensitivity pneumonitis (HP), or may be idiopathic (IPF). Referrals to our ILD MDT have increased since the limited availability of pirfenidone which is only prescribable for IPF with a FVC 50–80% predicted. We have reviewed presentation in 2014 to identify patients suitable for Pirfenidone prescription. <h3>Methods</h3> Our hospital provides a regional service for Pirfenidone prescription. All patients with a MDT diagnosis of definite UIP were included. A standard proforma requested information on exposures, CVD and antibodies relevant to CVD and HP. If there were no relevant exposures and CVD was excluded, a diagnosis of IPF was made. Asbestosis, HP and CVD associated UIP were diagnosed when the relevant information supported this, unspecified UIP was diagnosed in the absence of specific information. <h3>Results</h3> 202/546 referrals in 2014 were judged to have definite UIP after consideration by a fully constituted ILD MDT including histopathologists, radiologists, clinicians and CNS’. After exclusion of 22 with asbestosis, 11 with CVD associated UIP, 17 with CPFE and 17 with HP associated UIP, 51 with IPF and 84 with unspecified UIP remained for consideration of Pirfenidone treatment. Only 64/135 suitable patients had a FVC 50–80% predicted (Figure 1). <h3>Conclusions</h3> The decisions of an ILD MDT are limited by the completeness of investigation. We found causes for 50/200 patients with UIP. Pirfenidone was not prescribable for 53% of otherwise suitable patients. If the FVC limit was raised to 90% 32% would still be excluded, including 2 who died of their disease within 12 months. The FVC is often preserved even in terminal IPF.
PWE-074 Combination of nuclear textural analysis and image cytometric DNA analysis is more accurate than image cytometric DNA ploidy analysis alone for risk stratification in Barrett's oesophagus
Authors: J M Dunn, L B Lovat, M E Pretorius, D Oukrif, T Hveem, B Nielsen, F Albregtsen, M R Novelli, H E Danielsen
Journal: Gut (2010)

<h3>Introduction</h3> Dysplasia is a marker of cancer risk in Barrett9s oesophagus (BE), but this risk is variable and diagnosis is subject to inter-observer variability. Cancer risk in dysplastic and non-dysplastic BE is increased when large scale genomic instability (DNA ploidy) is present, with published data showing the incidence of aneuploidy in patients with HGD is 67%. Nuclear textural analysis (Nucleotyping) is a new method that uses ultra-high-resolution digital images of stained nuclei to classify DNA content, chromatin structure and organisation both quantitatively and qualitatively. This information is derived from the same sections used for image cytometric DNA ploidy analysis (ICDA). Our aim was to evaluate nucleotyping as a prognostic biomarker in Barrett9s oesophagus, and compare with ICDA. <h3>Methods</h3> 120 patients with BE were studied. 60 patients had high-grade dysplasia or intramucosal cancer and went on to ablative therapy or surgery. A further 60 patients had specialised intestinal metaplasia only on two consecutive endoscopies with a median of 51 months follow-up (IQR=25–120 months). The two groups were then randomly assigned to a training set (30 HGD, 30 non-dysplastic) and a blinded test set. 40 micron sections were cut from formalin fixed paraffin embedded (FFPE) biopsies and a Feulgen stained nuclear monolayer was made as previously described for ICDA. <h3>Results</h3> Analysis of the training set demonstrated a DNA ploidy rate of 64% in the HGD group vs 0% in non-dysplastic. By comparison, nuclear textural analysis was abnormal in 71%. A correct classification rate (CCR) of 84% was achieved if the two features were combined. The test set was blindly analysed using the same textural features. DNA ploidy rate was 61% in the HGD group vs 0% in non-dysplastic group. Nucleotyping was again more accurate at 78%, and combining the two features gave a CCR of 84%. When all patients were analysed, sensitivity and specifity of combined nucleotyping with ICDA for detecting dysplasia was 75% and 94%, respectively. <h3>Conclusion</h3> Nucleotyping yields additional prognostic information vs image cytometry alone on the same nuclear monolayers. The textural features used to differentiate normal from dysplastic tissue were similar to those used in studies of other early cancers. These data demonstrate that nucleotyping is a promising additional test for separating at-risk groups in Barrett9s oesophagus. This work is supported by the CRUK Experimental Cancer Medicine Centre at University College London and the NIHR Comprehensive Biomedical Research Centre at UCLH.
From Tonus to Tonicity
Authors: SIEGFRIED WALDEGGER, THOMAS J. JENTSCH
Journal: Journal of the American Society of Nephrology (2000)

Chloride channels are involved in a multitude of physiologic processes ranging from basal cellular functions such as cell volume regulation and acidification of intracellular vesicles to more specialized mechanisms such as vectorial transepithelial transport and regulation of cellular excitability. This plethora of functions is accomplished by numerous functionally highly diverse chloride channels that are only partially identified at the molecular level. The CLC family of chloride channels comprises at present nine members in mammals that differ with respect to biophysical properties, cellular compartmentalization, and tissue distribution. Their common structural features include a predicted topology model with 10 to 12 transmembrane regions together with two C-terminal CBS domains. Loss of function mutations affecting three different members of the CLC channel family lead to three human inherited diseases : myotonia congenita, Dent's disease, and Bartter's syndrome. These diseases, together with the diabetes insipidus symptoms of a knockout mouse model, emphasize the physiologic relevance of this ion channel family.
PTH-333 Public appreciation of lifestyle risk factors for colorectal cancer and awareness of the nhs bowel cancer screening programme
Authors: SA Kazmi, K Lynes, D Gilbert, MA Thaha
Journal: Gut (2015)

<h3>Introduction</h3> Prevention of colorectal cancer (CRC) via reduction of lifestyle risk factors, and participation in bowel screening, are two ways in which public engagement could lower mortality from colorectal cancer. Little is known about the current level of awareness of these factors. This study examined public awareness of lifestyle risk factors and bowel screening, with determination of the factors affecting this. <h3>Method</h3> A representative population sample (n = 1500) was surveyed using a study specific postal questionnaire to determine demographics, experience of bowel problems, awareness of lifestyle risk factors, knowledge about the incidence of CRC and potential benefits of screening, as well as personal experience of screening. Statistical analysis was carried out using the unpaired t-test and Chi-square test. <h3>Results</h3> The majority of respondents were aged over 50 (74%). 76% had either personal experience or a relative/friend with experience of a bowel problem. The majority of respondents had some awareness of lifestyle risk factors with two thirds answering over 50% of questions correctly. Knowledge of dietary advice was better than risks relating to weight and physical activity. Awareness of lifestyle risk factors was significantly worse in those less than 50 years old (p = 0.0002) and with a lower level of education (p = 0.0019). The majority (62%) were unaware how common bowel cancer is and 44% were unaware that CRC is one of the easiest cancers to cure if caught early. Awareness of bowel cancer diagnosis was significantly lower in those less than 50 years old (p= &lt;0.0001). Respondents were evenly divided over whether the NHS should prescribe exercise and lifestyle changes, with those over 50 years old (p = 0.0126), with no formal education (p= &lt;0.0001) and with no experience of bowel problems (p = 0.0168) being more likely to answer no. Of those who had received a screening kit but not completed it, 30% deemed themselves ineligible, with reasons including being outside the age bracket, having an ileostomy or being under surveillance following previous bowel cancer. By far the most frequent reason for non-completion in eligible respondents was that the process was dirty and unpleasant. <h3>Conclusion</h3> The majority of people have some experience of bowel problems. Initiatives are required to improve the awareness of younger people with regard to lifestyle risk factors for CRC, especially since this group stand to benefit most from risk reduction. Those with a lower level of education also had poor awareness but felt that the NHS should not prescribe exercise and lifestyle change; targeting this group would need to take this into account. <h3>Disclosure of interest</h3> None Declared.
Separation of the Complement-Fixing and Early Antigens From Epstein-Barr Soluble Antigen2
Authors: William H. Wainwright, Robert W. Veltri
Journal: JNCI Journal of the National Cancer Institute (1977)

The Epstein-Barr virus-associated complement-fixing (soluble) antigen (CFSA) and the early antigen (EA) were isolated by ion-exchange chromatography from the P3HR-1 lymphoblastoid cell line activated with 5-iodo-2′-deoxyuridine for 72 hours. As expected, these two antigens were not immunologically identical. The CFSA, but not the EA, was isolated from the RAJl lymphoblastoid cell line by the same method.
Nutrition and Exercise Rehabilitation in Obesity hypoventilation syndrome (NERO): a pilot randomised controlled trial
Authors: Swapna Mandal, Eui-Sik Suh, Rachel Harding, Anna Vaughan-France, Michelle Ramsay, Bronwen Connolly, Danielle E Bear, Helen MacLaughlin, Sharlene A Greenwood, Michael I Polkey, Mark Elliott, Tao Chen, Abdel Douiri, John Moxham, Patrick B Murphy, Nicholas Hart
Journal: Thorax (2017)

Background Respiratory management of obesity hypoventilation syndrome (OHS) focusses on the control of sleep-disordered breathing rather than the treatment of obesity. Currently, there are no data from randomised trials of weight loss targeted rehabilitation programmes for patients with OHS. Intervention A 3-month multimodal hybrid inpatient–outpatient motivation, exercise and nutrition rehabilitation programme, in addition to non invasive ventilation (NIV), would result in greater per cent weight loss compared with standard care. Methods A single-centre pilot randomised controlled trial allocated patients to either standard care or standard care plus rehabilitation. Primary outcome was per cent weight loss at 12 months with secondary exploratory outcomes of weight loss, exercise capacity and health-related quality of life (HRQOL) at the end of the rehabilitation programme to assess the intervention effect. Results Thirty-seven patients (11 male, 59.8±12.7 years) with a body mass index of 51.1±7.7 kg/m 2 were randomised. At 12 months, there was no between-group difference in per cent weight loss (mean difference −5.9% (95% CI −14.4% to 2.7%; p=0.17)). At 3 months, there was a greater per cent weight loss (mean difference −5% (95% CI −8.3% to −1.4%; p=0.007)), increased exercise capacity (6 min walk test 60 m (95% CI 29.5 to 214.5) vs 20 m (95% CI 11.5 to 81.3); p=0.036) and HRQL (mean difference SF-36 general health score (10 (95% CI 5 to 21.3) vs 0 (95% CI −5 to 10); p=0.02)) in the rehabilitation group. Conclusion In patients with OHS, a 3-month comprehensive rehabilitation programme, in addition to NIV, resulted in improved weight loss, exercise capacity and QOL at the end of the rehabilitation period, but these effects were not demonstrated at 12 months, in part, due to the limited retention of patients at 12 months. Trial registration number Pre-results; NCT01483716 .
Recent developments in the drug treatment of schizophrenia
Authors: J M Davis
Journal: American Journal of Psychiatry (1976)

The author reviews six topics relevant to the drug treatment of schizophrenia. The quantitative effectiveness of promazine is of interest with respect to the structural models of the phenothiazines and the dopamine theory of schizophrenia. The quantitative effectiveness of antipsychotic drugs is also important in evaluating new agents and therefore relevant to a discussion of two newly released neuroleptics, molindone and loxapine. The author's discussion of high-dose treatment of typical acute schizophrenics or treatment-resistant patients reviews the available data and calls attention to the fact that these areas of pharmacologic research have not received sufficient attention.