tbuckley/cabot-search huggingface dataset:
Prevention of Acute Ischemic Renal Failure by Targeted Delivery of Growth Factors to the Proximal Tubule in Transgenic Mice
Authors: Nathalie M. Fiaschi-Taesch, Soledad Santos, Vasumathi Reddy, Scott K. Van Why, William F. Philbrick, Arantxa Ortega, Pedro Esbrit, John J. Orloff, Adolfo Garcia-Ocan[Combining Tilde]a
Journal: Journal of the American Society of Nephrology (2004)

Treatment of acute renal failure (ARF) would be enhanced by identification of factors that accelerate renal recovery from injury. Parathyroid hormone-related protein (PTHrP) and hepatocyte growth factor (HGF) have been shown to stimulate proliferation in proximal nephron-derived cells. For studying the pathophysiologic roles and therapeutic potential of these two factors in ARF, transgenic mice overexpressing PTHrP or HGF in the proximal tubule under the direction of the gamma-glutamyl transpeptidase-I promoter were developed. These mice display (1) abundant expression of the respective transgenes in the kidney; (2) similar PTH type I receptor and HGF receptor (c-met) expression levels in the proximal tubule compared with control littermates; and (3) normal renal morphology, function, and tubule cell proliferation under basal conditions. However, in contrast to control mice, when acute ischemic renal injury was induced, renal function rapidly and dramatically recovered in HGF-overexpressing mice. In addition, 48 h after ischemia, HGF-overexpressing transgenic mice displayed a fourfold increase in tubule cell proliferation and a threefold decrease in apoptotic tubule cell death compared with control mice. In contrast, PTHrP-overexpressing mice responded to either ischemic or folic acid-induced renal damage similarly to control mice. These studies demonstrate that overexpression of PTHrP in the proximal nephron of mice does not seem to provide protection against acute renal injury. In marked contrast, HGF overexpression results in dramatic protection from ischemia-induced ARF, without inducing any apparent alteration in the physiology of the kidney under normal conditions. These studies suggest that HGF, when targeted specifically to the proximal tubule, may have therapeutic potential in providing protection against ischemia-induced renal failure.
The effects of recombinant human erythropoietin on functional health and well-being in chronic dialysis patients.
Authors: K M Beusterien, A R Nissenson, F K Port, M Kelly, B Steinwald, J E Ware
Journal: Journal of the American Society of Nephrology (1996)

As a component of the open-label, multicenter National Cooperative Recombinant Human Erythropoietin (Epo) Study, the health-related quality-of-life effects of Epo therapy were assessed in 484 dialysis patients who had not previously been treated with Epo therapy (New-to-Epo) and 520 dialysis patients who were already receiving Epo therapy at the time of study enrollment (Old-to-Epo). Using scales from the Medical Outcomes Study 36-item Short Form Health Survey (SF-36), health-related quality of life was assessed on study enrollment (baseline) and at an average of 99 days follow-up. At baseline, SF-36 scores for Old- and New-to-Epo patients were well below those observed in the general population, reflecting substantial impairments in functional status and well-being among patients with chronic renal failure. Significant improvements from baseline to follow-up were observed among New-to-Epo patients in vitality, physical functioning, social functioning, mental health, looking after the home, social life, hobbies, and satisfaction with sexual activity (P < 0.05 for each). The mean improvements in hematocrit values among New-to-Epo and Old-to Epo patients were 4.6 and 0.3, respectively. At the time of follow-up, SF-36 scores for New-to-Epo patients were comparable with those observed among Old-to-Epo patients, whose scores did not change significantly from baseline to follow-up. Analysis of the relationship between Epo therapy, hematocrit values, and health-related quality of life suggest that some of the beneficial quality-of-life effects of Epo are mediated through a change in hematocrit level.
Immunohistochemical and Biogenetic Features of Diffuse-Type Tenosynovial Giant Cell Tumors: The Potential Roles of Cyclin A, P53, and Deletion of 15q in Sarcomatous Transformation
Authors: Hsuan-Ying Huang, Robert B. West, Ching-Cherng Tzeng, Matt van de Rijn, Jun-Wen Wang, Shih-Cheng Chou, Wen-Wei Huang, Hock-Liew Eng, Ching-Nan Lin, Shih-Chen Yu, Jing-Mei Wu, Chiu-Chin Lu, Chien-Feng Li
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Diffuse-type tenosynovial giant cell tumor (D-TSGCT) is an aggressive proliferation of synovial-like mononuclear cells with inflammatory infiltrates. Despite the COL6A3-CSF1 gene fusion discovered in benign lesions, molecular aberrations of malignant D-TSGCTs remain unidentified. Experimental Design: We used fluorescent in situ hybridization and in situ hybridization to evaluate CSF1 translocation and mRNA expression in six malignant D-TSGCTs, which were further immunohistochemically compared with 24 benign cases for cell cycle regulators involving G1 phase and G1-S transition. Comparative genomic hybridization, real-time reverse transcription-PCR, and a combination of laser microdissection and sequencing were adopted to assess chromosomal imbalances, cyclin A expression, and TP53 gene, respectively. Results: Five of six malignant D-TSGCTs displayed CSF1 mRNA expression by in situ hybridization, despite only one having CSF1 translocation. Cyclin A (P = 0.008) and P53 (P &amp;lt; 0.001) could distinguish malignant from benign lesions without overlaps in labeling indices. Cyclin A transcripts were more abundant in malignant D-TSGCTs (P &amp;lt; 0.001). All malignant cases revealed a wild-type TP53 gene, which was validated by an antibody specifically against wild-type P53 protein. Chromosomal imbalances were only detected in malignant D-TSGCTs, with DNA losses predominating over gains. Notably, −15q was recurrently identified in five malignant D-TSGCTs, four of which showed a minimal overlapping deletion at 15q22-24. Conclusions: Deregulated CFS1 overexpression is frequent in malignant D-TSGCTs. The sarcomatous transformation involves aberrations of cyclin A, P53, and chromosome arm 15q. Cyclin A mRNA is up-regulated in malignant D-TSGCTs. Non–random losses at 15q22-24 suggest candidate tumor suppressor gene(s) in this region. However, P53 overexpression is likely caused by alternative mechanisms rather than mutations in hotspot exons.
Assessing peristomal skin changes in ostomy patients: validation of the Ostomy Skin Tool
Authors: G.B. Jemec, L. Martins, I. Claessens, E.A. Ayello, A.S. Hansen, L.H. Poulsen, R.G. Sibbald
Journal: British Journal of Dermatology (2010)

Peristomal skin problems are common and are treated by a variety of health professionals. Clear and consistent communication among these professionals is therefore particularly important. The Ostomy Skin Tool (OST) is a new assessment instrument for the extent and severity of peristomal skin conditions. Formal tests of reliability and validity are necessary for its use in clinical practice, research, and education.To estimate inter- and intra nurse assessment variability of the OST and validity by comparison to a 'gold standard' (GS) defined by an expert panel.Thirty photographs of peristomal skin were presented twice to 20 ostomy care nurses--10 from Denmark (DK) and 10 from Spain (ES)--to determine intra- and inter nurse assessment variability. The same photographs were presented to an international group of experts (dermatologist and ostomy care nurses), to establish a GS for comparison and validation of the results.A high intra-nurse assessment agreement, κ=0·84, was found with no differences in the intra-nurse assessments from the two groups of nurses (DK and ES). The inter-nurse assessment agreement was 'moderate to good', κ=0·54, with the agreement between the experts higher, κ=0·70. A high correlation between the scores from the nurses and the GS were seen in the lower part of the two scales [Discoloration, Erosion, Tissue overgrowth (DET) score<7)].The study supported the validity of the OST. It is suggested that a categorical scale can be used to illustrate the severity of the DET scores.
THE VASOCONSTRICTOR ACTION OF PLASMA FROM HYPERTENSIVE PATIENTS AND DOGS
Authors: Irvine H. Page
Journal: The Journal of Experimental Medicine (1940)

1. Plasma from the renal vein, femoral artery or vein of normal dogs and plasma from the femoral artery, femoral and antecubital veins of man cause little or no vasoconstriction when added in small amounts to blood from a bilaterally nephrectomized dog used as perfusing medium in an isolated rabbit's ear. 2. Plasma from the femoral vessels and antecubital vein of patients with essential hypertension, malignant hypertension, and chronic nephritic hypertension causes marked vasoconstriction under the same circumstances. The plasma of dogs made hypertensive either by constriction of the parenchyma by the scar of silk perinephritis or by constriction of the renal artery by a clamp also causes pronounced vasoconstriction. 3. Plasma from the renal vein of normal dogs produces little or no vasoconstriction, but that of hypertensive dogs elicits vasoconstriction but usually not so marked as that elicited by plasma collected from peripheral vessels. A sample of renal venous plasma from one hypertensive patient caused severe vasoconstriction, not quite so intense as that produced by the peripheral vein plasma. 4. Since renin is liberated into the renal vein in large amounts in hypertensive dogs and reacts with renin-activator to produce angiotonin and since the conditions of the experiment are such as to enhance greatly the sensitivity of the ear preparation to angiotonin, it is believed that the vasoconstriction is the result of the presence of angiotonin in the peripheral blood. 5. Since vasoconstriction occurs under the same experimental conditions with plasma from both hypertensive patients and dogs, this is considered cogent evidence in favor of the view that the chemical mediator of both is similar and is possibly angiotonin. 6. A method is presented which is believed will distinguish between plasma from patients with normal blood pressure and that from those with hypertension, and between plasma from normal dogs and that from dogs with experimental renal hypertension.
Systemic Antitumor Effect of Intratumoral Injection of Dendritic Cells in Combination with Local Photodynamic Therapy
Authors: Hisashi Saji, Wenru Song, Katsuyoshi Furumoto, Harubumi Kato, Edgar G. Engleman
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Photodynamic therapy (PDT), which is used clinically for the palliative treatment of cancer, induces local tumor cell death but has no effect on tumors in untreated sites. The purpose of this study was to determine if local PDT followed by intratumoral injection of naïve dendritic cells (IT-DC) induces systemic antitumor immunity that can inhibit the growth of untreated as well as PDT + IT-DC–treated tumors. Experimental Design: BALB/c or C57Bl/6 mice were injected s.c. with CT26 colorectal carcinoma cells and B16 melanoma cells, respectively, and following 10 to 12 days of tumor growth, the tumors were treated with PDT alone or PDT followed by IT-DC or IT-PBS. In other studies, tumors were established simultaneously in both lower flanks or in one flank and in the lungs, but only one flank was treated. Results: Whereas neither PDT nor IT-DC alone was effective, PDT + IT-DC eradicated both CT26 and B16 tumors in a significant proportion of animals and prolonged the survival of mice of which the tumors were not cured. The spleens of mice treated with PDT + IT-DC contained tumor-specific cytotoxic and IFN-γ-secreting T cells whereas the spleens of control groups did not. Moreover, adoptive transfer of splenocytes from successfully treated CT26 tumor-free mice protected naïve animals from a subsequent challenge with CT26, and this was mediated mainly by CD8 T cells. Most importantly, PDT plus IT-DC administered to one tumor site led to tumor regression at distant sites, including multiple lung metastases. Conclusions: PDT + IT-DC induces potent systemic antitumor immunity in mice and should be evaluated in the treatment of human cancer.
A miR-297/hypoxia/DGK-α axis regulating glioblastoma survival
Authors: Benjamin Kefas, Desiree H. Floyd, Laurey Comeau, Alyse Frisbee, Charli Dominguez, Charles G. diPierro, Fadila Guessous, Roger Abounader, Benjamin Purow
Journal: Neuro-Oncology (2013)

Despite advances in the treatment of the most aggressive form of brain tumor, glioblastoma, patient prognosis remains disappointing. This failure in treatment has been attributed to dysregulated oncogenic pathways, as observed in other tumors. We and others have suggested the use of microRNAs (miRs) as therapeutic tools able to target multiple pathways in glioblastoma. This work features PCR quantification of miRs and transient transfection of many glioblastoma cell lines with miRs, followed by cell number analysis, trypan blue staining, alamarBlue assay of cell viability, caspase-3/-7 activity assay, immunoblot of cleaved poly(ADP-ribose) polymerase and fluorescence activated cell sorting and imaging of apoptotic nuclei, cell invasion assays, MRIs of glioblastoma xenografts in mice using transiently transfected cells as well as posttumor treatment with lentiviral vector encoding miR-297, and analysis of miR-297 target diacylglycerol kinase (DGK)–α including immunoblot, 3′UTR luciferase activity, and rescue with DGK-α overexpression. Cell counts and DGK-α immunoblot were also analyzed in the context of hypoxia and with overexpression of heterogeneous ribonucleoprotein L (hnRNPL). We identified miR-297 as a highly cytotoxic microRNA in glioblastoma, with minimal cytotoxicity to normal astrocytes. miR-297 overexpression reduced in vitro invasiveness and in vivo tumor formation. DGK-α is shown to be a miR-297 target with a critical role in miR-297 toxicity. In addition, hypoxia and its mediator hnRNPL upregulated DGK-α and buffered the cytotoxic effects of miR-297. This work shows miR-297 as a novel and physiologic regulator of cancer cell survival, largely through targeting of DGK-α, and also indicates that hypoxia ameliorates miR-297 toxicity to cancer cells.
Elevated Expression of Mitogen-Activated Protein Kinase Phosphatase 3 in Breast Tumors: A Mechanism of Tamoxifen Resistance
Authors: Yukun Cui, Irma Parra, Mao Zhang, Susan G. Hilsenbeck, Anna Tsimelzon, Toru Furukawa, Akira Horii, Zhong-Yin Zhang, Robert I. Nicholson, Suzanne A.W. Fuqua
Journal: Cancer Research (2006)

Abstract Antiestrogen resistance is a major clinical problem in the treatment of breast cancer. Altered growth factor signaling with estrogen receptor (ER)-α is associated with the development of resistance. Gene expression profiling was used to identify mitogen-activated protein kinase (MAPK) phosphatase 3 (MKP3) whose expression was correlated with response to the antiestrogen tamoxifen in both patients and in vitro–derived cell line models. Overexpression of MKP3 rendered ER-α-positive breast cancer cells resistant to the growth-inhibitory effects of tamoxifen and enhanced tamoxifen agonist activity in endometrial cells. MKP3 overexpression was associated with lower levels of activated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation in the presence of estrogen but that estrogen deprivation and tamoxifen treatment decreased MKP3 phosphatase activity, leading to an up-regulation of pERK1/2 MAPK, phosphorylated Ser118-ER-α, and cyclin D1. The MAPK/ERK kinase inhibitor PD98059 blocked tamoxifen-resistant growth. Accumulation of reactive oxygen species was observed with tamoxifen treatment of MKP3-overexpressing cells, and antioxidant treatment increased MKP3 phosphatase activity, thereby blocking resistance. Furthermore, PD98059 increased the levels of phosphorylated c-Jun NH2-terminal kinase (JNK) in tamoxifen-treated MKP3-overexpressing cells, suggesting an interaction between MKP3 levels, activation of ERK1/2 MAPK, and JNK signaling in human breast cancer cells. MKP3 represents a novel mechanism of resistance, which may be a potential biomarker for the use of ERK1/2 and/or JNK inhibitors in combination with tamoxifen treatment. (Cancer Res 2006; 66(11): 5950-9)
Inflammation-mediated rheumatic diseases and atherosclerosis
Authors: S. MANZI
Journal: Annals of the Rheumatic Diseases (2000)

Inflammation-mediated rheumatic diseases and atherosclerosis6][7] These two autoimmune diseases share a propensity to target women of childbearing age and a treatment armamentarium that includes corticosteroids and other immunosuppressive agents.Despite clear distinctions in pathophysiology, the immune dysfunction unique to each disease results in a chronic inflammatory state, which may have implications for the atherogenesis seen in these young patients.As we compare and contrast potential cardiovascular risk factors in these two autoimmune diseases, we may further our understanding of why these young women are at high risk for premature atherosclerosis. Epidemiology of cardiovascular disease in SLE and RA2][3][4] Several investigators have convincingly shown that women with SLE under the age of 45 are at substantially increased risk of ischaemic heart disease. 1 4 We reported that women with SLE aged 35-44 were over 50 times more likely to have a myocardial infarction than were women of similar age from a population based sample (rate ratio = 52.43,95% CI 21.6 to 98.5). 1 In contrast, women with SLE in the 45-64 year age group were only two to four times more likely to have a myocardial infarction than women without SLE of the same age.We also found a small decline in the incidence rates for myocardial infarction in women with SLE aged 45-54 compared with those having the same diagnosis aged 35-44.The reasons for this are unclear.A diVerence in overall survival is an unlikely explanation as mortality rates from all causes were not significantly diVerent between women in these two age strata.A plausible hypothesis may be the prothrombotic eVects of oestrogen in combination with the generally more common renal disease and associated hypertension in the younger women, and a relatively protective eVect of declining oestrogen levels in women aged 45-54.Similarly, Ward reported that women with SLE aged 18-44 were 2.27 (95% CI 1.08 to 3.46) times more likely to be admitted to hospital with an acute myocardial infarction than young women without the disease. 4This increased risk of admission to hospital with ischaemic heart disease for women with SLE compared with women on August 14, 2023 by guest.
Doing our best: surgery for rectal cancer
Authors: M. M Bertagnolli
Journal: Gut (2008)

For resectable rectal cancer, surgical treatment must safely meet two objectives. The most important goal is to achieve an R0 tumour resection with adequate circumferential margins and a complete regional lymphadenectomy. A secondary objective is to optimise post-surgical quality of life by preserving anal sphincter function. Surgery for rectal cancer is technically demanding and requires sophisticated decision-making to achieve optimal results. How do we as a healthcare community achieve excellence in the performance of surgery for localised rectal cancer? Do quality indicators help achieve excellence, and if so, is the type of operation performed an effective quality indicator for surgery of localised rectal cancer?

Four operations encompass the majority of surgery for rectal cancer. Transanal excision is reserved for small, early stage distal tumours and is not the subject of this discussion. Anterior resection (AR) and Hartmann’s resection both involve excision of the tumour and entire mesorectum from an abdominal approach. Abdominoperineal excision (APE), which is utilised for the most distal tumours, requires removal of soft tissues below the levator muscles, an anatomical space also bounded by the fatty tissues of the ischiorectal fossae and the bony pelvis. Complete excision of the mesorectum should also be performed during an APE, although for a minority of cases the nodal drainage may also involve the lateral pelvis. The extent of APR must be broadened if necessary to obtain negative margins, which are defined by the absence of tumour for a distance of 1 mm or more from the resection plane.1 This may require complete resection of the levator muscles, partial resection of sacrum and/or ileum and, when required, reconstruction of the pelvic floor with autologous tissue.

A major contribution to improving surgical quality is the careful work of Dr Quirke and colleagues,1 who demonstrated the importance of technique and surgeon–pathologist …
Energy intake and appetite after netball exercise in 13- to 15-year-old trained girls
Authors: P L S Rumbold, A St Clair-Gibson, S Allsop, E Stevenson, C J Dodd-Reynolds
Journal: British Journal of Sports Medicine (2010)

The aim of the study was to establish whether free-living energy intake and subjective appetite are influenced by a bout of netball exercise in female adolescent netball players. Energy intake and subjective appetite over 3 days (with two preceding maintenance days) after a netball and sedentary period were compared in a counterbalanced fashion. Eleven trained adolescent netball players; age 14.7±0.9 years, stature 1.66±0.06 m, mass 59.4±7.1 kg, body fat 23.1±5.4%, body mass index 21.6±2.3 kg/m 2 and dietary restraint 2.13±0.63 (average category for high school females). During preliminary visits, a FLEX heart rate calibration1 and resting metabolic rate test were conducted, to later predict energy expenditure (EE) during the netball exercise and also 24-h EE over the 5 days. Subjects completed two 5-day treatment weeks, separated by a 2-week “wash out” period. A 47-min bout of netball exercise or equivalent sedentary period was carried out on day 3 of each treatment week. Energy intake was measured over each 5-day period using a combined self-reported, weighed, food diary and 24-h recall interview technique. Subjective hunger, prospective food consumption, fullness and mood were rated by subjects using visual analogue scales immediately before and after meals, the netball exercise and the sedentary period. 48-h energy intake was higher after netball exercise compared to the corresponding sedentary period, (18.6±2.5 MJ vs 16.7±3.5 MJ respectively; p=0.015, effect size=1.31). The girls felt more hungry immediately after the netball exercise compared to immediately before, (49±25 mm vs 35±21 mm respectively; p=0.037, effect size=1.08). Overall, trained adolescent girls felt hungrier and increased their energy intake during a 48-h period after netball exercise. Appetite hormones (acylated ghrelin) need to be examined to elucidate appetite responses to sport-specific exercise in adolescent girls.